The COVID-19 is an infectious disease caused by SARS-CoV-2 infection. A large number of clinical studies found high-level expression of pro-inflammatory cytokines in patients infected with ...SARS-CoV-2, which fuels the rapid development of the disease. However, the specific molecular mechanism is still unclear. In this study, we found that SARS-CoV-2 Nsp5 can induce the expression of cytokines IL-1β, IL-6, TNF-α, and IL-2 in Calu-3 and THP1 cells. Further research found that Nsp5 enhances cytokine expression through activating the NF-κB signaling pathway. Subsequently, we investigated the upstream effectors of the NF-κB signal pathway on Nsp5 overexpression and discovered that Nsp5 increases the protein level of MAVS. Moreover, Nsp5 can promote the SUMOylation of MAVS to increase its stability and lead to increasing levels of MAVS protein, finally triggering activation of NF-κB signaling. The knockdown of MAVS and the inhibitor of SUMOylation treatment can attenuate Nsp5-mediated NF-κB activation and cytokine induction. We identified a novel role of SARS-CoV-2 Nsp5 to enhance cytokine production by activating the NF-κB signaling pathway.
MicroRNAs (miRNAs) are important molecules that mediate virus-host interactions, mainly by regulating gene expression via gene silencing. Here, we demonstrated that HIV-1 infection upregulated ...miR-210-5p in HIV-1-inoculated cell lines and in the serum of HIV-1-infected individuals. Luciferase reporter assays and western blotting confirmed that a target protein of miR-210-5p, TGIF2, is regulated by HIV-1 infection. Furthermore, HIV-1 Vpr protein induced miR-210-5p expression. The use of a miR-210-5p inhibitor and TGIF2 overexpression showed that Vpr upregulated miR-210-5p and thereby downregulated TGIF2, which might be one of the mechanisms used by Vpr to induce G2 arrest. Moreover, we identified a transcription factor, NF-κB p50, which upregulated miR-210-5p in response to Vpr protein. In conclusion, we identified a mechanism whereby miR-210-5p, which is induced upon HIV-1 infection, targets TGIF2. This pathway was initiated by Vpr protein activating NF-κB p50, which promoted G2 arrest. These alterations orchestrated by miRNA provide new evidence on how HIV-1 interacts with its host during infection and increase our understanding of the mechanism by which Vpr regulates the cell cycle.
Inflammation caused by microglial activation is important in neurodegenerative diseases. In this research, we tried to identify safe and effective anti-neuroinflammatory agents by screening a natural ...compounds library and found that Ergosterol can inhibit the nuclear factor kappa-light-chain enhancer of the activated B cells (NF-κB) pathway induced by lipopolysaccharide (LPS) in microglia cells. Ergosterol has been reported to be an effective anti-inflammatory agent. Nevertheless, the potential regulatory role of Ergosterol in neuroinflammatory responses has not been fully investigated. We further investigated the mechanism of Ergosterol that regulates LPS-induced microglial activation and neuroinflammatory reactions both in vitro and in vivo. The results showed that Ergosterol can significantly decrease the pro-inflammatory cytokines induced by LPS in BV2 and HMC3 microglial cells, possibly by inhibiting the NF-κB, protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) signaling pathways. In addition, we treated Institute of Cancer Research (ICR) mice with a safe concentration of Ergosterol following LPS injection. Ergosterol treatment significantly decreased microglial activation-associated ionized calcium-binding adapter molecule-1 (IBA-1), NF-κB phosphorylation, and pro-inflammatory cytokine levels. Moreover, Ergosterol pretreatment clearly reduced LPS-induced neuron damage by restoring the expression of synaptic proteins. Our data may provide insight into possible therapeutic strategies for neuroinflammatory disorders.
Prevalent neurological disorders such as Alzheimer's disease, Parkinson's disease, and stroke are increasingly becoming a global burden as society ages. It is well-known that degeneration and loss of ...neurons are the fundamental underlying processes, but there are still no effective therapies for these neurological diseases. In recent years, plenty of studies have focused on the pharmacology and feasibility of natural products as new strategies for the development of drugs that target neurological disorders.
has become one of the most promising candidates, and the crude extracts and some active metabolites of it have been reported to play various pharmacological activities to alleviate neurological symptoms at cellular and molecular levels. This review highlights the current evidence of
against neurological disorders, including safety evaluation, metabolism, blood-brain barrier penetration, neuroprotective activities, and the potential on regulating the gut-microbiome-brain axis. Furthermore, potential strategies to resolve problematic issues identified in previous studies are also discussed. We aim to provide an overview for the ongoing development and utilization of
in cerebral neuropathology.
Autophagy is a conserved cellular process playing a role in maintenance of cellular homeostasis and response to changing nutrient conditions via degradation and recirculation of cellular redundant ...components. Autophagy-related proteins (Atg) play important function in autophagy pathway. Aedes albopictus mosquito is an effective vector transmitting multiple viruses which cause serious human diseases. Moreover, Aedes albopictus mosquito is becoming a serious threat to human health due to its widening distribution in recent years and thus worth of more research attention. It was reported that autophagy might play a role in viral infection in Aedes mosquito. To better understand the interaction between autophagy and arbovirus infection in mosquito system, it is necessary to identify autophagy pathway in the system. However, autophagy in Aedes albopictus mosquito is still poorly understood so far. We recently identified AaAtg8, the first Atg protein reported in Aedes albopictus mosquito. This work further identified twelve atg genes in Aedes albopictus mosquito. Sequence and phylogenetic analysis of the twelve atg genes were performed. Expression profiles of all the twelve Aaatg genes in different developmental stages and genders of Aedes albopictus mosquito were conducted. Effects of chemicals inhibiting or inducing autophagy on the levels of eight identified AaAtg proteins were examined. The function of two identified AaAtg proteins AaAtg6 and AaAtg16 and their response to arbovirus SINV infection were studied preliminarily. Taken together, this work systematically identified Aedes albopictus atg genes and provided basic information which might help to elucidate the autophagy pathway and the role of autophagy in arbovirus infection in Aedes mosquito system.
The pathogenesis of diabetes mellitus is mediated mainly by oxidative stress produced by damaged pancreatic β-cells. We identified that an ethyl-acetate fraction (EA) from a cinnamon-cortex extract ...(CCE) is rich in flavonoid, and showed no toxicity to β cells.
In this study, we evaluated the pharmacologic activities of EA on pancreatic β cells using a model of oxidative stress induced by H
O
or alloxan.
The results showed that EA could significantly reduce reactive oxygen (ROS) accumulation to improve the survival of cells. Western blot showed that EA treatment upregulated expression of nuclear factor erythroid 2 related factor 2, heme oxygenase-1, and gamma glutamylcysteine synthetase. The same model study found that EA also can protect β cells against the apoptosis induced by oxidative stress. Furthermore, EA can enhance insulin secretion in rat and mouse β cell lines treated or not with alloxan or H
O
. The expression of the insulin transcription factor PDX-1 increased in an EA concentration-dependent manner. At last, the major functional compounds of EA analysis showed that three compounds, cinnamyl alcohol, coumarin, and cinnamic acid, had similar effects as EA.
In sum, our data suggested that EA fraction from CCE can protect β cells from oxidative stress, and increase insulin secretion to improve the function of β cells. This function might be due to these three compounds found in EA. Our findings provide a theoretical basis and functional molecules for the use of CCE against diabetes mellitus.
SARS-CoV-2 is the causative agent for the global COVID-19 pandemic; however, the interaction between virus and host is not well characterized. Natural killer cells play a key role in the early phase ...of the antiviral response, and their primary functions are dependent on signaling through the killer cell immunoglobulin-like receptor (KIR). This study measured the association between KIR/HLA class I ligand pairings and the occurrence and development of COVID-19. DNA of blood samples from 257 COVID-19 patients were extracted and used to detect KIR and HLA-C gene frequencies using single strain sequence-specific primer (SSP) PCR. The frequency of these genes was compared among 158 individuals with mild COVID-19, 99 with severe disease, and 98 healthy controls. The frequencies of KIR2DL2 (P=0.04, OR=1.707), KIR2DS3 (P=0.047, OR=1.679), HLA-C1C1 (P<0.001, OR=3.074) and the KIR2DL2/HLA-C1C1 pairing (P=0.038, OR=2.126) were significantly higher in the COVID-19 patients than the healthy controls. At the same time, the frequency of KIR2DL3+KIR2DL2-/HLA-C1+Others+ was lower in COVID-19 patients than in healthy individuals (P=0.004, OR=0.477). These results suggest that the protective effect of KIR2DL3 against SARS-CoV-2 infection is related to the absence of the KIR2DL2 gene. This study found no correlation between the frequencies of these genes and COVID-19 pathogenesis. Global statistical analysis revealed that the incidence of COVID-19 infection was higher in geographic regions with a high frequency of KIR2DL2. Together these results suggest that the KIR2DL2/HLA-C1C1 gene pairing may be a risk factor for SARS-CoV-2 infection.
N6-methyladenosine (m6A) methylation of human immunodeficiency virus type 1 (HIV-1) RNA regulates viral replication, and the m6A of host RNA is affected by HIV-1 infection, but its global pattern and ...function are still unclear. In this study, we report that the number and position of m6A peaks in huge genes of human microglial HMC3 cells were modulated by a single cycle HIV-1 pseudotyped with VSV-G envelope glycoprotein infection using methylated RNA immunoprecipitation sequencing (MeRIP-seq). A conjoint analysis of MeRIP-seq and high-throughput sequencing for mRNA (RNA-seq) explored four groups of clearly classified genes, including 45 hyper-up (m6A-mRNA), 45 hyper-down, 120 hypo-up, and 54 hypo-down genes, in HIV-1 infected cells compared to uninfected ones. KEGG pathway analysis showed that these genes were mainly enriched in the Wnt and TNF signaling pathway, and cytokine–cytokine receptor interaction, which might be related to the immune response in HMC3 cells. And some of these genes might be associated with the pathway of axon guidance and neuroactive ligan-receptor interaction, which affect the neuronal state. However, the cognitive disorders caused by HIV-1 is associated with inflammatory changes that have not yet been well clarified. Furthermore, we confirmed the expression and m6A levels of four genes using RT-PCR and MeRIP-qPCR. Similar to the sequencing results, the expressions of these genes were significantly upregulated by HIV-1 infection. And the m6A level of IL-6 was downregulated, and those of HLA-B, CFB, and OLR1 were upregulated. These results suggest that HIV-1-induced changes in gene expression may be achieved through the regulation of methylation. Our study revealed the global m6A methylation and gene expression patterns under HIV-1 infection in human microglia, which might provide clues for understanding the interaction between HIV-1 and host cells and the cognitive disorders caused by HIV-1.
is a primary vector of hundreds of pathogens. Strong environmental adaptability and extensive global distribution of
make it a severe threat to human health. Autophagy is a cellular process involved ...in maintenance of cellular homeostasis and recirculation of cytoplasm to generate macromolecule constituents and energy under different stress conditions. Many autophagy-related (Atg) proteins have been identified in yeast and were found in various organisms subsequently, indicating that the basic mechanism of autophagy is well conserved in eukaryotes. Among all Atg proteins, Atg8 plays important roles in autophagy and is widely used as a marker to monitor autophagic activity in yeast,
, nematodes, zebrafish and mammals. By now, Atg proteins in
have not been reported yet and the autophagy pathway in
remains unclear. This study identified a homolog of Atg8 from
and named it AaAtg8. Sequence analysis revealed that AaAtg8 was highly conserved in the Atg8 family. This work proved that AaAtg8 was a functional Atg protein of
and expressed during developmental and adult stages of
. Moreover, the study also established the basic methods for autophagy study in C6/36 cells. First, it was proved that both rapamycin and starvation were applicable ways to induce autophagy in C6/36 cells, and that 3-methyladenine and chloroquine could be used to inhibit early and late stages of autophagy in C6/36 cells, respectively. Second, the results in this study showed that monodansylcadaverine staining could be used to detect autophagy in C6/36 cells. Additionally, the study revealed that the level of autophagy in C6/36 cells could be monitored by the turnover assay of AaAtg8 or fluorescent AaAtg8. Taken together, this study identified AaAtg8, the first reported Atg protein in
. It also provided useful methods for studying autophagy in
. To our knowledge, this is the first work about autophagy in
.
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