The COVID-19 pandemic has caused severe health threat globally, and novel SARS-Cov-2 inhibitors are urgently needed for antiviral treatment. The main protease (M
) of the virus is one of the most ...effective and conserved targets for anti-SARS-CoV-2 drug development. In this study, we utilized a molecular docking-based virtual screening approach against the conserved catalytic site to identify small-molecule inhibitors of SARS-CoV-2 M
. Further biological evaluation helped us identify two compounds, AF-399/40713777 and AI-942/42301830, with moderate inhibitory activity. Besides that, the in silico data, including molecular dynamics (MD) simulation, binding free energy calculations, and AMDET profiles, suggested that these two hits could serve as the starting point for the future development of COVID-19 intervention treatments.
Anticancer drugs have been developed with expectations to provide long-term or at least short-term survival benefits for patients with cancer. Unfortunately, drug therapy tends to provoke malignant ...biological and clinical behaviours of cancer cells relating not only to the evolution of resistance to specific drugs but also to the enhancement of their proliferation and metastasis abilities. Thus, drug therapy is suspected to impair long-term survival in treated patients under certain circumstances. The paradoxical therapeutic effects could be described as 'quenching thirst with poison', where temporary relief is sought regardless of the consequences. Understanding the underlying mechanisms by which tumours react on drug-induced stress to maintain viability is crucial to develop rational targeting approaches which may optimize survival in patients with cancer. In this review, we describe the paradoxical adverse effects of anticancer drugs, in particular how cancer cells complete resistance evolution, enhance proliferation, escape from immune surveillance and metastasize efficiently when encountered with drug therapy. We also describe an integrative therapeutic framework that may diminish such paradoxical effects, consisting of four main strategies: (1) targeting endogenous stress response pathways, (2) targeting new identities of cancer cells, (3) adaptive therapy- exploiting subclonal competition of cancer cells, and (4) targeting tumour microenvironment.
The polysaccharides (PS) have been widely used as biomaterials in drug delivery, due to their excellent biocompatibility, ease of functionalization, and intrinsic biological activities. Among the ...various PS-based biomaterials, the self-assembled PS nanogels (NG) featuring facile preparation are attracting evergrowing interests in various biomedical applications. Specifically, NG derived from the self-assembly of natural PS well maintain both the physicochemical and biological properties of PS while avoiding the chemical modification or alteration of PS structure, representing a potent drug delivery system for various therapeutic agents. In this review, the natural PS, such as chitosan, alginate, and hyaluronan, for self-assembled NG construction and their advantages in the applications of drug delivery have been summarized. The residues, such as amine, carboxyl, and hydroxyl groups, on these PS provide multiple sites for both ionic cross-linking and metal coordination, which greatly contribute to the formation of self-assembled NG as well as the drug loading, thus enabling a wide biomedical application of PS NG, especially for drug delivery. Future developments and considerations in the clinical translation of these self-assembled PS NG have also been discussed.
In this study, a three-dimensional (3D) hierarchical Co3O4@NiS core-shell heterostructure supported on nickel foam (NF) has been constructed. This Co3O4@NiS/NF can directly serve as a binder-free ...electrode for a pseudocapacitor, which could achieve a high specific capacitance of 1395.3 F g−1 at a current density of 1 A g−1 in 6 M KOH electrolyte, and an ideal rate capability of 711 F g−1 at a current density of 10 A g−1. Additionally, the electrode has a high capacitance retention of 89.9% after 5000 cycles. The asymmetric supercapacitor exhibits the maximum energy density of 61.34 W h kg−1 at a power density of 800 W kg−1, as well as an excellent cycling life of 89.3% capacitance retention. The enhanced electrochemical performance can be mainly ascribed to the special 3D core-shell nanowire arrays nanostructure with great conductivity, enlarged surface area, abundant accessible active sites and intrinsic stability. We anticipate that the present Co3O4@NiS/NF could be a promising electrode material for energy storage applications.
As an immune adjuvant, proinflammatory allogeneic dendritic cells (AlloDCs) have demonstrated promising immune-priming effects in several preclinical and clinical studies. The effector cells, ...including NK cells and T cells are widely acknowledged as pivotal factors in the effectiveness of cancer immunotherapy due to their ability to selectively identify and eradicate malignant cells. 4-1BB, as a costimulatory receptor, plays a significant role in the stimulation of effector cell activation. This study evaluated the anti-tumor effects when combining intratumoral administration of the immune-adjuvant AlloDCs with systemic α4-1BB treatment directly acting on effector cells. In both the CT-26 murine colon carcinoma model and B16 murine melanoma model, AlloDCs demonstrated a significant enhancement in the therapeutic efficacy of α4-1BB antibody. This enhancement was observed through the delayed growth of tumors and prolonged survival. Analysis of the tumor microenvironment (TME) in the combined-treatment group revealed an immune-inflamed TME characterized by increased infiltration of activated endogenous DCs and IFNγ
+
CD8
+
T cells, showing reduced signs of exhaustion. Furthermore, there was an augmented presence of tissue-resident memory (T
RM
) CD8
+
T cells (CD103
+
CD49a
+
CD69
+
). The combination treatment also led to increased infiltration of CD39
+
CD103
+
tumor-specific CD8
+
T cells and neoantigen-specific T cells into the tumor. Additionally, the combined treatment resulted in a less immunosuppressive TME, indicated by decreased infiltration of myeloid-derived suppressor cells and Tregs. These findings suggest that the combination of intratumoral AlloDCs administration with systemic agonistic α4-1BB treatment can generate a synergistic anti-tumor response, thereby warranting further investigation through clinical studies.
Immunoglobulin A nephropathy (lgAN) is a common primary glomerulonephritis, but paraneoplastic IgAN has been rarely reported. This current case report describes a 49-year-old male patient that was ...referred with proteinuria, oedema and hypoproteinaemia after lung cancer surgery and before the first cycle of chemotherapy. Renal biopsy confirmed lgAN. The patient received four cycles of chemotherapy (first cycle: pemetrexed + nedaplatin; second to fourth cycle: pemetrexed + carboplatin). The symptoms of IgAN were gradually relieved with additional cycles of chemotherapy. At the latest follow-up on 10 February 2020, there was no evidence of lung cancer recurrence and all symptoms of lgAN had disappeared. lgAN combined with lung adenocarcinoma is quite rare, which suggests that IgAN might be a paraneoplastic manifestation of lung adenocarcinoma.
The genus Gymnodinium contains more than 230 extant species, approximately 30% of which have not been reported since their original description. Approximately eight Gymnodinium species have been ...reported or described in the coastal waters of China. This work reports the presence of Gymnodinium trapeziforme from Jiaozhou Bay, China, in 2020, and its morphological and phylogenetic characterization by using light and scanning electron microscopy and systematic analysis based on partial LSU rDNA sequences. We observed the typical diagnostic features of G. trapeziforme, including a small size, biconical to ovoid shape, and a sulcal extension intruded to the epicone and connected to the horseshoe-shaped apical structure complex (ASC). Additionally, we firstly observed that the ASC consisted of three parallel series of vesicles, with the central one possessing knobs, and having more than 10 amphiesmal vesicles within the ASC. The nucleus was cucurbit-shaped, and the amphiesmal vesicles covering the cell surface, which would be peeled off for the cells in stress. While our molecular phylogeny inferred with the maximum likelihood (ML) and Bayesian inference (BI) confirmed the conspecificity of our isolate with the holotype G. trapeziforme (accession No. EF192414), we found a difference of 14 bases in the D1–D6 domains of the LSU rDNA sequences between the two entities, which indicates a detectable speciation of the two populations. Our work provides a detailed morphological and molecular characterization of G. trapeziforme that was isolated from the coastal water of China, which also broadens the geographical distribution of this species.
Oncolytic adenovirus is one of the most promising treatments against cancer and is widely evaluated clinically. During high titer production, "Wild-type-" like replication-competent adenovirus (RCA) ...contaminants can be generated through recombination events due to the DNA sequence similarity between oncolytic virus and host cells. These RCA contaminants raise various safety concerns in clinics. Cell culture-based methods have been developed to detect RCA contaminants in replication-deficient adenovirus vectors. These methods were based on that only RCA contaminants, but not the vectors, are able to grow in and lyse the test cell line. However, these methods are not suitable for distinguishing RCA contaminants from the oncolytic adenovirus products because both can replicate in test cell lines. Herein, we reported a qPCR-based method to quantify RCA contaminants quickly and reliably in E1B-deleted oncolytic adenovirus products. This method is based on specific detection of the E1B gene, which can be acquired during production
recombination events between viral and host cell DNA. The assay is sensitive with the limit of detection at 10 VP of the RCA contaminants and the limit of quantification at 75 VP of the RCA contaminants in each 40 µL qPCR reaction. We have also validated the method on virus batches produced in the non-GMP and GMP conditions. Our results showed that this qPCR-based method was reliable and robust for detecting and quantifying RCA contaminants in oncolytic adenovirus products. The method may also be adapted for other oncolytic adenoviruses products by switching primer sets.
Aim
The association between gamma-glutamyl transferase (GGT) and type 2 diabetes mellitus (T2DM) is controversial. In this study, we investigated the association between GGT and the risk of T2DM ...using real-world data, Mendelian randomization (MR) analysis, and literature mining.
Methods
A cross-sectional study enrolled 3,048 participants (>40 years) from a community in Northeastern China was conducted. A generalized additive model was used to examine the relation between GGT and T2DM. A two-sample MR was performed to investigate the causal effect of GGT (61,089 individuals, mostly of European ancestry) on T2DM (29,193 cases and 182,573 controls of European ancestry).
Results
GGT was related to glucose metabolism indicators, such as fasting plasma glucose and glycosylated hemoglobin (
P
< 0.05). The odds ratios (ORs) 95% confidence interval (95% CI),
P
for T2DM across the GGT categories (14–16, 17–20, 21–25, 26–35, ≥36) were 1.14 (0.88-1.47),
P
= 0.330, 1.55 (1.22-1.98),
P
< 0.001, 1.87 (1.47-2.28),
P
< 0.001, 1.97 (1.55-2.52),
P
< 0.001, and 2.29 (1.78-2.94),
P
< 0.001 versus GGT ≤ 13 category after adjusting for potential confounding factors. A generalized additive model identified a non-linear correlation between GGT and T2DM and indicated that the risk of T2DM almost levelled out when GGT exceeded 34 IU/L. The MR analysis showed that the odds of having T2DM for a one-time increase in genetically determined GGT was 0.998 (0.995-1.002),
P
= 0.34.
Conclusions
Our analysis of observational study suggested that GGT, its increment, within a certain range, is indicative of the development of T2DM. However, MR analysis provided no evidence that GGT is a linear causal factor of T2DM. Further investigation is required to determine if GGT exerts a non-linear causal effect on T2DM.
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