Abstract Traumatic brain injury (TBI) initiates inflammatory responses that result in an enduring cascade of secondary neuronal loss and behavioural impairment. Toll-like receptor 4 (TLR4), ...predominantly expressed by microglia, recognizes damage-associated molecular patterns (DAMPs) and regulates inflammatory processes. Interestingly, the switch of microglial M1/M2 phenotypes after TBI is highly important regarding damage and restoration of neurological function. Therefore, we investigated the role and mechanisms of the TLR4 signalling pathway in regulating microglial M1/M2 phenotypes. Using a controlled cortical impact (CCI) model, we found that TLR4 knockout (KO) mice exhibited decreased infarct volumes and improved outcomes in behavioural tests. In addition, mice lacking TLR4 had higher expression of M2 phenotype biomarkers but lower expression of M1 phenotype biomarkers. Compared with microglia derived from wild-type (WT) mice, increased expression of M2 phenotype biomarkers and decreased expression of M1 phenotype biomarkers were also noted in primary cultures of microglia from TLR4 KO mice. In TLR4 KO mice, the expression levels of downstream signalling molecules of TLR4, such as active Rac-1 and phospho-AKT, were higher, while MyD88 and phospho-NF-κB p65 expression levels were lower than in WT mice. Our results demonstrate that the absence of TLR4 induces microglial polarization toward the M2 phenotype and promotes microglial migration and, in turn, alleviates the development of neuroinflammation, which indicates potential neuroprotective effects in the TBI mouse model. Furthermore, up-regulation of IL-4 expression in TLR4 KO mice could contribute to anti-inflammatory functions and promote microglial polarization toward the M2 phenotype, which might be mediated by active Rac-1 expression. Taken together, TLR4 deficiency contributes to regulating microglia to switch to the M2 phenotype, which ameliorates neurological impairment after TBI.
Currently, cytogenetic and genetic markers are the most important for risk stratification and treatment of patients with acute myeloid leukemia (AML). Despite the identification of many prognostic ...factors, relatively few have made their way into clinical practice. Therefore, the identification of new AML biomarkers is useful in the prognosis and monitoring of AML and contributes to a better understanding of the molecular basis of the disease. Homeobox (HOX) genes are transcription factors that lead to cell differentiation blockade and malignant self-renewal. However, the roles of HOX genes in AML are still not fully understood and need further exploration, which may provide new strategies for the prognosis and monitoring of AML.
We analyzed the RNA sequencing and clinical data from The Cancer Genome Atlas (TCGA), VIZOME, GSE13159, and GSE9476 cohorts. Analyses were performed with GraphPad 7, the R language, and several online databases. We applied quantitative polymerase chain reaction, Western Blotting, CCK8 cell proliferation assays, and flow cytometry to verify the conclusions of the bioinformatics analysis.
We identified HOXB5 as the only gene among the HOX family that was not only elevated in AML but also a significant prognostic marker in AML patients. HOXB5 was highly expressed in AML patients with NPM1, FLT3, or DNMT3A mutations and was expressed at the highest level in patients with NPM1-FLT3-DNMT3A triple-mutant AML. Gene Ontology analysis and gene set enrichment analysis revealed that HOXB5 showed a negative correlation with the myeloid cell differentiation signature and that the tumor necrosis factor/nuclear factor κB signaling pathway was involved in the molecular mechanism. Moreover, we performed
protein-protein interaction analysis and 450K TCGA DNA methylation data analysis and found that HOXB5 interacted with two HOX genes (HOXA7 and HOXB4) that were commonly regulated by DNA methylation levels.
HOXB5 is associated with the malignant development of AML and may be a treatment target and biomarker for AML prognosis prediction.
To explore the clinical characteristics and prognosis of COVID‐19 patients with cerebral stroke. A total of 2,474 COVID‐19 patients from February 10th to March 24th, 2020 were admitted and treated in ...two branches (Optic Valley and Sino‐French New City branch) of the Tongji Hospital. Data on the clinical characteristics, laboratory parameters and prognosis of COVID‐19 patients with or without cerebral stroke were collected and comparatively analysed. Of the 2,474 COVID‐19 patients, 113 (4.7%) patients had cerebral stroke and 25 (1.0%) patients had new‐onset stroke. Eighty‐eight (77.9%) patients in the previous‐stroke group had cerebral ischaemia, while 25 (22.1%) patients in the new‐onset stroke group had cerebral ischaemia. Most COVID‐19 patients with stroke were elderly with more comorbidities such as hypertension, diabetes and heart diseases than patients without stroke. Laboratory examinations showed hypercoagulation and elevated serum parameters such as IL‐6, cTnI, NT pro‐BNP and BUN. Consciousness disorders, a long disease course and poor prognosis were also more commonly observed in stroke patients. The mortality rate of stroke patients was almost double (12.4% vs. 6.9%) that of patients without stroke. In addition, age, male sex and hypertension were independent predictors for new cerebral stroke in COVID‐19 patients. In conclusion, the high risk of new‐onset stroke must be taken into consideration when treating COVID‐19 patients with an elderly age combined with a history of hypertension. These patients are more vulnerable to multiorgan dysfunction and an overactivated inflammatory response, in turn leading to an unfavourable outcome and higher mortality rate.
Of the 2,474 COVID‐19 patients in the Tongji Hospital, 113 (4.7%) patients had cerebral stroke, and 25 (1.0%) patients had new‐onset stroke. In 113 (4.7%) stroke patients, 88 (77.9%) patients in the previous‐stroke, while 25 (22.1%) patients in the new‐onset. Most COVID‐19 patients with stroke were elderly with more comorbidities such as hypertension, diabetes and heart diseases. Laboratory examinations showed hypercoagulation and elevated serum parameters such as IL‐6, cTnI. The mortality rate of stroke patients was almost double that of patients without stroke. In conclusion, COVID‐19 patients with an elderly age combined with a history of hypertension were more likely happening new‐onset stroke. These patients are more vulnerable to multiorgan dysfunction and an overactivated inflammatory response, in turn leading to a higher mortality rate.
Current clinical research has reported the effectiveness and safety of venetoclax in combination with hypomethylating agents (VEN-HMA) in patients with myelodysplastic syndromes (MDS) and chronic ...myelomonocytic leukemia (CMML). Thus, this study aimed to examine the effectiveness and safety of VEN-HMA therapy in patients with MDS and CMML and compared its short-term and long-term therapeutic effects with HMA monotherapy.
We analyzed data from our center, comprising 19 patients with MDS and CMML who received VEN-HMA therapy, compared to 32 patients treated with HMA monotherapy.
The overall response rate (ORR) in the VEN-HMA group was 73.7%, compared to 59.4% in the HMA group. The survival analysis revealed that the median overall survival (mOS) time in the VEN-HMA group was 16 months, with a median progression-free survival (mPFS) time of 9 months, both of which were longer than those observed in the HMA group (
< 0.05). Key adverse events (AEs) included grade 3-4 neutropenia (89.5% in VEN-HMA group vs. 87.5% in HMA group), grade 3-4 thrombocytopenia (73.7% vs. 71.9%), and anemia (73.7% vs. 90.6%). Infection of grade 3 or higher occurred in 63.2% of patients in the VEN-HMA group and 65.6% of patients in the HMA group.
Our study has confirmed the effectiveness and safety of the combined treatment of HMAs and venetoclax, which offers significant advantages to patients due to the relatively high and rapid response rates.
Phytophthora sojae, a soil-borne oomycete pathogen, has been a yield limiting factor for more than 60 years on soybean. The resurgence of P. sojae (Phytophthora sojae) is primarily ascribed to the ...durable oospores found in soil and remnants of the disease. P. sojae is capable of infesting at any growth periods of the soybean, and the succeed infestation of P. sojae is predominantly attributed to long-lived oospores present in soil. Comprehending the molecular mechanisms that drive oospores formation and their significance in infestation is the key for effective management of the disease. However, the existing challenges in isolating and extracting significant quantities of oospores pose limitations in investigating the sexual reproductive stages of P. sojae.
The study focused on optimizing and refining the culture conditions and extraction process of P. sojae, resulting in establishment of an efficient and the dependable method for extraction. Novel optimized approach was yielded greater quantities of high-purity P. sojae oospores than traditional methods. The novel approach exceeds the traditional approaches with respect to viability, survival ability, germination rates of new oospores and the pathogenicity of oospores in potting experiments.
The proposed method for extracting P. sojae oospores efficiently yielded a substantial quantity of highly pure, viable, and pathogenic oospores. The enhancements in oospores extraction techniques will promote the research on the sexual reproductive mechanisms of P. sojae and lead to the creation of innovative and effective approaches for managing oomycete diseases.
Fatty acid metabolism has been reported to play important roles in the development of acute myeloid leukemia (AML), but there are no prognostic signatures composed of fatty acid metabolism-related ...genes. As the current prognostic evaluation system has limitations due to the heterogeneity of AML patients, it is necessary to develop a new signature based on fatty acid metabolism to better guide prognosis prediction and treatment selection.
We analyzed the RNA sequencing and clinical data of The Cancer Genome Atlas (TCGA) and Vizome cohorts. The analyses were performed with GraphPad 7, the R language and SPSS.
We selected nine significant genes in the fatty acid metabolism gene set through univariate Cox analysis and the log-rank test. Then, a fatty acid metabolism signature was established based on these genes. We found that the signature was as an independent unfavourable prognostic factor and increased the precision of prediction when combined with classic factors in a nomogram. Gene Ontology (GO) and gene set enrichment analysis (GSEA) showed that the risk signature was closely associated with mitochondrial metabolism and that the high-risk group had an enhanced immune response.
The fatty acid metabolism signature is a new independent factor for predicting the clinical outcomes of AML patients.
High mobility group box-1 protein (HMGB-1) is one of the most important DAMPs and has been previously shown to promote the formation of the NOD-like receptor with pyrin domain containing-3 (NLRP3) ...inflammasome in microglia. Interleukin 4 (IL4) is a Th2-derived cytokine that plays a significant role in the function of various immune cells. However, the underlying molecular mechanism by which IL4 signaling antagonizes NLRP3 inflammasome is poorly characterized. In particular, whether IL4 could modulate NLRP3 inflammasome in astrocytes remains unknown. In the present study, we elucidated this phenomenon and the mechanism by which IL4 inhibits HMGB1-mediated NLRP3 inflammasome formation in astrocytes. For this purpose, we cultured and extracted primary astrocytes, setup different concentrations of HMGB1, and used immunofluorescence and western blotting to detect NLRP3 inflammasome formation, including NLRP3, ASC and caspase-1, and signaling changes in the nuclear factor κB (NF-κB). Meanwhile, BAY 11–7082 and IL4 were added with HMGB1 to observe the NLRP3 inflammasome and changes in NF-κB expression. Our data showed that HMGB1 could effectively promote NLRP3 inflammasome formation by activating NF-κB in astrocytes. This effect can be inhibited by BAY 11–7082, a NF-κB inhibitor. Meanwhile, IL4 could activate PPARγ via the STAT6 singling pathway and inhibit NF-κB activation, significantly decreasing formation of the NLRP3 inflammasome complex. Our study demonstrated that the NLRP3 inflammasome complex is also expressed in astrocytes, and IL4 could inhibit HMGB1-mediated NLRP3 inflammasome formation, through negative regulation of NF-κB activity and promotion of PPARγ activation.
•The NLRP3 inflammasome is upregulated in activated astrocytes.•HMGB1 could effectively promote NLRP3 inflammasome formation in astrocytes, by activating NF-κB.•IL4 could inhibit NLRP3 inflammasome formation, through negative regulation NF-κB and promotion PPARγ activation.
Neuroinflammatory processes mediated by microglial activation and subsequent neuronal damage are the hallmarks of traumatic brain injury (TBI). As an inhibitor of the macrophage‑inducible C‑type ...lectin (Mincle)/spleen tyrosine kinase (Syk) signaling pathway, BAY61‑3606 (BAY) has previously demonstrated anti‑inflammatory effects on some pathological processes, such as acute kidney injury, by suppressing the inflammatory macrophage response. In the present study, the potential effects of BAY on microglial phenotype and neuroinflammation after TBI were investigated. BAY (3 mg/kg) was first administered into mice by intraperitoneal injection after TBI induction
and microglia were also treated with BAY (2 µM)
. The levels of inflammatory factors in microglia were assessed using reverse transcription‑quantitative PCR and ELISA. Cortical neuron, myelin sheath, astrocyte and cerebrovascular endothelial cell markers were detected using immunofluorescence. The levels of components of the Mincle/Syk/NF‑κB signaling pathway Mincle, phosphorylated (p)‑Syk and NF‑κB, in addition to proteins associated with inflammation (ASC, caspase‑1, TNF‑α, IL‑1β and IL‑6), apoptosis (Bax and Bim) and tight junctions (Claudin‑5), were measured via western blotting and ELISA. Migration and chemotaxis of microglial cells were evaluated using Transwell and agarose spot assays. Neurological functions of the mice were determined
using the modified neurological severity scoring system and a Morris water maze. The results of the present study revealed that the expression levels of proteins in the Mincle/Syk/NF‑κB signaling pathway (including Mincle, p‑Syk and p‑NF‑κB), inflammatory cytokines (TNF‑α, IL‑1β and IL‑6), proteins involved in inflammation (ASC and caspase‑1), apoptotic markers (Bax and Bim) and the tight junction protein Claudin‑5 were significantly altered post‑TBI. BAY treatment reversed these effects in both the cerebral cortex extract‑induced cell model and the controlled cortical impact mouse model. BAY was also revealed to suppress activation of the microglial proinflammatory phenotype and microglial migration. In addition, BAY effectively attenuated TBI‑induced neurovascular unit damage and neurological function deficits. Taken together, these findings provided evidence that BAY may inhibit the Mincle/Syk/NF‑κB signaling pathway in microglia; this in turn could attenuate microglia‑mediated neuroinflammation and improve neurological deficits following TBI.
Moyamoya disease (MMD) is characterized by frequent migration and phenotypic transformation of vascular smooth muscle cells (VSMCs) in the intima layer of blood vessels. However, the underlying ...mechanism is unclear. Toll-like receptor (TLR) 7 is abundantly expressed in smooth muscle cells (SMCs) in multiple vascular diseases, which might be linked to the disease-associated vascular remodeling. In the present study, the expression of TLR7 in MMD vessels was examined using the superficial temporal artery (STA) and middle cerebral artery (MCA) from MMD patients. Furthermore, the effect of TLR7 activation on the VSMC phenotype switch in vitro and vascular remodeling in vivo was assessed using a 9.4Tesla MRI. Our results demonstrated that the TLR7 and microRNA Let-7c expression are upregulated in VSMCs and the plasma of MMD patients, respectively. Additionally, TLR7 stimulation by Let-7c or Imiquimod induces a synthetic phenotype switch in VSMCs. Mechanistic studies revealed that Akt/mTOR signaling is responsible for this TLR-induced VSMC phenotypic switch. The Let-7c or Imiquimod treatment also resulted in reduced blood flow of internal carotid arteries (ICAs) in an in vivo model, while TLR7 inhibition attenuated the ICA stenosis. Besides, Let-7c was also found to be elevated in the hypoxic endothelial cells. Taken together, our study demonstrates that Let-7c released by endothelial cells under hypoxic conditions may activate TLR7 on VSMCs, ultimately leading to the phenotype switch and vascular wall remodeling. These findings thus elucidate the putative mechanisms underlying progressive stenosis of blood vessels in MMD and provide prospective therapeutic targets for further exploration.
The JASMONATE-ZIM DOMAIN (JAZ) family genes are key repressors in the jasmonic acid signal transduction pathway. Recently, the JAZ gene family has been systematically characterized in many plants. ...However, this gene family has not been explored in the tea plant. In this study, 13 CsJAZ genes were identified in the tea plant genome. Phylogenetic analysis showed that the JAZ proteins from tea and other plants clustered into 11 sub-groups. The CsJAZ gene transcriptional regulatory network predictive and expression pattern analyses suggest that these genes play vital roles in abiotic stress responses, phytohormone crosstalk and growth and development of the tea plant. In addition, the CsJAZ gene expression profiles were associated with tea postharvest processing. Our work provides a comprehensive understanding of the CsJAZ family and will help elucidate their contributions to tea quality during tea postharvest processing.
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