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Biomedical Journal Jun 2024The functions of activating transcription factor 3 (ATF3) within the human bladder remain unexplored. This study delves into the expressions, functions, and regulatory...
BACKGROUND
The functions of activating transcription factor 3 (ATF3) within the human bladder remain unexplored. This study delves into the expressions, functions, and regulatory mechanisms of ATF3 in human bladder cancer.
MATERIAL AND METHODS
Gene expressions were determined by immunoblot, RT-qPCR, and reporter assays. Assays of Ki67, colony formation, Matrigel invasion, and the xenograft animal study were used to assess the cell proliferation, invasion, and tumorigenesis in vitro and in vivo. Silico analysis from TCGA database examined the correlations between GDF15 and ATF3 expressions, clinicopathologic features, and progression-free survival rates.
RESULTS
Silico analysis confirmed that ATF3 is an antitumor gene, and the expression positively correlates with GDF15 in bladder cancer tissues. Multivariate analysis revealed that low ATF3/GDF15 but not a single low expression of ATF3 is an independent prognostic factor for progression-free survival of bladder cancer patients. Ectopic overexpression of ATF3 downregulated cell proliferation and invasion in bladder cancer cells in vitro, while ATF3-knockdown reversed these results. Knockdown of ATF3 upregulated EMT markers to enhance cell invasion in vitro and downregulated GDF15, NDRG1, and KAI-1 to elevate tumor growth in vivo. The activation of metformin on ATF3 and GDF15 in bladder cancer cells was blocked by SB431542, a TGFβ receptor inhibitor. ATF3 positively regulated GDF15 expression in bladder cancer cells through a feedback loop.
CONCLUSIONS
Our results identify that ATF3 is a metformin-upregulated antitumor gene. Results of Silico analysis align with cell-based studies suggesting that low ATF3/GDF15 could be a negative prognostic marker for bladder cancer.
PubMed: 38942385
DOI: 10.1016/j.bj.2024.100756 -
Indian Pacing and Electrophysiology... Jun 2024This paper presents a novel approach to gap mapping in pulmonary vein isolation (PVI) for atrial fibrillation (AF) treatment, utilizing the real-time Ripple (RR)...
This paper presents a novel approach to gap mapping in pulmonary vein isolation (PVI) for atrial fibrillation (AF) treatment, utilizing the real-time Ripple (RR) technique. Radiofrequency (RF) catheter ablation, particularly encircling PVI, is a common intervention for AF. Identifying left atrium-pulmonary vein conduction gaps is crucial for achieving PVI with minimal additional ablation if first-pass PVI is unsuccessful. However, identifying conduction gaps can be relatively challenging, often necessitating manual electrocardiogram reannotation due to the limitations of local activation time (LAT) maps. In the case of a 63-year-old patient with drug-resistant symptomatic persistent AF, the RR technique was utilized to identify conduction gaps during RF ablation. The technique involved pausing fast anatomical mapping (FAM), activating Ripple map (RM) feature on the CARTO 3 system and acquiring points with an ultrahigh-resolution mapping catheter. This approach revealed that the actual site of earliest activation differs from the LAT map indication, enabling successful PVI. The RM feature's capability to reflect actual excitation propagation without reliance on map annotations was crucial for precise conduction gap identification, overcoming inter-operator variability and inaccuracies of conventional methods. The RR technique not only facilitated real-time analysis during gap mapping but also significantly reduced the procedure time, minimizing potential complications. This case report highlights the efficacy of the RR technique in real-time gap mapping, demonstrating its value in cases where first-pass PVI is unsuccessful. The integration of this technique into PVI procedures can enhance both the accuracy and efficiency of catheter ablation for AF.
PubMed: 38942383
DOI: 10.1016/j.ipej.2024.06.008 -
Biochimica Et Biophysica Acta.... Jun 2024Obesity is a risk factor for developing severe COVID-19. However, the mechanism underlying obesity-accelerated COVID-19 remains unclear. Here, we report results from a...
Obesity is a risk factor for developing severe COVID-19. However, the mechanism underlying obesity-accelerated COVID-19 remains unclear. Here, we report results from a study in which 2-3-month-old K18-hACE2 (K18) mice were fed a western high-fat diet (WD) or normal chow (NC) over 3 months before intranasal infection with a sublethal dose of SARS-CoV2 WA1 (a strain ancestral to the Wuhan variant). After infection, the WD-fed K18 mice lost significantly more body weight and had more severe lung inflammation than normal chow (NC)-fed mice. Bulk RNA-seq analysis of lungs and adipose tissue revealed a diverse landscape of various immune cells, inflammatory markers, and pathways upregulated in the infected WD-fed K18 mice when compared with the infected NC-fed control mice. The transcript levels of IL-6, an important marker of COVID-19 disease severity, were upregulated in the lung at 6-9 days post-infection in the WD-fed mice when compared to NC-fed mice. Transcriptome analysis of the lung and adipose tissue obtained from deceased COVID-19 patients found that the obese patients had an increase in the expression of genes and the activation of pathways associated with inflammation as compared to normal-weight patients (n = 2). The K18 mouse model and human COVID-19 patient data support a link between inflammation and an obesity-accelerated COVID-19 disease phenotype. These results also indicate that obesity-accelerated severe COVID-19 caused by SARS-CoV-2 WA1 infection in the K18 mouse model would be a suitable model for dissecting the cellular and molecular mechanisms underlying pathogenesis.
PubMed: 38942338
DOI: 10.1016/j.bbadis.2024.167322 -
Fish & Shellfish Immunology Jun 2024Takifugu rubripes is a highly valued cultured fish in Asia, while pathogen infections can result in severe diseases and lead to substantial economic losses. Toll-like...
Takifugu rubripes is a highly valued cultured fish in Asia, while pathogen infections can result in severe diseases and lead to substantial economic losses. Toll-like receptors (TLRs), as pattern recognition receptors, play a crucial role on recognition pathogens and initiation innate immune response. However, the immunological properties of teleost-specific TLR23 remain largely unknown. In this study, we investigated the biological functions of TLR23 (TrTLR23) from T. rubripes, found that TrTLR23 existed in various organs. Following bacterial pathogen challenge, the expression levels of TrTLR23 were significantly increased in immune related organs. TrTLR23 located on the cellular membrane and specifically recognized pathogenic microorganism. Co-immunoprecipitation and antibody blocking analysis revealed that TrTLR23 recruited myeloid differentiation primary response protein (MyD88), thereby mediating the activation of the ERK signaling pathway. Furthermore, in vivo showed that, when TrTLR23 is overexpressed in T. rubripes, bacterial replication in fish tissues is significantly inhibited. Consistently, when TrTLR23 expression in T. rubripes is knocked down, bacterial replication is significantly enhanced. In conclusion, these findings suggested that TrTLR23 played a critical role on mediation TLR23-MyD88-ERK axis against bacterial infection. This study revealed that TLR23 involved in the innate immune mechanism, and provided the foundation for development disease control strategies in teleost.
PubMed: 38942251
DOI: 10.1016/j.fsi.2024.109724 -
Journal of Affective Disorders Jun 2024Post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) are psychiatric disorders that can present with overlapping symptoms and shared risk factors.... (Review)
Review
Similarities and differences between post-traumatic stress disorder and major depressive disorder: Evidence from task-evoked functional magnetic resonance imaging meta-analysis.
BACKGROUND
Post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) are psychiatric disorders that can present with overlapping symptoms and shared risk factors. However, the extent to which these disorders share common underlying neuropathological mechanisms remains unclear. To investigate the similarities and differences in task-evoked brain activation patterns between patients with PTSD and MDD.
METHODS
A coordinate-based meta-analysis was conducted across 35 PTSD studies (564 patients and 543 healthy controls) and 125 MDD studies (4049 patients and 4170 healthy controls) using anisotropic effect-size signed differential mapping software.
RESULTS
Both PTSD and MDD patients exhibited increased neural activation in the bilateral inferior frontal gyrus. However, PTSD patients showed increased neural activation in the right insula, left supplementary motor area extending to median cingulate gyrus and superior frontal gyrus (SFG), and left fusiform gyrus, and decreased neural activation in the right posterior cingulate gyrus, right middle temporal gyrus, right paracentral lobule, and right inferior parietal gyrus relative to MDD patients.
CONCLUSION
Our meta-analysis suggests that PTSD and MDD share some similar patterns of brain activation, but also have distinct neural signatures. These findings contribute to our understanding of the potential neuropathology underlying these disorders and may inform the development of more targeted and effective treatment and intervention strategies. Moreover, these results may provide useful neuroimaging targets for the differential diagnosis of MDD and PTSD.
PubMed: 38942203
DOI: 10.1016/j.jad.2024.06.095 -
Neurotoxicology Jun 2024There is a propensity for synthetic cannabinoid abuse to spread worldwide. CP-55,940, a synthetic cannabinoid having the ability to activate both CB1 and CB2 receptors,...
There is a propensity for synthetic cannabinoid abuse to spread worldwide. CP-55,940, a synthetic cannabinoid having the ability to activate both CB1 and CB2 receptors, has been shown to induce cell death in neurons as well as other cells. Here we investigate molecular events underling the adverse effects of CP-55,940 on neuronal cells. Exposure of mouse neuroblastoma Neuro2a cells to 10-50µM CP-55,940 results in concentration-dependent cell death that is not accompanied by an induction of apoptosis. CP-55,940 also stimulates autophagy, but the stimulation is not followed by an increase in autophagic degradation. Transcriptome analysis using DNA microarray revealed the increased expression of genes for the cholesterol biosynthesis pathway that is associated with the activation of SREBP-2, the master transcriptional regulator of cholesterol biosynthesis. However, free cholesterol is localized mainly to cytoplasmic structures, although it is localized to the plasma membrane in healthy cells. Thus, cellular trafficking of cholesterol seems to be somewhat disrupted in CP-55,940 stimulated cells. These results show for the first time that CP-55,940 stimulates autophagy as well as cholesterol biosynthesis, although not all the processes involved in the cellular response to CP-55,940 seem to be complete in these cells.
PubMed: 38942151
DOI: 10.1016/j.neuro.2024.06.013 -
EBioMedicine Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC,...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC, different oncolytic viruses (OVs) are currently investigated in clinical trials. However, systematic comparisons of these different OVs in terms of efficacy against PDAC and biomarkers predicting therapeutic response are lacking.
METHODS
We screened fourteen patient-derived PDAC cultures which reflect the intra- and intertumoural heterogeneity of PDAC for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H-1PV. Live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays and titration of viral progeny were conducted. Transcriptome profiling was employed to identify potential predictive biomarkers for response to OV treatment.
FINDINGS
Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the classical molecular subtype, the quasi-mesenchymal or basal-like subtype of PDAC was found to be more sensitive to H-1PV, jin-3, and T-VEC. Generally, expression of viral entry receptors did not correlate with sensitivity to OV treatment, with one exception: Expression of Galectin-1 (LGALS1), a factor involved in H-1PV entry, positively correlated with H-1PV induced cell killing. Rather, cellular pathways controlling immunological, metabolic and proliferative signaling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas low cyclic GMP-AMP synthase (cGAS) expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures and cells overexpressing cGAS were found to be less sensitive to MV oncolysis.
INTERPRETATION
Considering the heterogeneity of PDAC and the complexity of biological therapies such as OVs, no single biomarker can explain the spectrum of response patterns. For selection of a particular OV, PDAC molecular subtype, ISG expression as well as activation of distinct signaling and metabolic pathways should be considered. Combination therapies can overcome resistance in specific constellations. Overall, oncolytic virotherapy is a viable treatment option for PDAC, which warrants further development. This study highlights the need for personalised treatment in OVT. By providing all primary data, this study provides a rich source and guidance for ongoing developments.
FUNDING
German National Science Foundation (Deutsche Forschungsgemeinschaft, DFG), German Cancer Aid (Deutsche Krebshilfe), German National Academic Scholarship Foundation (Studienstiftung des deutschen Volkes), Survival with Pancreatic Cancer Foundation.
PubMed: 38941955
DOI: 10.1016/j.ebiom.2024.105219 -
Immunobiology May 2024Ovarian cancer, a fatal gynecological malignancy, is primarily managed through surgery and chemotherapy. However, a significant challenge arises as patients frequently...
BACKGROUND
Ovarian cancer, a fatal gynecological malignancy, is primarily managed through surgery and chemotherapy. However, a significant challenge arises as patients frequently experience relapse due to chemotherapy resistance. This study delves into the complex functions and underlying mechanisms of macrophages in chemotherapy resistance in ovarian cancer.
METHOD
The single-cell transcriptome sequencing data of ovarian cancer with or without chemotherapy were analyzed. Then, corresponding cell types were identified, and macrophages were extracted from all cells. Following the standardized single-cell analysis using the Seurat package, 15 distinct macrophage clusters were found and differentially expressed genes among them were analyzed. Moreover, their association with chemotherapy resistance was explored through cell proportions and gene expression.
RESULT
In the single-cell transcriptomic analysis of ovarian cancer tissues before and after chemotherapy, the cellular proportion of CXCL5 macrophages, THBS1 macrophages, and MMP9 macrophages were significantly increased following chemotherapy. Further investigation revealed that these macrophage subpopulations upregulated the expression of multiple pro-tumorigenic angiogenic or invasive factors, in addition to CXCL5, THBS1, and MMP9, including CTSL, CXCL1, and CCL18. Finally, pathway enrichment analysis revealed the significant activation of signaling pathways, such as NOD-like receptor, MAPK, and TNF in these macrophage subpopulations, which provides direction for studying the mechanism of these subpopulations.
CONCLUSION
CXCL5, THBS1, and MMP9 macrophage subpopulations exhibit an increased cellular prevalence post-chemotherapy and pro-tumorigenic molecular expression profiles, suggesting a close association with chemoresistance in ovarian cancer. These findings contribute to our understanding of the roles and mechanisms of macrophages in ovarian cancer chemoresistance, providing a theoretical basis and direction for the development of therapies targeting macrophages in overcoming ovarian cancer chemoresistance.
PubMed: 38941863
DOI: 10.1016/j.imbio.2024.152811 -
Journal of Hazardous Materials Jun 2024Nanoplastics (NPs) interact with cooccurring chemicals and natural organic matter (NOM) in the environment, forming complexes that can change their bioavailability and...
Exacerbated interfacial impacts of nanoplastics and 6:2 chlorinated polyfluorinated ether sulfonate by natural organic matter in adult zebrafish: Evidence through histopathology, gut microbiota, and transcriptomic analysis.
Nanoplastics (NPs) interact with cooccurring chemicals and natural organic matter (NOM) in the environment, forming complexes that can change their bioavailability and interfacial toxicity in aquatic organisms. This study aims to elucidate the single and combined impacts of 21-day chronic exposure to low levels of polystyrene NPs (size 80 nm) at 1 mg/L and 6:2 chlorinated polyfluorinated ether sulfonate (Cl-PFAES or F53B) at 200 μg/L in the presence and absence of NOM (humic acid-HA and bovine serum albumin-BSA at 10 mg/L) in adult zebrafish (Danio rerio). Our findings through multiple bioassays, revealed that the mixture group (M), comprising of NPs, F53B, HA, and BSA, caused a higher level of toxicity compared to the single NPs (AN), single F53B (AF), and combined NPs+F53B (ANF) groups. The mixture exposure caused the highest level of vacuolization and nuclear condensation in hepatocytes, and most of the intestinal villi were fused and highly reduced in villi length and crypt depth. Further, the T-AOC levels were significantly lower (p < 0.05), while the MDA levels in the liver and intestine were significantly higher (p < 0.05) in the M group with downregulation of nfkbiaa, while upregulation of prkcda, csf1ra, and il1b apoptosis genes in the liver. Pairwise comparison of gut microbiota showed significantly higher (p < 0.05) abundances of various genera in the M group, including Gordonia, Methylobacterium, Tundrisphaera, GKS98, Pedomicrobium, Clostridium, Candidatus and Anaerobacillus, as well as higher abundance of genera including pathogenic strains, while control group showed higher abundance of probiotic genus ZOR0006 than exposed group (p < 0.01). The transcriptomic analysis revealed highest number of DEGs in the M group (2815), followed by the AN group (506) and ANF group (206) with the activation of relaxin signaling pathway-RSP (slc9a1, slc9a2) and AMP-activated protein kinase (AMPK) pathway (plin1), and suppression of the toll-like receptor (TLR) pathway (tlr4a, tlr2, tlr1), cytokine-cytokine receptor interaction (CCRI) pathway (tnfb, il21r1, il21, ifng1), and peroxisome proliferator-activated receptors (PPAR) pathway (pfkfb3). Overall, toxicity in the M group was higher, indicating that the HA and BSA elevated the interfacial impacts of NPs and F53B in adult zebrafish after chronic environmentally relevant exposure, implying the revisitation of the critical interaction of NOM with co-occurring chemicals and associated impacts.
PubMed: 38941840
DOI: 10.1016/j.jhazmat.2024.135038 -
Phytomedicine : International Journal... Jun 2024Neuropathic pain (NP) due to nerve injury, disrupts neural plasticity by triggering the release of inflammatory mediators. Alongside the hypothesis that...
BACKGROUND
Neuropathic pain (NP) due to nerve injury, disrupts neural plasticity by triggering the release of inflammatory mediators. Alongside the hypothesis that neuro-inflammation contributes to this disruption, Andrographolide (Andro), a traditional bioactive compound derived from Andrographis paniculata, has garnered attention for its potent anti-inflammatory properties. However, whether Andro could ameliorate NP by regulating neuroinflammation remains unknown.
PURPOSE
This study aimed to investigate whether and how Andro regulates neuroinflammation and alleviates NP.
METHODS
The analgesic effects of Andro on NP were evaluated using both the spinal nerve ligation (SNL) and formalin rat models. A combination of network pharmacology, RNA sequencing, and experimental validation was employed to elucidate the underlying mechanism behind Andro's analgesic effects. Additionally, various techniques such as functional ultrasound, immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR), patch clamp, and electron microscopy were employed to investigate the specific neural cell types, neural functions, and changes in neural plasticity influenced by Andro.
RESULTS
Network pharmacology analysis unveiled the crucial roles played by shared targets of Andro and pain in regulating pain-related inflammation, including microglia activation, neuroinflammation, immune modulation, and synaptic transmission. Furthermore, we confirmed Andro's superior efficacy in pain relief compared to the traditional analgesic drug, Gabapentin. In these models, Andro was observed to modulate the haemodynamic response triggered by SNL. Transcriptome analysis and molecular docking studies indicated the involvement of major histocompatibility complex class II (MHCII) genes (Db1, Da, and Bb). Electron microscopy revealed improvements in synaptic ultrastructure, and electrophysiological investigations showed a selective reduction in glutamatergic transmission in neuropathic rats after following Andro treatment. The integration of systems pharmacology analysis and biological validation collectively demonstrated that the mechanism of pain relief involves immune modulation, enhancement of synaptic plasticity, and precise regulation of excitatory neurotransmission.
CONCLUSION
In conclusion, this study has demonstrated that Andro, by targeting MHCII genes, may serve as a promising therapeutic candidate for neuropathic pain.
PubMed: 38941815
DOI: 10.1016/j.phymed.2024.155823