Role In Activation Research Articles

Transcription factor YY1 accelerates hepatic fibrosis development by activating NLRP3 inflammasome-mediated pyroptosis.

Hepatic fibrosis is the basis of multiple liver diseases and may eventually develop into hepatocellular carcinoma. Hepatic stellate cell (HSC) activation is a driving factor of hepatic fibrogenesis. In the liver microenvironment, liver cells and others play a crucial role in HSC activation. The liver tissues of CCl4-induced rats show excessive fibrosis, inflammation, and cell apoptosis. Yin Yang 1 (YY1) was highly expressed in hepatic fibrosis rats and TGF-β1-treated liver cells. In animal experiments, YY1 knockdown effectively attenuated CCl4-induced liver injury and pyroptosis-related IL-1β and IL-18 expression. In cellular experiments, NLRP3 inflammasome-mediated pyroptosis was activated by TGF-β1 treatment, while YY1 knockdown significantly inhibited the activation of the NLRP3 inflammasome, pyroptosis, and the secretion of IL-1β and IL-18. In addition, our data showed that TGF-β1-treated liver cell conditional medium markedly induced HSC activation, which was rescued by YY1 knockdown in liver cells. YY1 overexpression in liver cells contributed to the activation of TGF-β1-treated liver cell conditional medium in HSCs, however, this effect of YY1 was attenuated by NLRP3 inhibition. Overall, YY1 overexpression in liver cells contributed to HSC activation by facilitating IL-1β and IL-18 production via activating NLRP3 inflammasome-mediated pyroptosis, thus aggravating hepatic fibrogenesis. Our data indicate that YY1 may be a novel target for the treatment of hepatic fibrosis and associated liver diseases.

NOX-2 Inhibitors may be Potential Drug Candidates for the Management of COVID-19 Complications.

COVID-19 is an RNA virus that attacks the targeting organs, which express angiotensin- converting enzyme-2 (ACE-2), such as the lungs, heart, renal system, and gastrointestinal tract. The virus that enters the cell by endocytosis triggers ROS production within the confines of endosomes via a NOX-2 containing NADPH-oxidase. Various isoforms of NADPH oxidase are expressed in airways and alveolar epithelial cells, endothelial and vascular smooth muscle cells, and inflammatory cells, such as alveolar macrophages, monocytes, neutrophils, and Tlymphocytes. The key NOX isoform expressed in macrophages and neutrophils is the NOX-2 oxidase, whereas, in airways and alveolar epithelial cells, it appears to be NOX-1 and NOX-2. The respiratory RNA viruses induce NOX-2-mediated ROS production in the endosomes of alveolar macrophages. The mitochondrial and NADPH oxidase (NOX) generated ROS can enhance TGF-β signaling to promote fibrosis of the lungs. The endothelium-derived ROS and platelet-derived ROS, due to activation of the NADPH-oxidase enzyme, play a crucial role in platelet activation. It has been observed that NOX-2 is generally activated in COVID-19 patients. The post-COVID complications like pulmonary fibrosis and platelet aggregation may be due to the activation of NOX-2. NOX-2 inhibitors may be a useful drug candidate to prevent COVID-19 complications like pulmonary fibrosis and platelet aggregation.

Signalling Pathways Involved in Microglial Activation in Alzheimer's Disease and Potential Neuroprotective Role of Phytoconstituents.

Alzheimer's disease (AD) is a commonly reported neurodegenerative disorder associated with dementia and cognitive impairment. The pathophysiology of AD comprises Aβ, hyperphosphorylated tau protein formation, abrupt cholinergic cascade, oxidative stress, neuronal apoptosis, and neuroinflammation. Recent findings have established the profound role of immunological dysfunction and microglial activation in the pathogenesis of AD. Microglial activation is a multifactorial cascade encompassing various signalling molecules and pathways such as Nrf2/NLRP3/NF-kB/p38 MAPKs/ GSK-3β. Additionally, deposited Aβ or tau protein triggers microglial activation and accelerates its pathogenesis. Currently, the FDA-approved therapeutic regimens are based on the modulation of the cholinergic system, and recently, one more drug, aducanumab, has been approved by the FDA. On the one hand, these drugs only offer symptomatic relief and not a cure for AD. Additionally, no targeted-based microglial medicines are available for treating and managing AD. On the other hand, various natural products have been explored for the possible anti-Alzheimer effect via targeting microglial activation or different targets of microglial activation. Therefore, the present review focuses on exploring the mechanism and associated signalling related to microglial activation and a detailed description of various natural products that have previously been reported with anti-Alzheimer's effect via mitigation of microglial activation. Additionally, we have discussed the various patents and clinical trials related to managing and treating AD.

In silico approaches of gandarusa (Justicia gendarussa Burm. f.) potential for osteoporosis prevention via EGF pathway

Context: On a cellular level, osteoporosis is a metabolic bone disease caused by osteoclastic bone resorption that is not offset by osteoblastic bone synthesis. This increases the risk of fractures by making bones weak and brittle. The selective inactivation of the epidermal growth factor receptor (EGFR) in osteoblast lineage cells demonstrated that EGFR promotes bone formation by increasing the number of mesenchymal progenitors. Active compounds of gandarusa (Justicia gendarussa Burm. f.) are potentially playing crucial roles in EGFR activation. Aims: To evaluate the potential of J. gendarussa for osteoporosis prevention via EGF pathway in silico. Methods: A GC-MS approach was used to screen the active compounds from 70 and 95% methanol extraction, which was continued with molecular docking analysis by PyRx v0.8. The visualization and amino acid interactions were also revealed using Discovery Studio software R17. ADME analysis was performed using the SwissADME webserver to consider whether the best compound could be classified as a drug following Lipinsky rule’s of five. Results: The top five compounds with high binding affinity were selected from a total of 33 active compounds detected. One compound, namely eslicarbazepine, has a -6.7 kcal/mol affinity score and passes the threshold for drugs bioavailability, supported by the data of MW compounds 254.28 kDa, low rotatable bonds 1 bond, hydrogen bond acceptors and donors (2), high GI absorption, and ability to permeant to blood-brain barrier system. Conclusions: This finding added new insight into J. gendarussa extract potential as anti-osteoporosis in humans. Nevertheless, in vitro and in vivo experiments are necessary to confirm the potential.

A 21-bp deletion in the complement regulator CD55 promotor region is associated with multifocal motor neuropathy and its disease course.

To further substantiate the role of antibody-mediated complement activation in multifocal motor neuropathy (MMN) immunopathology, we investigated the distribution of promotor polymorphisms of genes encoding the membrane-bound complement regulators CD46, CD55, and CD59 in patients with MMN and controls, and evaluated their association with disease course. We used Sanger sequencing to genotype five common polymorphisms in the promotor regions of CD46, CD55, and CD59 in 133 patients with MMN and 380 controls. We correlated each polymorphism to clinical parameters. The genotype frequencies of rs28371582, a 21-bp deletion in the CD55 promotor region, were altered in patients with MMN as compared to controls (p .009; Del/Del genotype 16.8% vs. 7.7%, p .005, odds ratio: 2.43 [1.27-4.58]), and patients carrying this deletion had a more favorable disease course (mean difference 0.26 Medical Research Council [MRC] points/year; 95% confidence interval [CI]: 0.040-0.490, p .019). The presence of CD59 rs141385724 was associated with less severe pre-diagnostic disease course (mean difference 0.940 MRC point/year; 95% CI: 0.083-1.80, p .032). MMN susceptibility is associated with a 21-bp deletion in the CD55 promotor region (rs2871582), which is associated with lower CD55 expression. Patients carrying this deletion may have a more favorable long-term disease outcome. Taken together, these results point out the relevance of the pre-C5 level of the complement cascade in the inflammatory processes underlying MMN.

Abstract 6805: CD81 and CD82 in tumor infiltrating lymphocytes within the NSCLC tumor microenvironment play a crucial role in T cell activation and cytokine production

Abstract Background: The role of tetraspanins, particularly CD81 and CD82, in T cell activation, shedding light on their contribution to anti-tumor effects in the tumor microenvironment. The findings provide insights for potential applications of these tetraspanins in immunotherapy. Method: The study employed 10x Genomics for single-cell RNA sequencing and processed the data using Seurat. It focused on the tumor microenvironment, categorizing cell types, especially TIL subsets. T cells were sorted based on CD81 and CD82 expression and activated, and their activation markers and cytokine production were analyzed. Bulk RNA sequencing was performed on both sorted T cells and tumor samples, and the TCR repertoire was examined. Cytotoxicity of CD81 and CD82 transduced cells was measured using the xCELLigence RTCA HT system. Result: Tetraspanins have been linked to T cell co-stimulation and activation, with CD81 and CD82 playing a significant role in TCR signaling and activation. Single-cell and bulk RNA sequencing data from lung cancer patients reveal high expression of CD81 and CD82 in the tumor microenvironment, especially in T cells, correlating with T cell activation and cytokine production. In vitro experiments confirm the activation and effector cytokines, especially IFN-γ, TNF-α, and IL-2, producing potential of T cells expressing CD81 and CD82, suggesting their importance in anti-cancer immunity. Overexpression of CD81 and CD82 enhances T cell cytotoxicity against cancer cells, further supporting their role in T cell function. Despite some limitations, these findings shed light on the significant impact of tetraspanins in modulating immune responses, particularly in the context of cancer immunotherapy. Conclusion: We report that CD81 and CD82 serve as specific markers for activated T cells within the TME. CD81 and CD82 are correlated with the activation and regulation of T cells, and they may also mediate the regulation of relevant cytokines. Overall, our findings provide better insights into the molecular mechanisms regulating TILs present in the TME of non-small cell carcinoma and propose CD81 and CD82 as associated markers. These discoveries could serve as a foundation for the development of new immunotherapies targeting the TME. Citation Format: Kwangmin Na, Seul Lee, Dong Kwon Kim, Young Seob Kim, Joon Yeon Hwang, Seong-san Kang, Sujeong Baek, Chai Young Lee, Seung Min Yang, Yu Jin Han, Mi hyun Kim, Heekyung Han, Youngtaek Kim, Jae Hwan Kim, Seunghyun Jeon, Youngseon Byeon, Jii Bum Lee, Sun Min Lim, Min Hee Hong, Kyoung-Ho Pyo, Byoung Chul Cho. CD81 and CD82 in tumor infiltrating lymphocytes within the NSCLC tumor microenvironment play a crucial role in T cell activation and cytokine production [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6805.

Abstract 1941: AXL activation promotes adaptive resistance to KRAS-G12C inhibitors in KRAS-G12C-mutated non-small cell lung cancer

Abstract Background: KRAS is the most frequent targetable oncogene in non-small cell lung cancer (NSCLC). Recently, novel KRAS inhibitor have been clinically developed for treatment of KRAS G12C-mutated NSCLC patients. However, it is difficult to achieve complete remission of tumor. Therefore, the optimal combined therapeutic intervention with KRAS G12C inhibitors has a potentially crucial role in the clinical outcomes of patients. In this study, we focused on the mechanisms underlying adaptive resistance to KRAS G12C inhibitors and therapeutic strategies required to overcome them. Methods: We used KRAS G12C-mutated NSCLC cell lines to evaluate the adaptive response to KRAS G12C inhibitors in vitro and in vivo. We also investigated the correlation between AXL expression in pre-treated tumors and clinical outcomes with sotorasib for KRAS G12C-mutated NSCLC patients. Results: We revealed that AXL signaling leads to the adaptive resistance to KRAS G12C inhibitors in KRAS-G12C mutated NSCLC, activation of which is induced by GAS6 production via transcriptional coactivator YAP. AXL inhibition reduced the viability of AXL-overexpressing KRAS G12C-mutated lung cancer cells by enhancing KRAS G12C inhibition-induced apoptosis. In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or the combination after acquired resistance to KRAS G12C inhibitor. AXL was highly expressed in clinical specimens of KRAS G12C-mutated lung cancers and its high expression was associated with a low treatment response to sotorasib. Conclusions: These results indicated pivotal roles for AXL activation and its inhibition in the intrinsic resistance to KRAS G12C inhibitor. Citation Format: Kenji Morimoto, Tadaaki Yamada, Soichi Hirai, Yuki Katayama, Kei Kunimasa, Takaaki Sasaki, Makoto Nishida, Satoshi Watanabe, Shinsuke Shiotsu, Hisanori Uehara, Koichi Takayama. AXL activation promotes adaptive resistance to KRAS-G12C inhibitors in KRAS-G12C-mutated non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1941.

O189: Exploring the polyclonal origins of intestinal tumours

Abstract Introduction Some reports have shown that a proportion of intestinal tumours in the human colorectal cancer (CRC) predisposition syndrome Familial Adenomatous Polyposis (FAP) may have a multi-ancestral structure, challenging the widely-held monoclonal theory of tumour initiation. The nature of these polyclonal tumours and the reasons for their existence have not yet been elucidated. Methods Intestinal tumorigenesis was promoted through chemical mutagenesis in Villin-CreERT2-Apcfl/+ mice containing a multicolour reporter. The clonal status of tumours was determined with confocal microscopy. Targeted cancer driver sequencing was performed to determine if certain driver mutations were associated with monoclonal or polyclonal routes of tumour formation. Finally, transcriptomic analysis was performed to identify differentially expressed pathways. Results Confocal imaging reveals that more than 40% of tumours are heterotypic, and therefore polyclonal. Transcriptomic profiling of clones within these tumours demonstrates a non-cell autonomous interplay between Myc and Ras pathways, suggestive of oncogenic cooperation between adjacent clones. Strikingly, sequencing reveals that the nature of the Apc mutation dictates clonal architecture. Using a large publicly available dataset of sporadic CRCs, these mutational differences are confirmed, suggesting a role for differential Wnt activation in tumour initiation. Conclusions Taken together, these data suggest that a significant proportion of intestinal tumours arise through clonal cooperation, and that early RAS/MAPK pathway activation may obviate the need for this. Clonal cooperation appears to be at play not just in FAP but also in sporadic CRCs. Uncovering this mechanism may pave the way for therapeutics aimed at reducing tumour burden in patients with FAP.

High-Valent Copper Catalysis Enables Regioselective Fluoroarylation of Gem-Difluorinated Cyclopropanes.

Transition-metal (TM) catalyzed reaction of gem-difluorinated cyclopropanes (gem-DFCPs) has drawn much attention recently. The reaction generally occurs via the activation of the distal C─C bond in gem-DFCPs by a low-valent TM through oxidative addition, eventually producing mono-fluoro olefins as the coupling products. However, achieving regioselective activation of the proximal C─C bond in gem-DFCPs that overcomes the intrinsic reactivity via TM catalysis remains elusive. Here, a new reaction mode of gem-DFCPs enabled by high-valent copper catalysis, which allows exclusive activation of the congested proximal C─C bond is presented. The reaction that achieves fluoroarylation of gem-DFCPs uses NFSI (N-fluorobenzenesulfonimide) as electrophilic fluoro reagent and arenes as the C─H nucleophiles, enabling the synthesis of diverse CF3-containing scaffolds. It is proposed that a high-valent copper species plays an important role in the regioselective activation of the proximal C─C bond possibly via a σ-bond metathesis.

Activation of Piezo1 increases the sensitivity of breast cancer to hyperthermia therapy.

Photothermal therapy (PTT) of nanomaterials is an emerging novel therapeutic strategy for breast cancer. However, there exists an urgent need for appropriate strategies to enhance the antitumor efficacy of PTT and minimize damage to surrounding normal tissues. Piezo1 might be a promising novel photothermal therapeutic target for breast cancer. This study aims to explore the potential role of Piezo1 activation in the hyperthermia therapy of breast cancer cells and investigate the underlying mechanisms. Results showed that the specific agonist of Piezo1 ion channel (Yoda1) aggravated the cell death of breast cancer cells triggered by heat stress in vitro. Reactive oxygen species (ROS) production was significantly increased following heat stress, and Yoda1 exacerbated the rise in ROS release. GSK2795039, an inhibitor of NADPH oxidase 2 (NOX2), reversed the Yoda1-mediated aggravation of cellular injury and ROS generation after heat stress. The in vivo experiments demonstrate the well photothermal conversion efficiency of TiCN under the 1,064 nm laser irradiation, and Yoda1 increases the sensitivity of breast tumors to PTT in the presence of TiCN. Our study reveals that Piezo1 activation might serve as a photothermal sensitizer for PTT, which may develop as a promising therapeutic strategy for breast cancer.

STUB1 increases adiponectin expression by inducing ubiquitination and degradation of NR2F2, thereby reducing hepatic stellate cell activation and alleviating non-alcoholic fatty liver disease

BackgroundAdiponectin (APN) has exhibited ameliorating effects on non-alcoholic fatty liver disease (NAFLD). This study investigates the roles of APN and its regulatory molecules in hepatic stellate cell (HSC) activation and the progression of NAFLD. MethodsMice were subjected to a high-fat diet (HFD) to establish NAFLD models. Liver tissue was examined for lipid metabolism, fibrosis, and inflammation. Mouse 3T3-L1 adipocytes were exposed to palmitic acid (PA) to mimic a high-fat environment. The conditioned medium (CM) from adipocytes was collected for the culture of isolated mouse HSCs. Gain- or loss-of-function studies of APN, nuclear receptor subfamily 2 group F member 2 (NR2F2), and STIP1 homology and U-box containing protein 1 (STUB1) were performed to analyze their roles in NAFLD and HSC activation in vivo and in vitro. ResultsAPN expression was poorly expressed in HFD-fed mice and PA-treated 3T3-L1 adipocytes, which was attributed to the transcription inhibition mediated by NR2F2. Silencing of NR2F2 restored the APN expression, ameliorating liver steatosis, fibrosis, and inflammatory cytokine infiltration in mouse livers and reducing HSC activation. Similarly, the NR2F2 silencing condition reduced HSC activation in vitro. However, these effects were counteracted by artificial APN silencing. STUB1 facilitated the ubiquitination and protein degradation of NR2F2, and its upregulation mitigated NAFLD-like symptoms in mice and HSC activation, effects reversed by the NR2F2 overexpression. ConclusionThis study highlights the role of STUB1 in reducing HSC activation and alleviating NAFLD by attenuating NR2F2-mediated transcriptional repression of APN.

Complement C3 From Astrocytes Plays Significant Roles in Sustained Activation of Microglia and Cognitive Dysfunctions Triggered by Systemic Inflammation After Laparotomy in Adult Male Mice

Aberrant activation of complement cascades plays an important role in the progress of neurological disorders. Complement C3, the central complement component, has been implicated in synaptic loss and cognitive impairment. Recent study has shown that wound injury-induced systemic inflammation can trigger the increase of C3 in the brain. Our previous studies have demonstrated that laparotomy-triggered systemic inflammation could induce neuroinflammation and cognitive dysfunctions. Furthermore, sustained activation of microglia was observed even 14 days after laparotomy, while most of cytokines had returned to basal levels rapidly at the earlier time point. Although we have demonstrated that anti-inflammatory intervention successfully attenuated cognitive dysfunction by preventing increase of cytokines and activation of microglia, how sustained activation of microglia and cognitive dysfunction occur is still a mystery. In this study, we investigated the role of C3 in mediating activation of microglia and cognitive dysfunction by using laparotomy in adult male mouse only as the experimental model of systemic inflammation and AAV9-C3shRNA. Our data observed that laparotomy induced neurotoxic reactive astrocytes with an increase of C3 in the hippocampus. Furthermore, inhibition of C3 by AAV9-C3shRNA prevented synaptic engulfment by microglia and attenuated cognitive dysfunctions after laparotomy. Inhibition of C3 did not modulate activation of astrocytes and expression of various cytokines. Current findings demonstrated that C3 plays significant roles in sustained activation of microglia and cognitive dysfunctions, which suggests that C3 is the valuable molecule target to attenuate in neurological conditions characterised by neuroinflammation and cognitive dysfunction.Graphical

Bergapten inhibits airway inflammation and MRGPRX2-mediated mast cells activation by targeting NR4A1

Asthma is a serious global health problem affecting 300 million persons around the world. Mast cells (MCs) play a major role in airway hyperresponsiveness (AHR) and inflammation in asthma, their exact effector mechanisms remain unclear. Here, we aim to investigate the inhibitory effect of Bergapten (BER) on MRGPRX2-mediated MCs activation through asthma model.Mouse model of asthma was established to examine the anti-asthmatic effects of BER. Calcium (Ca2+) influx, β-hexosaminidase and histamine release were used to assess MCs degranulation in vitro. RNA-Seq technique was conducted to study the gene expression profile. RT-PCR and Western Blotting were performed to examine targeting molecules expression. BER inhibited AHR, inflammation, mucous secretion, collagen deposition and lung MCs activation in asthma model. BER dramatically reduced levels of IL4, IL-5, and IL-13 in bronchoalveolar lavage fluid (BALF), as well as inflammatory cells. BER also reduced serum IgE levels. Pretreatment MCs with BER inhibited substance P (SP)-induced Ca2+ influx, degranulation and cytokines release from MCs. BER also reduced the phosphorylation levels of PKC, PLC, IP3R, AKT and ERK, which were induced by SP. Furthermore, RNA-seq analysis showed that SP up-regulated 68 genes in MCs, while were reversed by BER. Among these 68 genes, SP up-regulated NR4A1 expression, and this effect was inhibited by BER. Meanwhile, knockdown of NR4A1 significantly attenuated SP-induced MCs degranulation. In conclusion, NR4A1 plays a major role in MRGPRX2-mediated MCs activation, BER inhibited AHR and inflammation in asthmatic model by inhibiting MCs activation through MRGPRX2-NR4A1 pathway.

Adult-Onset Still's Disease (AOSD): Advances in Understanding Pathophysiology, Genetics and Emerging Treatment Options.

Adult-onset Still's disease (AOSD) is a multisystemic complex disorder clinically characterised by episodes of spiking fever, evanescent rash, polyarthritis or diffuse arthralgias; multiorgan involvement may develop according to the hyper-inflammatory extent. The pathogenesis of AOSD is not completely recognised. The central role of macrophage activation, which results in T helper 1 (Th1) cell cytokine activation, is well established. Pro-inflammatory cytokines such as interleukin (IL)-1, IL-6 and IL-18 play a fundamental role in disease onset and progression. The disease may develop in both children and adults with overlapping clinical features, and although several subsets depending on the clinical manifestations and the cytokines expressed have been identified, the dichotomy between systemic juvenile idiopathic arthritis (sJIA) and AOSD nowadays has been overcome, and the pathology is considered a disease continuum between ages. Various therapeutic approaches have been evaluated thus far, and different compounds are under assessment for AOSD treatment. Historically, glucocorticoids have been employed for treating systemic manifestations of Still's disease, while conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) demonstrated efficacy in controlling the articular manifestations. Currently, biological (b) DMARDs are widely employed; IL-1 inhibitors such as anakinra and canakinumab have proven to have high efficacy and an excellent safety profile and the anti-IL-6 tocilizumab is approved for sJIA, with several trials and longitudinal studies confirming its efficacy and safety. Moreover, in the light of the 'window of opportunity', new evidence showed that the earlier these treatments are initiated, the sooner clinical inactivity can be achieved. Other treatment options are being considered since several molecules involved in the disease pathophysiology can be targeted through various mechanisms. This review will provide a broad overview of AOSD pathophysiology, insights into specific organ manifestations and the currently available treatments with the identification of potential therapeutic targets involved in AOSD pathogenesis will be outlined.

The central role of mitochondrial metabolism in hepatic steatosis

Mitochondria are present in all mammalian cells except matured red blood cells. Mitochondria consist of several metabolic pathways for glucose, fatty acids, amino acids, and bioenergetic pathways for ATP synthesis, membrane potential, and reactive oxygen production. In the liver, hepatic mitochondria play a key role in hepatic steatosis because mitochondrial metabolism produces acetyl-CoA which is the building block for synthesis of lipids and cholesterol. Mitochondria inner membrane is impermeable of metabolites, reducing equivalents, and small molecules such as phosphate, and sulfate. Thus, mitochondrial shuttles and carriers function as the routes of influx and efflux of these metabolites and molecules across the inner membrane. The signal regulation of these shuttles and mitochondrial enzymes could play a key role in coordinating the mitochondrial metabolism to adapt the cytosolic part of metabolic pathways in liver metabolic stress. Intriguingly, the interaction of mitochondria protein SH3 domain-binding protein 5 (SAB/SH3BP5) and c-Jun N-terminal kinase (JNK) was found as a pivotal role in sustained activation of JNK and phosphorylated-JNK (P-JNK) mediated activation of lipogenic pathway in nutritional excess. Knockout or knockdown of SAB prevented or reversed the hepatic steatosis, inflammation, and fibrosis, and improved metabolic intolerance and energy expenditure. Moreover, blocking the SAB peptide prevents palmitic acid-induced P-JNK interaction with SAB and inhibition of mitochondrial bioenergetics, implying the P-JNK effect on mitochondrial metabolism. This review focuses on the flow of mitochondrial metabolites in metabolic stress conditions and the contribution of mitochondria and mitochondrial stress signals in hepatic steatosis.

Oxygen-Activated Boron Nitride for Selective Photocatalytic Coupling of Methanol to Ethylene Glycol.

The controllable photocatalytic C-C coupling of methanol to produce ethylene glycol (EG) is a highly desirable but challenging objective for replacing the current energy-intensive thermocatalytic process. Here, we develop a metal-free porous boron nitride catalyst that demonstrates exceptional selectivity in the photocatalytic production of EG from methanol under mild conditions. Comprehensive experiments and calculations are conducted to thoroughly investigate the reaction mechanism, revealing that the OB3 unit in the porous BN plays a critical role in the preferential activation of C-H bond in methanol to form ⋅CH2OH via a concerted proton-electron transfer mechanism. More prominent energy barriers are observed for the further dehydrogenation of the ⋅CH2OH intermediate on the OB3 unit, inhibiting the formation of some other by-products during the catalytic process. Additionally, a small downhill energy barrier for the coupling of ⋅CH2OH in the OB3 unit promotes the selective generation of EG. This study provides valuable insights into the underlying mechanisms and can serve as a guide for the design and optimization of photocatalysts for efficient and selective EG production under mild conditions.

Oxygen‐Activated Boron Nitride for Selective Photocatalytic Coupling of Methanol to Ethylene Glycol

AbstractThe controllable photocatalytic C−C coupling of methanol to produce ethylene glycol (EG) is a highly desirable but challenging objective for replacing the current energy‐intensive thermocatalytic process. Here, we develop a metal‐free porous boron nitride catalyst that demonstrates exceptional selectivity in the photocatalytic production of EG from methanol under mild conditions. Comprehensive experiments and calculations are conducted to thoroughly investigate the reaction mechanism, revealing that the OB3 unit in the porous BN plays a critical role in the preferential activation of C−H bond in methanol to form ⋅CH2OH via a concerted proton‐electron transfer mechanism. More prominent energy barriers are observed for the further dehydrogenation of the ⋅CH2OH intermediate on the OB3 unit, inhibiting the formation of some other by‐products during the catalytic process. Additionally, a small downhill energy barrier for the coupling of ⋅CH2OH in the OB3 unit promotes the selective generation of EG. This study provides valuable insights into the underlying mechanisms and can serve as a guide for the design and optimization of photocatalysts for efficient and selective EG production under mild conditions.

Essential roles of ferric reductase-like proteins in growth, development, stress response, and virulence of the filamentous entomopathogenic fungus Beauveria bassiana

In yeasts, ferric reductase catalyzes reduction of ferric ion to ferrous form, which is essential for the reductive iron assimilation system. However, the physiological roles of ferric reductases remain largely unknown in the filamentous fungi. In this study, genome-wide annotation revealed thirteen ferric reductase-like (Fre) proteins in the filamentous insect pathogenic fungus Beauveria bassiana, and all their functions were genetically characterized. Ferric reductase family proteins exhibit different sub-cellular distributions (e.g., cell periphery and vacuole), which was due to divergent domain architectures. Fre proteins had a synergistic effect on fungal virulence, which was ascribed to their distinct functions in different physiologies. Ten Fre proteins were not involved in reduction of ferric ion in submerged mycelia, but most proteins contributed to blastospore development. Only two Fre proteins significantly contributed to B. bassiana vegetative growth under the chemical-induced iron starvation, but most Fre proteins were involved in resistance to osmotic and oxidative stresses. Notably, a bZIP-type transcription factor HapX bound to the promoter regions of all FRE genes in B. bassiana, and displayed varying roles in the transcription activation of these genes. This study reveals the important role of BbFre family proteins in development, stress response, and insect pathogenicity, as well as their distinctive role in the absorption of ferric iron from the environment.

UPF1 ATPase autoinhibition and activation modulate RNA binding kinetics and NMD efficiency.

The RNA helicase UPF1 interacts with mRNAs, mRNA decay machinery, and the terminating ribosome to promote nonsense-mediated mRNA decay (NMD). Structural and biochemical data have revealed that UPF1 exists in an enzymatically autoinhibited 'closed' state. Upon binding the NMD protein UPF2, UPF1 undergoes an extensive conformational change into a more enzymatically active 'open' state, which exhibits enhanced ATPase and helicase activity. However, mechanically deficient UPF1 mutants (i.e. poorly processive, slow, and mechanochemically uncoupled) can support efficient NMD, bringing into question the roles of UPF1 enzymatic autoinhibition and activation in NMD. Here, we identify two additional important features of the activated open state: slower RNA binding kinetics and enhanced ATP-stimulated RNA dissociation kinetics. Computational modeling based on empirical measurements of UPF1, UPF2 and RNA interaction kinetics predicts that the majority of UPF1-RNA binding and dissociation events in cells occur independently of UPF2 binding. We find that UPF1 mutants with either reduced or accelerated dissociation from RNA have NMD defects, whereas UPF1 mutants that are more dependent on UPF2 for catalytic activity remain active on well-established NMD targets. These findings support a model in which the kinetics of UPF1-mRNA interactions are important determinants of cellular NMD efficiency.

Blocking cerebral lymphatic system reduces central and peripheral inflammatory response in ischemic stroke

Reduced blood supply to the brain activates the intracranial inflammatory response, a key contributor to secondary brain damage in ischemic stroke. Post-stroke, activation of peripheral immune cells leads to systemic inflammatory responses. Usingin vivo approaches, we investigated meningeal lymphatics’ role in central immune cell infiltration and peripheral immune cell activation. The bilateral deep cervical lymph nodes (dCLNs) were removed 7 days before right middle cerebral artery occlusion in Sprague Dawley (SD) rats. At 3, 24, and 72 h post-intervention, brain immune cell infiltration and microglial and astrocyte activation were measured, while immune cells were classified in the spleen and blood. Inflammatory factor levels in peripheral blood were analyzed. Simultaneously, reverse verification was conducted by injecting AAV-vascular endothelial growth factor C (AAV-VEGFC) adenovirus into the lateral ventricle 14 days before middle cerebral artery occlusion (MCAO) induction to enhance meningeal lymph function. Blocking meningeal LVs in MCAO rats significantly reduced infarct area and infiltration, and inhibited microglia and pro-inflammatory astrocytes activation. After removing dCLNs, CD4+ T lymphocytes, CD8+ T lymphocytes, B lymphocytes, macrophages, and neutrophils in the spleen and blood of MCAO rats decreased significantly at different time points. The levels of inflammatory factors IL-6, IL-10, IL-1β, and TNF-α in plasma decreased significantly. Tests confirmed the results, and AAV-VEGFC-induced MCAO rats provided reverse validation.