Immunological Mechanisms behind Anti-PD-1/PD-L1 Immune Checkpoint Blockade: Intratumoral Reinvigoration or Systemic Induction?

Anti-PD-1/PD-L1 immune checkpoint blockade (ICB) has been widely used to treat many types of cancer. It is well established that PD-L1 expressing cancer cells could directly inhibit the cytotoxicity of PD-1+ T cells via PD-L1-PD-1 interaction. However, histological quantification of intratumoral PD-L1 expression provides limited predictive value and PD-L1 negative patients could still benefit from ICB treatment. Therefore, the current major clinical challenges are low objective response rate and unclear immunological mechanisms behind responding vs. non-responding patients. Here, we review recent studies highlighting the importance of longitudinal pre- and post-ICB treatment on patients with various types of solid tumor to elucidate the mechanisms behind ICB treatment. On one hand, ICB induces changes in the tumor microenvironment by reinvigorating intratumoral PD-1+ exhausted T cells ("releasing the brakes"). On the other hand, ICB can also affect systemic antitumor immunity in the tumor-draining lymph node to induce priming/activation of cancer specific T cells, which is evident by T cell clonal expansion/replacement in peripheral blood. These studies reveal that ICB treatment not only acts on the tumor microenvironment ("battlefield") but also acts on immune organs ("training camp") of patients with solid tumors. A deeper understanding of the immunological mechanisms behind ICB treatment will pave the way for further improvements in clinical response.

Regulation of lipid metabolism by E3 ubiquitin ligases in lipid-associated metabolic diseases.

Previous studies have progressively elucidated the involvement of E3 ubiquitin (Ub) ligases in regulating lipid metabolism. Ubiquitination, facilitated by E3 Ub ligases, modifies critical enzymes in lipid metabolism, enabling them to respond to specific signals. In this review, we aim to present a comprehensive analysis of the role of E3 Ub ligases in lipid metabolism, which includes lipid synthesis and lipolysis, and their influence on cellular lipid homeostasis through the modulation of lipid uptake and efflux. Furthermore, it explores how the ubiquitination process governs the degradation or activation of pivotal enzymes, thereby regulating lipid metabolism at the transcriptional level. Perturbations in lipid metabolism have been implicated in various diseases, including hepatic lipid metabolism disorders, atherosclerosis, diabetes, and cancer. Therefore, this review focuses on the association between E3 Ub ligases and lipid metabolism in lipid-related diseases, highlighting enzymes critically involved in lipid synthesis and catabolism, transcriptional regulators, lipid uptake translocators, and transporters. Overall, this review aims to identify gaps in current knowledge, highlight areas requiring further research, offer potential targeted therapeutic approaches, and provide a comprehensive outlook on clinical conditions associated with lipid metabolic diseases.

Esculin inhibits hepatic stellate cell activation and CCl4-induced liver fibrosis by activating the Nrf2/GPX4 signaling pathway.

BACKGROUND: Liver fibrosis (LF) is a pathological process of the liver that threatens human health. Currently, effective treatments are still lacking. Esculin, a prominent constituent found in the Fraxinus rhynchophylla. (bark), Aesculus hippocastanum. (bark), and Cichorium intybus. (herb), has been shown to possess significant anti-inflammatory, antioxidant, and antibacterial properties. However, to date, there have been no studies investigating its potential efficacy in the treatment of LF. OBJECTIVE: The study aims to investigate the therapeutic effect of esculin on LF and elucidate its potential molecular mechanism. METHODS: Carbon tetrachloride (CCl4) was injected intraperitoneally to induce LF in mice, and transforming growth factor ß1 (TGF-ß1) was injected to induce LX-2 cells to investigate the improvement effect of esculin on LF. Kit, histopathological staining, immunohistochemistry (IHC), immunofluorescence (IF), polymerase chain reaction (PCR), and western blot (WB) were used to detect the expression of fiber markers and nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway in liver tissue and LX-2 cells. Finally, molecular docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) were used to verify the targeting between Nrf2 and esculin. RESULTS: Esculin significantly inhibited CCl4-induced hepatic fibrosis and inflammation in mice. This was evidenced by the improvement of liver function indexes, fibrosis indicators, and histopathology. Additionally, esculin treatment prominently reduced the levels of pro-inflammatory factors, oxidative stress, and liver Fe2+ in CCl4-induced mice. In vitro studies also showed that esculin treatment significantly inhibited TGF-ß1-induced LX-2 cell activation and decreased alpha-smooth muscle actin (α-SMA) and collagen I expression. Mechanism experiments proved that esculin can activate the Nrf2/GPX4 signaling pathway and inhibit liver ferroptosis. However, when LX-2 cells were treated with the Nrf2 inhibitor (ML385), the therapeutic effect of esculin significantly decreased. CONCLUSION: This study is the first to demonstrate that esculin is a potential natural active ingredient in the treatment of LF, which can inhibit the activation of hepatic stellate cells (HSC) and improve LF. Its therapeutic effect is related to the activation of the Nrf2/GPX4 signaling pathway.

ANXA3 interference inactivates ERK/ELK1 pathway to mitigate inflammation and apoptosis in sepsis-associated acute lung injury.

Acute lung injury (ALI) is a prevailing and deadly complication of sepsis coupled with increasing incidence and fatality rate. Annexin A3 (ANXA3) has been unraveled to be upregulated during sepsis. This study purposed to assess the role and the mechanism of ANXA3 in sepsis-induced ALI. After the construction of mouse model of sepsis, the pathological changes of mice lung tissues were estimated by H&E staining. ANXA3 expression in mice lung tissues and serum was examined. The degree of pulmonary edema and the levels of inflammatory factors in bronchoalveolar lavage fluid (BALF) were analyzed. In lipopolysaccharide (LPS)-induced mouse ALI model in vitro, CCK-8 assay measured cell viability and flow cytometry analysis detected cell apoptosis. Besides, ELISA assay detected the release of inflammatory cytokines. Western blot analyzed the expression of proteins associated with inflammation, apoptosis and extracellular-signal-regulated kinase (ERK)/ETS-like gene 1 (ELK1) signaling. Results revealed that ANXA3 was overexpressed in the lung tissues and serum of septic mice. Following the knockdown of ANXA3, sepsis-induced lung injury was alleviated, manifested as reduced lung edema, decreased inflammatory cell infiltration and inhibited cell apoptosis. Additionally, ANXA3 silence blocked ERK/ELK1 signaling both in sepsis mouse models and in vitro model of ALI induced by lipopolysaccharide (LPS). Moreover, the inhibitory effects of ANXA3 silencing on ERK/ELK1 signaling activation, the viability damage, inflammation and apoptosis in LPS-induced mouse ALI model in vitro were partially reversed by ERK activator. Collectively, depletion of ANXA3 exerted suppressive effects on the inflammation and apoptosis in sepsis-induced ALI through blocking ERK/ELK1 signaling.

Dubosiella newyorkensis modulates immune tolerance in colitis via the L-lysine-activated AhR-IDO1-Kyn pathway.

Commensal bacteria generate immensely diverse active metabolites to maintain gut homeostasis, however their fundamental role in establishing an immunotolerogenic microenvironment in the intestinal tract remains obscure. Here, we demonstrate that an understudied murine commensal bacterium, Dubosiella newyorkensis, and its human homologue Clostridium innocuum, have a probiotic immunomodulatory effect on dextran sulfate sodium-induced colitis using conventional, antibiotic-treated and germ-free mouse models. We identify an important role for the D. newyorkensis in rebalancing Treg/Th17 responses and ameliorating mucosal barrier injury by producing short-chain fatty acids, especially propionate and L-Lysine (Lys). We further show that Lys induces the immune tolerance ability of dendritic cells (DCs) by enhancing Trp catabolism towards the kynurenine (Kyn) pathway through activation of the metabolic enzyme indoleamine-2,3-dioxygenase 1 (IDO1) in an aryl hydrocarbon receptor (AhR)-dependent manner. This study identifies a previously unrecognized metabolic communication by which Lys-producing commensal bacteria exert their immunoregulatory capacity to establish a Treg-mediated immunosuppressive microenvironment by activating AhR-IDO1-Kyn metabolic circuitry in DCs. This metabolic circuit represents a potential therapeutic target for the treatment of inflammatory bowel diseases.

The Protective Effect of Chronic Intermittent Hypobaric Hypoxia on Preventing the Destruction of CD34+ Haematopoietic Stem Cells in Aplastic Anaemia by Modulating the Th1/Th2 Balance.

Aplastic anaemia (AA) is a haematopoietic disorder caused by immune-mediated attack on haematopoietic stem cells (HSCs). Stem cell transplantation and immunosuppressive therapy remain the major treatment choice for AA patients but have limited benefits and undesired side effects. The aim of our study was to clarify the protective role of immunity of chronic intermittent hypobaric hypoxia (CIHH) and the underlying mechanism in AA. Our integrative analysis demonstrated that CIHH pre-treatment significantly improved haematopoiesis and survival in an AA rat model. We further confirmed that CIHH pre-treatment was closely associated with the Th1/Th2 balance and a large number of negative regulatory haematopoietic factors, such as TNF-α and IFN-γ, produced by hyperactive Th1 lymphocytes released in AA rats, which induced the death program in a large number of CD34+ HSCs by activating the Fas/FasL apoptosis pathway, while CIHH pre-treatment effectively downregulated the expression of TNF-α and IFN-γ, resulting in a reduction in Fas antigen expression in CD34+ HSCs. In summary, this study provides evidence that CIHH has good protective effect against AA by modulating immune balance in Th1/Th2 cells and may provide a new therapeutic strategy.

Advances in the study of exosomes in cardiovascular diseases.

BACKGROUND: Cardiovascular disease (CVD) has been the leading cause of death worldwide for many years. In recent years, exosomes have gained extensive attention in the cardiovascular system due to their excellent biocompatibility. Studies have extensively researched miRNAs in exosomes and found that they play critical roles in various physiological and pathological processes in the cardiovascular system. These processes include promoting or inhibiting inflammatory responses, promoting angiogenesis, participating in cell proliferation and migration, and promoting pathological progression such as fibrosis. AIM OF REVIEW: This systematic review examines the role of exosomes in various cardiovascular diseases such as atherosclerosis, myocardial infarction, ischemia-reperfusion injury, heart failure and cardiomyopathy. It also presents the latest treatment and prevention methods utilizing exosomes. The study aims to provide new insights and approaches for preventing and treating cardiovascular diseases by exploring the relationship between exosomes and these conditions. Furthermore, the review emphasizes the potential clinical use of exosomes as biomarkers for diagnosing cardiovascular diseases. KEY SCIENTIFIC CONCEPTS OF REVIEW: Exosomes are nanoscale vesicles surrounded by lipid bilayers that are secreted by most cells in the body. They are heterogeneous, varying in size and composition, with a diameter typically ranging from 40 to 160 nm. Exosomes serve as a means of information communication between cells, carrying various biologically active substances, including lipids, proteins, and small RNAs such as miRNAs and lncRNAs. As a result, they participate in both physiological and pathological processes within the body.

Ginsenoside Rg3 enriches SCFA-producing commensal bacteria to confer protection against enteric viral infection via the cGAS-STING-type I IFN axis.

The microbiota-associated factors that influence host susceptibility and immunity to enteric viral infections remain poorly defined. We identified that the herbal monomer ginsenoside Rg3 (Rg3) can shape the gut microbiota composition, enriching robust short-chain fatty acid (SCFA)-producing Blautia spp. Colonization by representative Blautia coccoides and Blautia obeum could protect germ-free or vancomycin (Van)-treated mice from enteric virus infection, inducing type I interferon (IFN-I) responses in macrophages via the MAVS-IRF3-IFNAR signaling pathway. Application of exogenous SCFAs (acetate/propionate) reproduced the protective effect of Rg3 and Blautia spp. in Van-treated mice, enhancing intracellular Ca2+- and MAVS-dependent mtDNA release and activating the cGAS-STING-IFN-I axis by stimulating GPR43 signaling in macrophages. Our findings demonstrate that macrophage sensing of metabolites from specific commensal bacteria can prime the IFN-I signaling that is required for antiviral functions.

ZIF-67-Derived Co/N-Doped Carbon-Functionalized MXene for Enhanced Electrochemical Sensing of Carbendazim.

Herein, ZIF-67-derived Co and N-doped carbon (Co/NC) particle-modified multilayer MXene (MXene@Co/NC) was developed as remarkable electrode material for carbendazim (CBZ) detection. MXene as a substrate provides an excellent conductive framework and plentiful accessibility sites. Co/NC particles embedding in MXene can not only prevent the interlayer stacking of MXene but also contribute a great deal of metal catalytic active sites and finally improve the adsorption and catalytic properties of the composite. Accordingly, the MXene@Co/NC electrode displays excellent electrocatalytic activity toward CBZ oxidation. Experimental parameters such as pH value, accumulation time, MXene@Co/NC modification volume and constituent materials' mass ratios were optimized. Under optimal conditions, the as-prepared sensor based on MXene@Co/NC holds a broad linearity range from 0.01 µM to 45.0 µM with a low limit of detection (LOD) of 3.3 nM (S/N = 3, S means the detection signal, while N represents the noise of the instrument). Moreover, the proposed sensor displays excellent anti-interference ability, superior reproducibility, excellent stability, and successfully achieves actual applications for CBZ detection in a lettuce sample.

The role of glycolytic metabolic pathways in cardiovascular disease and potential therapeutic approaches.

Cardiovascular disease (CVD) is a major threat to human health, accounting for 46% of non-communicable disease deaths. Glycolysis is a conserved and rigorous biological process that breaks down glucose into pyruvate, and its primary function is to provide the body with the energy and intermediate products needed for life activities. The non-glycolytic actions of enzymes associated with the glycolytic pathway have long been found to be associated with the development of CVD, typically exemplified by metabolic remodeling in heart failure, which is a condition in which the heart exhibits a rapid adaptive response to hypoxic and hypoxic conditions, occurring early in the course of heart failure. It is mainly characterized by a decrease in oxidative phosphorylation and a rise in the glycolytic pathway, and the rise in glycolysis is considered a hallmark of metabolic remodeling. In addition to this, the glycolytic metabolic pathway is the main source of energy for cardiomyocytes during ischemia-reperfusion. Not only that, the auxiliary pathways of glycolysis, such as the polyol pathway, hexosamine pathway, and pentose phosphate pathway, are also closely related to CVD. Therefore, targeting glycolysis is very attractive for therapeutic intervention in CVD. However, the relationship between glycolytic pathway and CVD is very complex, and some preclinical studies have confirmed that targeting glycolysis does have a certain degree of efficacy, but its specific role in the development of CVD has yet to be explored. This article aims to summarize the current knowledge regarding the glycolytic pathway and its key enzymes (including hexokinase (HK), phosphoglucose isomerase (PGI), phosphofructokinase-1 (PFK1), aldolase (Aldolase), phosphoglycerate metatase (PGAM), enolase (ENO) pyruvate kinase (PKM) lactate dehydrogenase (LDH)) for their role in cardiovascular diseases (e.g., heart failure, myocardial infarction, atherosclerosis) and possible emerging therapeutic targets.

Activation of cannabinoid receptors 2 alleviates myocardial damage in cecal ligation and puncture-induced sepsis by inhibiting pyroptosis.

BACKGROUND: It has been reported that cannabinoid receptors 2 (CB2 receptors) play an important role in the pathophysiological process of sepsis, which may also be associated with the regulation of pyroptosis, an inflammatory programmed cell death. The present study aimed to investigate the protective effect of CB2 receptors on myocardial damage in a model of septic mice by inhibiting pyroptosis. METHODS: The C57BL/6 mice underwent cecal ligation and puncture (CLP) to induce sepsis. All mice were randomly divided into the sham, CLP, or CLP+HU308 group. Blood and heart tissue samples were collected 12 h after surgery. Hematoxylin and eosin staining was used for analyzing histopathological results. Creatine kinase isoenzymes (CK-MB) and IL-1ß were measured using ELISA, while lactate dehydrogenase (LDH) level was determined using photoelectric colorimetry. The expression levels of CB2 receptors and pyroptosis-associated proteins (NLRP3, caspase-1, and GSDMD) were measured using western blotting. The location and distribution of CB2 receptors and caspase-1 in myocardial tissues were assessed by immunofluorescence. TUNEL staining was used to quantify the number of dead cells in myocardial tissues. RESULTS: The CLP procedure increased CB2 receptor expression in mice. CB2 receptors were located in myocardial macrophages. Activating CB2 receptors decreased the levels of myocardial damage mediator LDH, CK-MB, and inflammatory cytokine IL-1ß. The results also showed that CLP increased the pyroptosis in myocardial tissues, while CB2 agonist HU308 inhibited pyroptosis by decreasing the level of NLRP3 and activating caspase-1 and GSDMD. CONCLUSIONS: CB2 receptor activation has a protective effect on the myocardium of mice with sepsis by inhibiting pyroptosis.

Biological treatment processes for saline organic wastewater and related inhibition mechanisms and facilitation techniques: A comprehensive review.

Owing to its profound pollution-inducing properties and resistance to biodegradation, saline organic wastewater (SOW) has unavoidably emerged as a predominant focal point within the wastewater treatment domain. Substantial quantities of SOW are discharged by diverse industries encompassing food processing, pharmaceuticals, leather manufacturing, petrochemicals, and textiles. Within this review, the inhibitory repercussions of elevated salinity upon biological water treatment systems are subject to methodical scrutiny spanning from sludge characteristics, microbial consortia to the physiological functionality of microorganisms have been investigated. This exposition elucidates the application of both anaerobic and aerobic biological technologies for SOW treatment, which noting that conventional bioreactors can effectually treat SOW through microbial adaptation, and elaborating that cultivation of salt-tolerant bacteria and the design of advanced bioreactors represents a promising avenue for SOW treatment. Furthermore, the mechanisms underpinning microbial acclimatization to hypersaline milieus and the methodologies aimed at amplifying the efficacy of biological SOW treatment are delved into, which point out that microorganism exhibit salt tolerance via extracellular polymeric substance accumulation or by facilitating the influx of osmolarity-regulating agents into the bacterial matrix. Finally, the projections for future inquiry are proffered, encompassing the proliferation and deployment of high salt-tolerant strains, as well as the development of techniques enhancing the salt tolerance of microflora engaged in wastewater treatment.

Quadruple Plasmon-Induced Transparency and Dynamic Tuning Based on Bilayer Graphene Terahertz Metamaterial.

This study proposes a terahertz metamaterial structure composed of a silicon-graphene-silicon sandwich, aiming to achieve quadruple plasmon-induced transparency (PIT). This phenomenon arises from the interaction coupling of bright-dark modes within the structure. The results obtained from the coupled mode theory (CMT) calculations align with the simulations ones using the finite difference time domain (FDTD) method. Based on the electric field distributions at the resonant frequencies of the five bright modes, it is found that the energy localizations of the original five bright modes undergo diffusion and transfer under the influence of the dark mode. Additionally, the impact of the Fermi level of graphene on the transmission spectrum is discussed. The results reveal that the modulation depths (MDs) of 94.0%, 92.48%, 93.54%, 96.54%, 97.51%, 92.86%, 94.82%, and 88.20%, with corresponding insertion losses (ILs) of 0.52 dB, 0.98 dB, 1.37 dB, 0.70 dB, 0.43 dB, 0.63 dB, 0.16 dB, and 0.17 dB at the specific frequencies, are obtained, achieving multiple switching effects. This model holds significant potential for applications in versatile modulators and optical switches in the terahertz range.

Monotropein inhibits colitis associated cancer through VDR/JAK1/STAT1 regulation of macrophage polarization.

Colorectal cancer (CRC) is a growing concern due to its high morbidity and mortality, and the search for effective and less toxic active substances against inflammatory bowel diseases has been a hot topic in the research and development of drugs against CRC. It is reported that monotropein isolated from the roots of Morinda officinalis, can improve Dextran Sodium Sulfate (DSS)-induced ulcerative colitis in mice, but its therapeutic effects and mechanisms for CRC treatment are still to be investigated. In the present study, we first used molecular docking, BLI, CESTA, and DARTS methods to detest whether monotropein targets VDR proteins. In addition, we used tumor cell conditioned co-culture and four models of macrophage polarisation to investigate the regulation of four macrophage polarisations by monotropein using RT-PCR, IF and western blot. Furthermore, we further validated the target of action of monotropein for the treatment of Azoxymethane (AOM)/DSS induced colitis associated cancer (CAC) using knockout animals. Meanwhile, we further explored the mechanism of action of monotropein in regulating polarisation by detecting JAK/STAT1-related genes and proteins. Molecular docking and biofilm interference techniques showed that monotropein bound to the VDR, and additional results from CESTA and DARTS suggested that VDR proteins are targets of monotropein. Furthermore, in tumor cell conditioned co-cultures or LPS + IFN-γ induced RAW264.7 cells, VDR translocation to the nucleus was reduced, JAK1/STAT1 signaling pathway proteins were up-regulated, and macrophages were polarised towards the M1-type after monotropein intervention. Animal models in which normal VDR or myeloid VDR was knocked out confirmed that JAK1 levels in intestinal tissues were increased after monotropein intervention, macrophages were polarised towards the M1 type, and CAC paracarcinomas were ameliorated. Taken together, the present study concluded that monotropein inhibited colitis-associated cancers through macrophage polarisation regulated by VDR/JAK1/STAT1.

hUC-MSC transplantation therapy effects on lupus-prone MRL/lpr mice at early disease stages.

BACKGROUND: The efficacy of human umbilical cord mesenchymal stem cell (hUC-MSC) transplantation in treating systemic lupus erythematosus (SLE) has been confirmed by small-scale clinical trials. However, these trials focused on severe or refractory SLE, while few studies focused on mild SLE. Therefore, this study focused on the therapeutic effects of hUC-MSC transplantation in early-stage or mild MRL/lpr lupus model mice. METHODS: Commercially available hUC-MSCs were transplanted into 8-week-old MRL/lpr mice by tail vein injection. Flow cytometry was used to analyze B cells and their subsets in the peripheral blood. Further, plasma inflammatory factors, autoantibodies, and plasma biochemical indices were detected using protein chip technology and ELISA kits. In addition, pathological staining and immunofluorescence were performed to detect kidney injury in mice. RESULTS: hUC-MSC transplantation did not affect the mice's body weight, and both middle and high dose hUC-MSC transplantation (MD and HD group) actually reduced spleen weight. hUC-MSC transplantation significantly decreased the proportion of plasmablasts (PB), IgG1- PB, IgG1+ PB, IgG1+ memory B (MB) cells, IgG1+ DN MB, and IgG1+ SP MB cells. The hUC-MSC transplantation had significantly reduced plasma levels of inflammatory factors, such as TNF-α, IFN-γ, IL-6, and IL-13. Pathological staining showed that the infiltration of glomerular inflammatory cells was significantly reduced and that the level of glomerular fibrosis was significantly alleviated in hUC-MSC-transplanted mice. Immunofluorescence assays showed that the deposition of IgG and IgM antibodies in the kidneys of hUC-MSC-transplanted mice was significantly lower than in the control. CONCLUSION: hUC-MSC transplantation could inhibit the proliferation and differentiation of peripheral blood B cells in the early-stage of MRL/lpr mice, thereby alleviating the plasma inflammatory environment in mice, leading to kidney injury remission. The study provides a new and feasible strategy for SLE treatment.

Integrated machine learning and bioinformatic analyses used to construct a copper-induced cell death-related classifier for prognosis and immunotherapeutic response of hepatocellular carcinoma patients.

Background: Copper as phytonutrient has powerful activity against health diseases. A newly discovered mechanism of cell death that affects energy metabolism by copper ("cuproptosis") can induce multiple cuproptosis-related genes. Hepatocellular carcinoma (HCC) is a poorly prognosed widespread cancer having danger of advanced metastasis. Therefore, earlier diagnosis followed by the specific targeted therapy are required for improved prognosis. The work herein constructed scoring system built on ten cuproptosis-related genes (CRGs) to predict progression of tumor and metastasis more accurately and test patient reaction toward immunotherapy. Methods: A comprehensive assessment of cuproptosis patterns in HCC samples from two databases and a real-world cohort was performed on ten CRGs, that were linked to immune cell infiltration signatures of TME (tumor microenvironment). Risk signatures were created for quantifying effect of cuproptosis on HCC, and the effects of related genes on cellular function of HCC were investigated, in addition to the effects of immunotherapy and targeted therapy drugs. Results: Two distinct cuproptosis-associated mutational patterns were identified, with distinct immune cell infiltration characteristics and survival likelihood. Studies have shown that assessment of cuproptosis-induced tumor mutational patterns can help predict tumor stage, phenotype, stromal activity, genetic diversity, and patient prognosis. High risk scores are characterized by lower survival and worse treatment with anti-PD-L1/CTAL4 immunotherapy and first-line targeted drugs. Cytological functional assays show that CDKN2A and GLS promote proliferation, migration and inhibit copper-dependent death of HCC cells. Conclusion: HCC patients with high-risk scores exhibit significant treatment disadvantage and survival rates. Cuproptosis plays a non-negligible role in the development of HCC. Quantifying cuproptosis-related designs of tumors will aid in phenotypic categorization, leading to efficient personalized and targeted therapeutics and precise prediction of prognosis and metastasis.

Interspecies/Intergroup Complementation of Orthotospovirus Replication and Movement through Reverse Genetics Systems.

Orthotospoviruses, the plant-infecting bunyaviruses, cause serious diseases in agronomic crops and pose major threats to global food security. The family of Tospoviridae contains more than 30 members that are classified into two geographic groups, American-type and Euro/Asian-type orthotospovirus. However, the genetic interaction between different species and the possibility, during mixed infections, for transcomplementation of gene functions by orthotospoviruses from different geographic groups remains underexplored. In this study, minireplicon-based reverse genetics (RG) systems have been established for Impatiens necrotic spot virus (INSV) (an American-type orthotospovirus) and for Calla lily chlorotic spot virus and Tomato zonate spot virus (CCSV and TZSV) (two representative Euro/Asian orthotospoviruses). Together with the earlier established RG system for Tomato spotted wilt virus (TSWV), a type species of the Orthotospovirus American-clade, viral replicase/movement proteins were exchanged and analyzed on interspecies transcomplementation. Whereas the homologous RNA-dependent RNA polymerase (RdRp) and nucleocapsid (N) protein supported the replication of orthotospoviruses from both geographic groups, heterologous combinations of RdRp from one group and N from the other group were unable to support the replication of viruses from both groups. Furthermore, the NSm movement protein (MP), from both geographic groups of orthotospoviruses, was able to transcomplement heterologous orthotospoviruses or a positive-strand Cucumber mosaic virus (CMV) in their movement, albeit with varying efficiency. MP from Rice stripe tenuivirus (RSV), a plant-infecting bunyavirus that is distinct from orthotospoviruses, or MP from CMV also moves orthotospoviruses. Our findings gain insights into the genetic interaction/reassortant potentials for the segmented plant orthotospoviruses. IMPORTANCE Orthotospoviruses are agriculturally important negative-strand RNA viruses and cause severe yield-losses on many crops worldwide. Whereas the emergence of new animal-infecting bunyaviruses is frequently associated with genetic reassortants, this issue remains underexposed with the plant-infecting orthotospovirus. With the development of reverse genetics systems for orthotospoviruses from different geographic regions, the interspecies/intergroup replication/movement complementation between American- and Euro/Asian-type orthotospoviruses were investigated. Genomic RNAs from American orthotospoviruses can be replicated by the RdRp and N from those of Euro/Asia-group orthotospoviruses, and vice versa. However, their genomic RNAs cannot be replicated by a heterologous combination of RdRp from one geographic group and N from another geographic group. Cell-to-cell movement of viral entity is supported by NSm from both geographic groups, with highest efficiency by NSm from viruses belonging to the same group. Our findings provide important insights into the genetic interaction and exchange ability of viral gene functions between different species of orthotospovirus.

Coupling of Fenton reaction and white rot fungi for the degradation of organic pollutants.

Advanced oxidation processes (AOPs) are a class of highly efficient pollution remediation technologies that produce oxidising radicals under specific conditions to degrade organic pollutants. The Fenton reaction is a commonly applied AOP. To combine the advantages of AOPs and biodegradation in the remediation of organic pollutants, some studies have developed coupled systems between Fenton AOPs and white rot fungi (WRF) for environmental organic pollutant remediation and have achieved some success. Moreover, a promising system, termed as advanced bio-oxidation processes (ABOPs), mediated by the quinone redox cycling of WRF, has attracted increasing attention in the field. In this ABOP system, the radicals and H2O2 produced through the quinone redox cycling of WRF can strengthen Fenton reaction. Meanwhile, in this process, the reduction of Fe3+ to Fe2+ ensures the maintenance of Fenton reaction, leading to a promising application potential for the remediation of environmental organic pollutants. ABOPs combine the advantages of bioremediation and advanced oxidation remediation. Further understanding the coupling of Fenton reaction and WRF in the degradation of organic pollutants will be of great significance for the remediation of organic pollutants. Therefore, in this study, we reviewed recent remediation techniques for organic pollutants involving the coupled application of WRF and the Fenton reaction, focusing on the application of new ABOPs mediated by WRF, and discussed the reaction mechanism and conditions of ABOPs. Finally, we discussed the application prospects and future research directions of the joint application of WRF and advanced oxidation technologies for the remediation of environmental organic pollutants.

A pair of G-type lectin receptor-like kinases modulates nlp20-mediated immune responses by coupling to the RLP23 receptor complex.

Plant cells recognize microbial patterns with the plasma-membrane-localized pattern-recognition receptors consisting mainly of receptor kinases (RKs) and receptor-like proteins (RLPs). RKs, such as bacterial flagellin receptor FLS2, and their downstream signaling components have been studied extensively. However, newly discovered regulatory components of RLP-mediated immune signaling, such as the nlp20 receptor RLP23, await identification. Unlike RKs, RLPs lack a cytoplasmic kinase domain, instead recruiting the receptor-like kinases (RLKs) BAK1 and SOBIR1. SOBIR1 specifically works as an adapter for RLP-mediated immunity. To identify new regulators of RLP-mediated signaling, we looked for SOBIR1-binding proteins (SBPs) in Arabidopsis thaliana using protein immunoprecipitation and mass spectrometry, identifying two G-type lectin RLKs, SBP1 and SBP2, that physically interacted with SOBIR1. SBP1 and SBP2 showed high sequence similarity, were tandemly repeated on chromosome 4, and also interacted with both RLP23 and BAK1. sbp1 sbp2 double mutants obtained via CRISPR-Cas9 gene editing showed severely impaired nlp20-induced reactive oxygen species burst, mitogen-activated protein kinase (MAPK) activation, and defense gene expression, but normal flg22-induced immune responses. We showed that SBP1 regulated nlp20-induced immunity in a kinase activity-independent manner. Furthermore, the nlp20-induced the RLP23-BAK1 interaction, although not the flg22-induced FLS2-BAK1 interaction, was significantly reduced in sbp1 sbp2. This study identified SBPs as new regulatory components in RLP23 receptor complex that may specifically modulate RLP23-mediated immunity by positively regulating the interaction between the RLP23 receptor and the BAK1 co-receptor.

Asperuloside alleviates lipid accumulation and inflammation in HFD-induced NAFLD via AMPK signaling pathway and NLRP3 inflammasome.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a clinical pathological syndrome of hepatic parenchymal cell steatosis caused by excessive lipid deposition, which is the chronic liver disease with the highest incidence in China. Asperuloside (ASP), a kind of iridoid compound, possesses natural pharmacological effects of anti-tumor, anti-inflammatory, antioxidant and anti-obesity. However, whether ASP can improve NAFLD remains unclear. PURPOSE: We aimed to investigate the effect of ASP on NAFLD mice induced by high-fat diet (HFD), and explore its mechanism in vivo and in vitro. METHODS: Pharmacodynamics of ASP was studied by HFD induction in NAFLD mice. HepG2 cells were induced by palmitic acid (PA) as cell model to investigate the effect of ASP on lipid deposition and inflammatory infiltration. Expression of Adenosine monophosphate - activated protein kinase (AMPK) signaling pathway and NOD-like receptor pyrin containing 3 (NLRP3) inflammasome were detected by Western blot and RT-PCR. Cytokines IL-1ß and TNF-α were detected by ELISA. RESULTS: ASP alleviated liver injury and inflammatory damage in mice with NAFLD. In addition, ASP improved lipid deposition as well as inflammatory response in HFD-induced NAFLD mice and PA-stimulated HepG2 cells. ASP ameliorated lipid deposition and inflammatory response by regulating the p-AMPK/SREBP-1c signaling pathway and NLRP3 inflammasome. CONCLUSION: Our results suggest that ASP improve lipid deposition and inflammatory infiltration in NAFLD mice via regulating the AMPK/SREBP-1c signaling pathway and NLRP3 inflammasome, which may be an effective candidate for the treatment of NAFLD.