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Quality control and data integration of single-cell datasets. (A) Scatter plot showing the relationship between cell characteristics in the single-cell data before data filtering. (B) Scatter plot showing the relationship between cell characteristics, mitochondrial proportions (pMT), and RNA counts. The red line represents the threshold used in performing cell mass filtering. (C–F) Violin plots showing the distribution of cellular features in each sample after data filtering. (G,H) UMAP showing the overlaps and distribution of single-cell data after integration. These plots show the removal of batch effects.
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Introduction
The objective of this study was to determine the NF-kappaB pathway, hub genes, and transcription factors (TFs) in monocytes implicated in the progression of neurovascular-related sepsis-induced cardiomyopathy (SIC) as well as potential miRNAs with regulatory functions.
Methods
: Sepsis-induced cardiomyopathy—and heart failure (HF)-rel...
Citations
... 21 In addition, a growing number of studies have reported that microRNAs attenuate cardiac dysfunction and cell apoptosis in sepsis by the NF-κB signaling pathway. [22][23][24] Intriguingly, one recent study reported that IL-5 knockout exacerbates sepsis-induced cardiac injury via the NF-κB p65 pathway. 25 article Importantly, IL-5 and IL-15 are both members of the IL-2 superfamily, which is also known as the γ-chain family, owing to their ability to bind IL-2Rγ. ...
Sepsis-induced myocardial dysfunction (SIMD) is associated with poor prognosis and increased mortality in patients with sepsis. Cytokines are important regulators of both the initiation and progression of sepsis. Interleukin-15 (IL-15), a pro-inflammatory cytokine, has been linked to protective effects against myocardial infarction and myocarditis. However, the role of IL-15 in SIMD remains unclear. We established a mouse model of SIMD via cecal ligation puncture (CLP) surgery and a cell model of myocardial injury via lipopolysaccharide (LPS) stimulation. IL-15 expression was prominently upregulated in septic hearts as well as cardiomyocytes challenged with LPS. IL-15 pretreatment attenuated cardiac inflammation and cell apoptosis and improved cardiac function in the CLP model. Similar cardioprotective effects of IL-15 pretreatment were observed in vitro. As expected, IL-15 knockdown had the opposite effect on LPS-stimulated cardiomyocytes. Mechanistically, we found that IL-15 pretreatment reduced the expression of the pro-apoptotic proteins cleaved caspase-3 and Bax and upregulated the anti-apoptotic protein Bcl-2. RNA sequencing and Western blotting further confirmed that IL-15 pretreatment suppressed the activation of nuclear factor kappa B (NF-κB) signaling in mice with sepsis. Besides, the addition of NF-κB inhibitor can significantly attenuate cardiomyocyte apoptosis compared to the control findings. Our results suggest that IL-15 pretreatment attenuated the cardiac inflammatory responses and reduced cardiomyocyte apoptosis by partially inhibiting NF-κB signaling in vivo and in vitro, thereby improving cardiac function in mice with sepsis. These findings highlight a promising therapeutic strategy for SIMD.
... NF-κB is recognized as a key regulator of cellular in ammatory responses triggered by proin ammatory stimuli [40]. It plays a pivotal role in modulating molecular pathways associated with in ammation [41]. Activation of NF-κB signaling induces the transcription of pro-IL-1β and NLRP3, which is essential for in ammasome activation [42]. ...
Doxorubicin (DOX) is a medication employed in the treatment of cancer as a chemotherapeutic agent. However, it induces cardiotoxicity via activating inflammatory pathways. Cytokines dysregulation is a key factor that can lead to activation of inflammatory mechanisms. Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that triggers pathogenic immune responses. The objective of this study was to investigate the defensive power of secukinumab (SEC), a fully human monoclonal IgG1/κ antibody targeting IL-17A, designed to combat DOX-induced cardiotoxicity (DIC). Male Wistar rats were treated with DOX and co-treated with SEC for two weeks. The results showed that DOX caused heart tissue injury, increased cardiotoxicity markers significantly (P < 0.0001), oxidative stress and inflammation. Additionally, DOX activated the nuclear factor kappa beta (NF-κB) pathway and Pyrin domain containing 3 (NLRP3) inflammasome, potentially contributing to DIC. The co-treatment with SEC successfully reversed all DOX-related abnormalities by restoring cardiac functions to normal levels, decreasing levels of inflammatory cytokines, including IL-17A and Interleukin-1β (IL-1β), and improving oxidative stress by lowering malondialdhyde (MDA) levels and increasing reduced glutathione (GSH) levels. Furthermore, it also decreased the upregulation of the NF-κB/NLRP3 axis induced by doxorubicin. This study highlights the protective properties of SEC against DIC by modulating the NF-κB/NLRP3/caspase1/IL-1β axis.
... The lack of uniformity suggests a multifactorial etiology, type of bacteria, or immune response. It is important to highlight that 13(43.3%) of those with myocardial dysfunction had culture negative sepsis, hence SIRS might be a possibility, or mitochondrial depletion (18)(19)(20)(21). In neonates with sepsis, the discharge of cytokines, acidosis and hypoxia may result in the advancement of pulmonary hypertension and in this way right ventricular dysfunction, whereas right-heart dysfunction will impair left-heart function (22). ...
... The JAK-STAT signaling pathway plays a key role in sepsis and is involved in both the systemic inflammatory response syndrome (SIRS) and the compensatory anti-inflammatory response syndrome (CARS) phases of sepsis (16). Similarly, MicroRNAs promote sepsisinduced cardiomyopathy progression and neurovascular dysfunction by upregulating genes associated with the NFkB signaling pathway (17). In the experimental models of sepsis, JAK2 inhibitors have been shown to block the classical p65RelA/ p50 NFkB pathway, inhibiting the production of inflammatory factors, thus saving animals from sepsis (18). ...
The JAK/STAT and NFκB signaling pathways are two major inflammatory signaling pathways that are usually activated simultaneously in the body’s inflammatory response to bacterial or viral infections. Hyperactivation of these two prominent signaling pathways is associated with various immune-related diseases and mortality, pointing to an urgent need for drug development targeting JAK/STAT and/or NFκB signaling. In this study, we screened 18,840 compounds using our well-established dual STAT-NFκB driven luciferase reporter based high-throughput screening system and identified a bioactive compound C498-0670, which inhibits both JAK/STAT and NFκB signaling. C498-0670 inhibits the activation of STATs and p-IKKα/β in both the immortalized cell lines and primary peritoneal macrophages, while suppressing the expression of LPS-induced inflammatory mediators in vitro. In addition, the overall anti-inflammatory effects of C498-0670 were investigated using transcriptome sequencing and bioinformatics approaches. C498-0670 was predicted to alleviate sepsis/septic shock by disease/function analysis using IPA software, which was further verified in the LPS-induced mouse sepsis model in vivo. C498 reduced LPS-induced liver and kidney damage, myeloid cell infiltration, and pro-inflammatory cytokine and chemokine production in vivo. Furthermore, the SPR-HPLC-MS-based target fishing approach was used to identify the putative drug targets, and the high affinities of JAK2 (JAK/STAT signaling), NFKBIA (NFκB signaling), and IL-1β, NLRP1b (inflammasome signaling) for C498-0670 were verified by molecular docking approach. These results suggest that C498-0670 can be used as a dual-target inhibitor of JAK/STAT and NFκB signaling pathways for the treatment of various inflammatory diseases, especially septic shock.
In this study, we aimed to investigate the effect and underlying mechanism of betulinic acid (BA) on myocardial dysfunction in septic rats. Twenty‐four male Sprague–Dawley rats were randomly allocated into four groups ( n = 6 rats/group): the sham operation (Control) group, the cecal ligation and puncture (CLP) group, the BA 10 mg/kg group, and the BA 50 mg/kg group. The septic rat model was induced through cecal ligation and puncture in the CLP and BA groups, except for the Control group. Then, cardiac function parameters were assessed using echocardiography, myocardial injury markers were quantified via biochemical assays, and myocardial histopathological injuries were observed through H&E staining. Inflammatory factors in the serum were measured using ELISA assays, immunohistochemistry and qRT‐PCR were performed to determine macrophage numbers and the expression of iNOS, CD86, Arg‐1, and Mrc1 in myocardial tissue. The protein expression levels of TLR4, Myd88, and NF‐κB in myocardial tissue were assessed through western blot analysis. The results showed that BA significantly improved cardiac function, reduced myocardial injury, and attenuated inflammation in CLP rats. Specifically, BA decreased LVEDD and LVESD while increasing LVEF and LVFS. Furthermore, BA upregulated the levels of BNP, cTnT, CK‐MB, LDH, IL‐6, IL‐1β, and TNF‐α in CLP rat serum. Additionally, BA reduced macrophage infiltration, inhibited M1/M2 gene expression, and downregulated TLR4, Myd88 and NF‐κB protein expression in CLP rats myocardial tissues. In conclusion, BA can inhibit myocardial inflammation and prevent sepsis‐induced myocardial dysfunction by inhibiting TLR4/MyD88/NF‐κB signaling, thereby promoting M2 macrophage polarization in myocardial tissues.
Patients with viral myocarditis are at risk of sudden death and may progress to dilated cardiomyopathy (DCM). Currently, no disease‐specific therapies exist to treat viral myocarditis. Here it is examined whether reconstituted, lyophilized extracellular vesicles (EVs) from platelets from healthy men and women reduce acute or chronic myocarditis in male mice. Human‐platelet‐derived EVs (PEV) do not cause toxicity, damage, or inflammation in naïve mice. PEV administered during the innate immune response significantly reduces myocarditis with fewer epidermal growth factor (EGF)‐like module‐containing mucin‐like hormone receptor‐like 1 (F4/80) macrophages, T cells (cluster of differentiation molecules 4 and 8, CD4 and CD8), and mast cells, and improved cardiac function. Innate immune mediators known to increase myocarditis are decreased by innate PEV treatment including Toll‐like receptor (TLR)4 and complement. PEV also significantly reduces perivascular fibrosis and remodeling including interleukin 1 beta (IL‐1β), transforming growth factor‐beta 1, matrix metalloproteinase, collagen genes, and mast cell degranulation. PEV given at days 7–9 after infection reduces myocarditis and improves cardiac function. MicroRNA (miR) sequencing reveals that PEV contains miRs that decrease viral replication, TLR4 signaling, and T‐cell activation. These data show that EVs from the platelets of healthy individuals can significantly reduce myocarditis and improve cardiac function.
Head and neck squamous cell carcinoma (HNSCC), the most common malignancy of the head and neck, has an overall 5-year survival rate of <50%. Genes associated with cuproptosis, a newly identified copper-dependent form of cell death, are aberrantly expressed in various tumours. However, their role in HNSCC remains unknown. In this study, bioinformatic analysis revealed that the cuproptosis-related gene CDKN2A was correlated with the malignant behaviour of HNSCC. Kaplan-Meier (KM) curves showed that patients with high CDKN2A expression had a better prognosis. Multiomic analysis revealed that CDKN2A may be associated with cell cycle and immune cell infiltration in the tumour microenvironment and is important for maintaining systemic homeostasis in the body. Furthermore, molecular docking and molecular dynamics simulations suggested strong binding between plicamycin and CDKN2A. And plicamycin inhibits the progression of HNSCC in cellular assays. In conclusion, this study elucidated a potential mechanism of action of the cuproptosis-associated gene CDKN2A in HNSCC and revealed that plicamycin targets CDKN2A to improve the prognosis of patients.
