Signaling Molecules Research Articles

Two-way role of iron-carbon in biochemical reactions: microelectrolysis and enhanced activity of aerobic granular sludge for efficient refractory wastewater treatment

Industrial wastewater contained a large amount of refractory organics, and single treatment processes had limitations. This study investigated the mechanism of refractory organics removal using iron-carbon built-in coupled activated sludge (ICAS) and explored the role and function of iron-carbon (IC) within the ICAS system. The aerobic granular sludge (AGS) cultivated with IC exhibited a loose surface and a tight interior structure. Iron in the AGS concentrated near the outer layer to form a crust, which protected the inner microorganisms. IC promoted EPS secretion and regulated the abundance of positive and negative signaling molecules to maintain AGS stability. Experiments using quinoline as a model refractory organic showed that both physical adsorption by IC and biological adsorption by sludge rapidly fixed a large amount of pollutants, providing a buffer capacity for the system. The iron mineral crust on the AGS surface enhanced quinoline adsorption. Hydroxylation was the first step in quinoline degradation, with IC upregulating the genes iorA/B, qorB, and wrbA involved in this process, and the relative abundances of quinoline-degrading bacteria. Both pyridine ring opening and benzene ring cleavage occurred in the single IC system, and the microelectrolysis process produced •OH and [H], which made degradation pathway for quinoline through IC more complex than microbial degradation. Although the IC-mediated pathway accounted for only a small part of overall quinoline removal in the ICAS system, the ICAS system not only preserved the microelectrolysis process but also enhanced microbial metabolic activity. This work provided insights into the synergistic removal of pollutants and maintenance of AGS stability by the ICAS process, ensuring efficient treatment of refractory organic wastewater.

H2S protects rat cerebral ischemia-reperfusion injury by inhibiting expression and activation of hippocampal ROCK2 at the Thr436 and Ser575 sites

BackgroundH2S is an endogenous gas signal molecule, which protects cerebral ischemia/reperfusion (I/R) injury by phosphorylating rho-associated coiled coil-containing protein kinase 2 (ROCK2) at Tyr722, and inhibiting ROCK2 protein expression and activities. We previously reported that H2S protected rat neurons from hypoxia/reoxygenation injury in vitro through inhibiting phosphorylation of ROCK2 at Thr436 and Ser575, but it is unclear whether these two sites are involved in protection of H2S against cerebral I/R injury. MethodRats transfected with wild-type and mutant eukaryotic plasmids of ROCK2 in hippocampus were used to establish I/R model by ligating bilateral common carotid artery. Rat behavioral deficit was detected by water maze assay, and ROCK2, lactate dehydrogenase (LDH), nerve-specific enolase (NSE) and reactive oxygen species (ROS) were determined by ELISA. ROCK2 expressions was examined by western-blot assay, and bcl-2 and Bax mRNAs were examined by RT-qPCR. ResultsNaHS (4.8mg/kg) significantly inhibited the I/R-increased serum LDH, NSE and ROS in the ROCK2wild-pEGFP-N1-transfected rats, but had no obvious effect in the ROCK2T436A-pEGFP-N1- or the ROCK2S575F-pEGFP-N1-transfected rats; inhibitions of NaHS on the I/R-increased escape latency and the I/R-decreased percentage of target quadrant distance to total distance were markedly attenuated or abolished in the ROCK2T436A-pEGFP-N1- or the ROCK2S575F-pEGFP-N1-transfected rats compared with those in the ROCK2wild-pEGFP-N1-transfected rats; NaHS obviously inhibited the I/R-increased hippocampal ROCK2 and GFP-ROCK2 proteins, Bax mRNA, and ROCK2 activity, as well as the I/R-decreased hippocampal bcl-2 mRNA in the hippocampus of the ROCK2wild-pEGFP-N1-transfected rats, but had no significant effect in the ROCK2T436A-pEGFP-N1- or the ROCK2S575F-pEGFP-N1-transfected rats. ConclusionH2S protects cerebral I/R injury in rats by inhibiting expression and activation of hippocampal ROCK2 via the Thr436 and Ser575 sites.

Photo-tunable hydrogels reveal cellular sensing of rapid rigidity changes through the accumulation of mechanical signaling molecules.

Cells use traction forces to sense mechanical cues in their environment. While the molecular clutch model effectively explains how cells exert more forces on stiffer substrates, it falls short in addressing their adaptation to dynamic mechanical fluctuations prevalent in tissues and organs. Here, using hydrogel with photo-responsive rigidity, we show that cells' response to rigidity changes is frequency dependent. Strikingly, at certain frequencies, cellular traction forces exceed those on static substrates 4-fold stiffer, challenging the established molecular clutch model. We discover that the discrepancy between the rapid adaptation of traction forces and the slower deactivation of mechanotransduction signaling proteins results in their accumulation, thereby enhancing long-term cellular traction in dynamic settings. Consequently, we propose a new model that melds immediate mechanosensing with extended mechanical signaling. Our study underscores the significance of dynamic rigidity in the development of synthetic biomaterials, emphasizing the importance of considering both immediate and prolonged cellular responses.

Poly(L-lactide-co-ɛ-caprolactone)/gelatin-based small-diameter vascular grafts: Salutatory effect of the BVLD and EGCG-Cu to promote hemocompatibility and nitric oxide production for in situ blood vessel regeneration

Polymeric small-diameter vascular grafts (SDVGs, inner diameter, < 6 mm) with characteristics, such as thrombo-protection and adequate short-term as well as long-term patency are still in the development and exploration stage. In this study, based on the gas signaling molecule release strategy, SDVGs were prepared by electrospinning using poly(L-lactide-co-ɛ-caprolactone) (PLCL) and gelatin (Gel). Bivalirudin (BVLD) and epigallocatechin gallate-copper (EGCG-Cu) complex were loaded into SDVGs to improve hemocompatibility and nitric oxide (NO) release, respectively. Vascular grafts manifested drug release for up to 40 days in vitro; BVLD effectively inhibited thrombosis while the EGCG-Cu complex catalyzed the NO production from endogenous donors (S-nitroso glutathione (GSNO) and glutathione (GSH)), thereby conferring vascular grafts with functions similar to that of the natural vascular endothelium layer. Both in vitro and in vivo tests demonstrated that SDVGs co-loaded with BVLD and EGCG-Cu (PG-EB) could effectively inhibit thrombosis, alleviate inflammation, and suppress the proliferation of smooth muscle cells (SMCs) while promoting the proliferation of endothelial cells (ECs), and finally regenerate vascular tissues. In vivo animal experiments demonstrated that vascular grafts could promote endothelialization and vascular remodeling. In summary, our simultaneous utilization of BVLD and EGCG-Cu may offer a promising avenue for the fabrication of in situ regenerable SDVGs.

Knockout of histone deacetylase 8 gene in breast cancer cells may alter the expression pattern of the signaling molecules

PurposeBreast cancer (BC) is the most common cancer diagnosed in the world and it is also the main leading cause of cancer deaths in women. Change in epigenetic mechanisms promotes BC initiation and progression. Histone deacetylase 8 (HDAC8) was found to act as a potential oncogene in different malignancies. For better understanding of the HDAC8 function in BC development, we investigated the effect of HDAC8 deletion on the expression of genes involved in signaling pathways. Materials and methodsIn this study, CRISPR technology was used to knockout the HDAC8 gene in MDA-MB-468, MDA-MB-231 and MCF-7 ​cell lines. For this purpose, two gRNAs were designed and cloned into the PX459 vector. The gRNA-containing vectors were transfected into the BC cell lines and then the effect of this deletion on the expression of genes involved in signaling pathway was determined using quantitative real-time PCR (qRT-PCR). ResultsAnalysis of qRT-PCR results showed a reduction in the expression of studied genes in BC cell lines after deletion of the HDAC8 gene compared to untreated controls. Although this decline was not significant for FGF2 and FGFR1 genes, however the mTOR, IGF1R, INSR, VEGFA and VEGFR2 genes showed statistically significant reduction in the studied BC cell lines. In addition, the down-regulation of PDGFC and PDGFRA genes were only significant in the TNBC cell lines. ConclusionOverall, our study showed that HDAC8 can exert its oncogenic effects by altering the expression level of molecules involved in some signaling pathways, and inhibiting HDAC8 can revert these effects.

The Role of Nitric Oxide, Lipocalin-2, and Proinflammatory Cytokines on Proteinuria and Insulin Resistance in Type 2 Diabetes Mellitus Subgroups.

Nitric oxide (NO) is a bioactive signaling molecule that mediates various physiological and biological processes. Type 2 diabetes mellitus (T2DM) can be categorized into several subgroups according to fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) levels. Few studies have closely examined the effect of NO and lipocalin-2 on albuminuria and insulin resistance in T2DM subgroups. This study investigated the role of NO, lipocalin-2, and proinflammatory cytokines on the development of proteinuria and insulin resistance in patients with T2DM subgroups. A total of 256 subjects, including 191 patients with T2DM and 65 non-diabetic healthy individuals, were evaluated. NO metabolites (NOx), lipocalin-2, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were measured. Patients with T2DM were classified into three subgroups: patients with FPG-defined diabetes (PG-DM), those with HbA1c-defined diabetes (HA-DM), and those who met the criteria for both FPG and HbA1c (PG/HA-DM). The albumin-to-creatinine ratio (ACR) and the homeostasis model assessment of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) were calculated. NOx, lipocalin-2, and TNF-α levels were significantly higher in patients with T2DM than in healthy individuals. Patients with PG/HA-DM had significantly higher NOx levels than those with PG-DM or HA-DM. Of the patients with high NOx levels, patients with lipocalin-2 elevation exhibited higher ACR and HOMA-IR than those without lipocalin-2 elevation. NOx was positively correlated with lipocalin-2, ACR, HOMA-IR, and TNF-α but not with HOMA-B and IL-6. The upper quartile of NOx levels led to a 1.2-fold increase in the risk of albuminuria (odds ratio: 1.215; 95% CI: 1.012-2.418; p < 0.001). NO plays a crucial role in proteinuria and insulin resistance by collaborating with lipocalin-2 and TNF-α, showing significantly higher levels in patients with PG/HA-DM than in those with PG-DM or HA-DM.

Limosilactobacillus fermentum CGMCC 1.7434 and Debaryomyces hansenii GDMCC 2.149 synergize with ultrasound treatment to efficiently degrade nitrite in air-dried ducks

Nitrites in meat products are important food additives with coloring, antibacterial and antioxidant effects, but excessive intake of nitrites can pose health risks, including an increased risk of cancer due to the formation of carcinogenic nitrosamines. In the present study, Limosilactobacillus fermentum CGMCC 1.7434 was screened and the effects of it and Debaryomyces hansenii GDMCC 2.149 and their combination on nitrite degradation were investigated. It was found that the co-culture of L. fermentum CGMCC 1.7434 and D. hansenii GDMCC 2.149 significantly enhanced nitrite degradation (99.58%). The findings on salt and ethanol tolerance suggest suitability for application in meat fermentation processes. Scanning electron microscopy and additional data indicate that D. hansenii GDMCC 2.149 facilitates the growth, acid production, adhesion, secretion of AI-2 signaling molecules, and biofilm formation of L. fermentum CGMCC 1.7434. Metabolomics analysis suggests that these microorganisms reduce nitrite levels by converting NH3 derived from nitrite into L-glutamine, which is further transformed into N-nitroso compounds and their downstream derivatives through the ABC transporter pathway, the TCA cycle, and the amino acid metabolism pathway. Microbial community analyses showed that L. fermentum CGMCC 1.7434 and D. hansenii GDMCC 2.149 were successfully inoculated into air-dried ducks, becoming dominant strains and effectively inhibiting the growth of pathogenic bacteria. Furthermore, during the processing of air-dried duck, the combination of ultrasonic cavitation (250 W, 4 min, 30°C, 40 kHz) with the co-fermentation of L. fermentum CGMCC 1.7434 and D. hansenii GDMCC 2.149 effectively reduced nitrite content (84.55%) and TVB-N levels in the meat, without compromising color or TBARS values. This is crucial for understanding the mechanism of nitrite degradation by LAB in synergy with yeast and for the advancement of low-nitrite air-dried duck products.

Mechanistic insights into the orthogonal functionality of an AHL-mediated quorum-sensing circuit in Yersinia pseudotuberculosis

YpsR, a pivotal regulatory protein in the quorum-sensing (QS) of Yersinia pseudotuberculosis(Y. pstb), is essential for molecular signaling, yet its molecular mechanisms remain poorly understood. Herein, this study systematically investigates the interactions between YpsR and acyl-homoserine lactones (AHLs), shedding light on the selective mechanism of YpsR to various AHL molecules. Using molecular docking and surface plasmon resonance (SPR) analysis, we confirmed YpsR’s binding affinities, with the strongest observed for 3OC6-HSL, which notably inhibited Y. pstb growth. Additionally, we engineered a whole-cell biosensor based on YpsR-AHL interaction, which exhibited sensitivity to the signal molecule 3OC6-HSL produced by Y. pstb. Furthermore, key YpsR residues (S32, Y50, W54, D67) involved in AHL binding were identified and validated. Overall, this research elucidates the mechanisms of QS signal recognition in Y. pstb, providing valuable insights that support the development of diagnostic tools for detecting Y. pstb infections.

A dual-signal biosensor based on surface-enhanced Raman spectroscopy for high-sensitivity quantitative detection and imaging of circRNA in living cells

Circular RNAs (circRNAs) are non-coding RNAs that play key roles in the development and progression of cancer through various mechanisms of action, making them promising biomarkers for cancer diagnosis, prognosis, and treatment. In the present study, a biosensor based on surface-enhanced Raman spectroscopy (SERS) was developed for rapid, simple, and sensitive quantitative detection of intracellular circRNAs for the first time. A dual-signal SERS nanoprobe with a 4MBN and ROX signal molecule was fabricated, and the ROX signal intensity was used to determine the concentration of target circSATB2. 4MBN was used as an internal standard to calibrate the ROX signal, thereby achieving highly sensitive and reliable detection of the target circRNA with a limit of detection of 0.043 pM. Furthermore, the relatively high expression of circSATB2 in lung cancer cells compared to that in normal lung epithelial cells was successfully characterized by the proposed SERS imaging method, which is consistent with the results of standard reverse transcription-polymerase chain reaction (RT-PCR). Monitoring of specific circRNAs using this SERS-based biosensor is a promising method for cancer diagnosis and gene therapy.

Duck plague virus UL24 protein initiates K48/K63-linked IRF7 polyubiquitination to antagonize the innate immune response

Duck plague virus (DPV), which is the causative agent of duck viral enteritis, is highly infectious and can cause severe disease and death in ducks, geese and other waterfowl. Several tegument proteins of DPV have been shown to affect the cyclic GMP-AMP synthase (cGAS)-STING signaling pathway to modulate host innate immune responses. DPV UL24, an important DPV tegument protein, can inhibit the activity of the IFN-β promoter. However, the mechanism by which the DPV UL24 protein regulates the host innate immune response remains unclear. In this study, we found that the UL24 protein can significantly inhibit the activity of the interferon-β promoter induced by poly(I:C) and reduce the production of IFN-β, interferon-stimulated genes (OASL, Mx), and the cellular inflammatory factor IL-6. (2) The UL24 protein can widely inhibit the mRNA level of immune signaling molecules. The UL24 protein can also downregulate the protein expression of RIG-I, MDA5, MAVS, cGAS, STING, TBK1 and IRF7 in DEFs. RT-qPCR results revealed that UL24 significantly inhibited the mRNA accumulation for the immune signaling molecules cGAS, STING, TBK1 and IRF7. (3) The UL24 protein induced the degradation of IRF7 via ubiquitination. After the DEFs were treated with the ubiquitin proteasome inhibitor MG132, the degradation of IRF7 by the UL24 protein was alleviated. Coimmunoprecipitation results revealed that DPV UL24 induced the K48/K63-linked ubiquitination of IRF7, which promoted its degradation and thus antagonized the host innate immune response.

Time-course transcriptomic analysis reveals transcription factors involved in modulating nitrogen sensibility in maize

Nitrogen (N) serves both as a vital macronutrient and a signaling molecule for plants. Unveiling key regulators involved in N metabolism helps dissect the mechanisms underlying N metabolism, which is essential for developing maize with high N use efficiency. Two maize lines, B73 and Ki11, show differential chlorate and low-N tolerance. Time-course transcriptomic analysis reveals that the expression of NUGs in B73 and Ki11 have distinct responsive patterns to nitrate variation. By the coexpression networks, significant differences in the number of N response modules and regulatory networks of transcription factors (TFs) are revealed between B73 and Ki11. There are 23 unique TFs in B73 and 41 unique TFs in Ki11. MADS26 is a unique TF in the B73 N response network, with different expression level and N response pattern in B73 and Ki11. Overexpression of MADS26 enhances the sensitivity to chlorate and the utilization of nitrate in maize, at least partially explaining the differential chlorate tolerance and Low-N sensitivity between B73 and Ki11. The findings in this work provide unique insights and promising candidates for maize breeding to reduce unnecessary N overuse.

Exploring the regulation mechanism of signaling molecules on algal-bacterial granular sludge through different N-acyl-homoserine lactones

As a recently emerging wastewater treatment technology, Algal-bacterial granular sludge (ABGS) process shows significant advantages. However, current research on the ABGS system is a lack of a clear and complete understanding of the potential mechanism of signal molecules on the growth of ABGS. This study comprehensively explores the variations in the ABGS under different N-acyl-homoserine lactone (AHL)conditions by constructing three sequencing batch reactor (SBR) systems. The results indicate that N-hexanoyl-L-homoserine lactone (C6-HSL) accelerates the granulation process in the early stages by promoting the loosely bound extracellular polymeric substances (LB-EPS) secretion and filamentous bacteria growth, thereby shortening required time for initial granule formation. On the other hand, N-(3-oxodecanoyl)-L-homoserine lactone (3-oxo-C12-HSL) expedites the granulation process by promoting the tightly bound extracellular polymeric substances (TB-EPS) and aromatic protein secretion, benefiting structural stability and nitrogen and phosphorus removal efficiency of mature ABGS.

Explore the Role of the Sphingosine-1-Phosphate Signalling as a Novel Promising Therapeutic Target for the Management of Parkinson's Disease.

Sphingosine-1-phosphate (S1P) is a cellular signalling molecule derived from sphingosine, which is a pro-apoptotic sphingolipid. Sphingolipids control various cellular actions like growth, homeostasis, and stress-related responses. The main sources of S1P in our body are erythrocytes. S1P controls both cellular mediators and other second messengers intracellularly. The S1P receptor also helps in inflammatory and neuroprotective effects (required to manage of Parkinson's). A large number of anti-Parkinson drugs are available, but still, there is a need for more effective and safer drugs. S1P and its receptors could be targeted as novel drugs due to their involvement in neuro-inflammation and Parkinson's. The present review effort to explore the biological role of S1P and related receptors, for their possible involvement in PD; furthermore. Overall, S1P and other related metabolizing enzymes have significant therapeutic opportunities for Parkinson's disease along with other neurological disorders.

Fatty acid synthesis promoted by PA1895-1897 operon delays quorum sensing activation in Pseudomonas aeruginosa

PA1895-1897 is a quorum sensing (QS) operon regulated by the anti-activator LuxR homologue QscR in Pseudomonas aeruginosa. We aimed to investigate its impact on bacterial metabolism, and whether it contributes to the delayed QS activation. We performed liquid chromatograph-mass spectrometer-based metabolomics using wildtype PAO1, PA1895-1897-knockout mutant, and mutant with pJN105.PA1895-1897 overexpression vector. The impact of metabolites on QS signaling molecule (3OC12-HSL and C4-HSL) concentrations, pyocyanin production, and QS gene (lasR, lasI, rhlR, and rhlI) expression was examined. Metabolomics analysis found that fatty acid biosynthesis had the highest fold enrichment among all metabolic pathways in PA1895-1897-overexpressed mutants. Among these enriched fatty acids, palmitoleic acid and acetic acid were the predominantly abundant ones that significantly affected by PA1895-1897 operon. When different doses of exogenous palmitoleic acid or acetic acid were added to the cultures of PA1895-1897 knockout mutants, their levels of 3OC12-HSL, C4-HSL, and pyocyanin were decreased in a dose-dependent manner. High doses of palmitoleic acid and acetic acid suppressed the mRNA expression of lasR, rhlR, and rhlI. Inhibition of fatty acid biosynthesis increased the production of 3OC12-HSL, C4-HSL, and pyocyanin in PA1895-1897-overexpressed cultures. Our data suggest that fatty acid synthesis is promoted by PA1895-1897 operon, and contributes the delayed expression of QS phenotypes, furthering the understanding about the regulation of bacterial QS activation.

Effect of the quorum sensing signal molecule auto-inducer-2 on fermentation performance of Lactobacillus delbrueckii subsp. Bulgaricus DPUL-F36

Fermented milk is a typically product of co-fermentation by a variety of lactic acid bacteria (LAB). Quorum sensing (QS), as an intercellular communication mechanism of bacteria, may serve as a key factor influencing the quality of fermented milk. In this study, the fermentation performance of Lactobacillus delbrueckii subsp. bulgaricus DPUL-F36 were evaluated after supplementation with auto-inducer-2 (AI-2). The protein-protein interaction network (PPIN) was used to retrieve the interactions between QS genes and four major metabolic pathway genes. The expression of luxS gene in DPUL-F36 may affect amino acid metabolism, carbohydrate metabolism and cell wall formation. The key differential metabolites were identified by metabolomics analysis. A variety of amino acids including L-Glutamic, L-Tryptophan, L-Threonine, L-Histidine and L-Glutamine were found to be up-regulated in response to the addition of AI-2. Malic acid and succinate gradually accumulate in the tricarboxylic acid cycle. The consumption of citric acid increased with the fermentation process. In terms of rheological and texture characteristics of fermented milk, addition of AI-2 could effectively improve its shear stress resistance, firmness and index of viscosity. Our research provided a theoretical basis for improving the fermentation performance of DPUL-F36 strains, and support for the screening of excellent composite starter culture.

MAP kinase kinase 1 (MEK1) within extracellular vesicles inhibits tumour growth by promoting anti-tumour immunity.

Extracellular vesicles (EVs) mediate intercellular communication in many physiologic processes and can modulate immune responses in individuals with cancer. Most studies of EVs in cancer have focused on their tumour promoting properties. Whether and how EVs might mediate tumour regression besides carrying antigens has not been well characterized. Using a mouse model of highly immunogenic regressor versus poorly immunogenic progressor tumour cells, we have characterized the role of EVs in activating macrophages and promoting tumour rejection. We found that the signalling molecule MAP2K1 (MEK1) is enriched in EVs secreted by regressor relative to progressor cells. Progressor EVs engineered to have levels of MEK1 similar to regressor EVs could inhibit tumour growth by indirectly promoting adaptive immunity in both syngeneic and 3rd party tumours. This effect required MEK1 activity and could occur by activating macrophages to promote adaptive immune responses against the tumour via the cytokine interferon-gamma. Our results suggest that MEK inhibition may be deleterious to cancer treatment, since MEK1 plays an important cell-extrinsic, tumour-suppressive role within EVs. Moreover, the delivery of MEK1 to tumour-associated macrophages, either by EVs, nanoparticles, or some other means, could be a useful strategy to treat cancer via the activation of anti-tumour immunity.

Experimental Insights into the Formation, Reactivity, and Crosstalk of Thionitrite (SNO-) and Perthionitrite (SSNO-).

Hydrogen sulfide (H2S) and nitric oxide (NO) are important gaseous biological signaling molecules that are involved in complex cellular pathways. A number of physiological processes require both H2S and NO, which has led to the proposal that different H2S/NO• crosstalk species, including thionitrite (SNO-) and perthionitrite (SSNO-), are responsible for this observed codependence. Despite the importance of these S/N hybrid species, the reported properties and characterization, as well as the fundamental pathways of formation and subsequent reactivity, remain poorly understood. Herein we report new experimental insights into the fundamental reaction chemistry of pathways to form SNO- and SSNO-, including mechanisms for proton-mediated interconversion. In addition, we demonstrate new modes of reactivity with other sulfur-containing potential crosstalk species, including carbonyl sulfide (COS).

A rising star involved in tumour immunity: Lactylation.

In recent years, continuous exploration worldwide has revealed that some metabolites produced during cellular and tissue metabolism can act as signalling molecules to exert different effects on the human body. These metabolites may act as cofactors for proteases or as post-translational modifications linked to proteins. Lactate, a traditional metabolite, is found at high levels in the tumour microenvironment (TME). Many studies have shown that lactate influences tumorigenesis and development via different mechanisms, not only through the metabolic reprogramming of tumours but also through its significant impact on tumour immunity. Previously, tumour cells were reported to use glucose and glutamine to fuel lactate metabolism; however, lactate serves not only as an energy source for tumour cells but also as a precursor substance needed for the post-translational modification of proteins. Recent studies identified a novel form of epigenetic modification, lactate-mediated histone lysine lactylation (Kla) and demonstrated that histone lactylation directly stimulates chromatin after gene transcription; consequently, lactylation has become a popular research topic in recent years. This article focuses on the research progress and application prospects of lactylation in the context of tumour immunity.

Purines and purinergic receptors in primary tumors of the central nervous system.

Purine nucleotides and nucleosides play critical roles in various pathological conditions, including tumor cell growth. Adenosine triphosphate (ATP) activates pro-tumor receptors, while adenosine (ADO) is a potent immunosuppressant and modulator of cell growth. This study aims to analyze the purinergic actions of ATP and its metabolites, associated enzymes, and P1 or P2 class receptors in primary central nervous system tumors. Additionally, we sought to correlate the levels of nucleosides and the density of P1, P2X, and P2Y receptors in cells with tumor progression. The results indicate that purinergic signaling depends on the receptor concentration and signaling molecules specific to each cell type, tissue, and tumor histology. The purinergic system may function as either a tumor-promoting agent or an antitumor factor, depending on the microenvironmental conditions and the concentrations of receptors and their respective activators. Notably, ATP emerges as the most significant extracellular signal, capable of being converted into other cellular stimulators pertinent to neoplasms, such as adenosine diphosphate, adenosine monophosphate, adenosine, and inosine. Consequently, a cascade of responses to these stimuli promotes tumor development, cell division, and metastasis. Purine nucleotides in central nervous system tumors are pivotal in cellular responses in glioblastoma multiforme, vestibular schwannoma, medulloblastoma, adenomas, gliomas, meningiomas, and pineal tumors. These findings hold the potential for developing novel therapeutic strategies and aiding in therapeutic management.

An agonist of the adenosine A2A receptor, CGS21680, promotes corneal epithelial wound healing via the YAP signalling pathway.

The adenosine A2A receptor (A2AR) is involved in various physiological and pathological processes in the eye; however, the role of the A2AR signalling in corneal epithelial wound healing is not known. Here, the expression, therapeutic effects and signalling mechanism of A2AR in corneal epithelial wound healing were investigated using the A2AR agonist CGS21680. A2AR localization and expression during wound healing in the murine cornea were determined by immunofluorescence staining, quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blotting. The effect of CGS21680 on corneal epithelial wound healing in the lesioned corneal and cultured human corneal epithelial cells (hCECs) by modulating cellular proliferation and migration was critically evaluated. The role of Hippo-YAP signalling in mediating the CGS21680 effect on wound healing by pharmacological inhibition of YAP signalling was explored. A2AR expression was up-regulated after corneal epithelial injury. Topical administration of CGS21680 dose-dependently promoted corneal epithelial wound healing in the injured corneal epithelium by promoting cellular proliferation. Furthermore, CGS21680 accelerated the cellular proliferation and migration of hCECs in vitro. A2AR activation promoted early up-regulation and later down-regulation of YAP signalling molecules, and pharmacological inhibition of YAP signalling reverted CGS21680-mediated wound healing effect in vivo and in vitro. A2AR activation promotes wound healing by enhancing cellular proliferation and migration through the YAP signalling pathway. A2ARs play an important role in the maintenance of corneal epithelium integrity and may represent a novel therapeutic target for facilitating corneal epithelial wound healing.