Integrating network pharmacology and animal experimental validation to investigate the action mechanism of oleanolic acid in obesity.

BACKGROUND: Obesity, a condition associated with the development of widespread cardiovascular disease, metabolic disorders, and other health complications, has emerged as a significant global health issue. Oleanolic acid (OA), a pentacyclic triterpenoid compound that is widely distributed in various natural plants, has demonstrated potential anti-inflammatory and anti-atherosclerotic properties. However, the mechanism by which OA fights obesity has not been well studied. METHOD: Network pharmacology was utilized to search for potential targets and pathways of OA against obesity. Molecular docking and molecular dynamics simulations were utilized to validate the interaction of OA with core targets, and an animal model of obesity induced by high-fat eating was then employed to confirm the most central of these targets. RESULTS: The network pharmacology study thoroughly examined 42 important OA targets for the treatment of obesity. The key biological processes (BP), cellular components (CC), and molecular functions (MF) of OA for anti-obesity were identified using GO enrichment analysis, including intracellular receptor signaling, intracellular steroid hormone receptor signaling, chromatin, nucleoplasm, receptor complex, endoplasmic reticulum membrane, and RNA polymerase II transcription Factor Activity. The KEGG/DAVID database enrichment study found that metabolic pathways, PPAR signaling pathways, cancer pathways/PPAR signaling pathways, insulin resistance, and ovarian steroidogenesis all play essential roles in the treatment of obesity and OA. The protein-protein interaction (PPI) network was used to screen nine main targets: PPARG, PPARA, MAPK3, NR3C1, PTGS2, CYP19A1, CNR1, HSD11B1, and AGTR1. Using molecular docking technology, the possible binding mechanism and degree of binding between OA and each important target were validated, demonstrating that OA has a good binding potential with each target. The molecular dynamics simulation's Root Mean Square Deviation (RMSD), and Radius of Gyration (Rg) further demonstrated that OA has strong binding stability with each target. Additional animal studies confirmed the significance of the core target PPARG and the core pathway PPAR signaling pathway in OA anti-obesity. CONCLUSION: Overall, our study utilized a multifaceted approach to investigate the value and mechanisms of OA in treating obesity, thereby providing a novel foundation for the identification and development of natural drug treatments.

Salidroside Mediated the Nrf2/GPX4 Pathway to Attenuates Ferroptosis in Parkinson's Disease.

Parkinson's Disease (PD) is characterized by the loss of dopaminergic neurons, with ferroptosis playing a significant role. Salidroside (SAL) has shown neuroprotective potential, this study aims to explore its capacity to mitigate ferroptosis in PD, focusing on the modulation of the Nuclear Factor E2-Related Factor 2 (Nrf2)/ Glutathione Peroxidase 4 (GPX4) pathway. Male C57BL/6 mice were subjected to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD-like symptoms, followed by SAL and Nrf2 inhibitor administration. Then behavioral tests, immunohistochemical staining, transmission electron microscopy, and Western blot analysis were conducted to assess motor functions, pathological changes, ferroptosis, and related protein expressions. In vitro, SH-SY5Y cells were treated with erastin to induce ferroptosis to assess the protective effects of SAL. Additionally, A53T-α-synuclein (α-syn) was used to stimulate the PD model, SAL and a Nrf2 inhibitor (ML385) was utilized to elucidate the role of the Nrf2/GPX4 pathway in mitigating ferroptosis in PD. In vivo, SAL significantly improved motor functions and reduced the expression of α-syn, while increasing tyrosine hydroxylase (TH) expression of PD mice. Additionally, SAL treatment notably enhanced the levels of antioxidants and reduced MDA and iron content in the substantia nigra of PD mice. In vitro, SAL treatment increased the TH, GPX4, Nrf2 expression, and mitochondrial membrane potential whereas alleviated ferroptosis through the Nrf2/GPX4 pathway, as evidenced in erastin-induced and α-syn overexpressing SH-SY5Y cells. While these effects were reversed upon Nrf2 inhibition. SAL demonstrates significant potential in mitigating PD pathology and ferroptosis, positioning the Nrf2/GPX4 pathway as a promising therapeutic target. However, future studies should focus on the long-term effects of SAL, its pharmacokinetics, addressing the multifactorial nature of PD pathogenesis.

Enhancing effect of sodium butyrate on phosphatidylserine-liposome-induced macrophage polarization.

OBJECT: Phosphatidylserine-containing liposomes (PSLs) can mimic the immunomodulatory effects of apoptotic cells by binding to the phosphatidylserine receptors of macrophages. Sodium butyrate, an antiinflammatory short-chain fatty acid, is known to facilitate the M2 polarization of macrophages. This study aimed to investigate the effect of sodium butyrate on PSLs-induced macrophage polarization. METHODS: PSLs physical properties and cellular uptake tests, reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, immunofluorescence staining, and flow cytometry analysis were performed to assess the polarization-related indicators of M1/M2 macrophages. RESULTS: The results showed that sodium butyrate did not affect the size and cellular uptake of PSLs. For M1 macrophage polarization, sodium butyrate significantly intensified the antiinflammatory function of PSLs, inhibiting LPS-induced proinflammatory genes expression, cytokines and enzyme release (tumor necrosis factor-alpha, interleukin (IL)-1ß, IL-6, and inducible nitric oxide synthase), as well as CD86 (M1 marker) expression. In addition to the enhancing effect of antiinflammation, sodium butyrate also promoted PSL-induced M2 macrophages polarization, especially elevated thymus and activation-regulated chemokine (TARC) and arginase-1 (Arg-1) enzyme levels which are involved in tissue repair. CONCLUSION: Sodium butyrate enhanced antiinflammatory properties and M2-polarization inducing effect of PSLs. Therefore, sodium butyrate may represent a novel approach to enhance PSL-induced macrophage polarization.

Commensal bacteria-derived extracellular vesicles suppress ulcerative colitis through regulating the macrophages polarization and remodeling the gut microbiota.

BACKGROUND: The extracellular vesicles (EVs) traffic constitutes an essential pathway of cellular communication. And the molecules in EVs produced by procaryotes help in maintaining homeostasis, addressing microbial imbalance and infections, and regulating the immune system. Despite the fact that Clostridium butyricum (C. butyricum) is commonly used for treating ulcerative colitis (UC), the potential role of C. butyricum-secreted EVs in commensals-host crosstalk remains unclear. RESULTS: Here, we performed flow cytometry, western blot, immunohistochemistry and 16S rRNA analysis to explore the role of C. butyricum-derived EVs on macrophage polarization and gut microbiota composition in a dextran sulfate sodium (DSS)-induced UC mouse model. The antibiotic cocktail-induced microbiome depletion and faecal transplantations were used to further investigate the mechanisms by which EVs regulate macrophage balance. Our findings showed that C. butyricum-derived EVs improved the remission of murine colitis and polarized the transformation of macrophages to the M2 type. Furthermore, C. butyricum-derived EVs restored gut dysbiosis and altered the relative abundance of Helicobacter, Escherichia-Shigella, Lactobacillus, Akkermansia and Bacteroides, which, in turn, faecal transplantations from EVs-treated mice relieved the symptoms of UC and improved the impact of EVs on the reprogramming of the M2 macrophages. CONCLUSION: C. butyricum-derived EVs could protect against DSS-induced colitis by regulating the repolarization of M2 macrophages and remodelling the composition of gut microbiota, suggesting the potential efficacy of EVs from commensal and probiotic Clostridium species against UC.

NAIL: an evolutionarily conserved lncRNA essential for licensing coordinated activation of p38 and NFκB in colitis.

OBJECTIVE: NFκB is the key modulator in inflammatory disorders. However, the key regulators that activate, fine-tune or shut off NFκB activity in inflammatory conditions are poorly understood. In this study, we aim to investigate the roles that NFκB-specific long non-coding RNAs (lncRNAs) play in regulating inflammatory networks. DESIGN: Using the first genetic-screen to identify NFκB-specific lncRNAs, we performed RNA-seq from the p65-/- and Ikkß-/- mouse embryonic fibroblasts and report the identification of an evolutionary conserved lncRNA designated mNAIL (mice) or hNAIL (human). hNAIL is upregulated in human inflammatory disorders, including UC. We generated mNAILΔNFκB mice, wherein deletion of two NFκB sites in the proximal promoter of mNAIL abolishes its induction, to study its function in colitis. RESULTS: NAIL regulates inflammation via sequestering and inactivating Wip1, a known negative regulator of proinflammatory p38 kinase and NFκB subunit p65. Wip1 inactivation leads to coordinated activation of p38 and covalent modifications of NFκB, essential for its genome-wide occupancy on specific targets. NAIL enables an orchestrated response for p38 and NFκB coactivation that leads to differentiation of precursor cells into immature myeloid cells in bone marrow, recruitment of macrophages to inflamed area and expression of inflammatory genes in colitis. CONCLUSION: NAIL directly regulates initiation and progression of colitis and its expression is highly correlated with NFκB activity which makes it a perfect candidate to serve as a biomarker and a therapeutic target for IBD and other inflammation-associated diseases.

Effects of chronic nitrate exposure on the intestinal morphology, immune status, barrier function, and microbiota of juvenile turbot (Scophthalmus maximus).

Coming along with high water reuse in sustainable and intensive recirculating aquaculture systems (RASs), the waste products of fish in rearing water is continuously accumulated. Nitrate, the final product of biological nitrification processes, which may cause aquatic toxicity to fish in different degrees when exposed for a long time. Therefore, the present study was conducted to evaluate the impact of chronic nitrate exposure on intestinal morphology, immune status, barrier function, and microbiota of juvenile turbot. For that, groups of juvenile turbot were exposed to 0 (control check, CK), 50 (low nitrate, L), 200 (medium nitrate, M), and 400 (high nitrate, H) mg L-1 nitrate-N in small-sized recirculating aquaculture systems. After the 60-day experiment period, we found that exposure to a high concentration of nitrate-N caused obvious pathological damages to the intestine; for instance, atrophy of intestinal microvilli and necrosis in the lamina propria. Quantitative real-time PCR analysis revealed a significant downregulation of the barrier forming tight junction genes like occludin, claudin-like etc. under H treatment (P < 0.05). Intestinal MUC-2 expression also decreased significantly in the nitrate treatment groups compared to that in the control (P < 0.05). Additionally, the expression of HSP70 and HSP90 heat-shock proteins, toll-like receptor-3 (TLR-3), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) significantly increased (P < 0.05), whereas that of transforming growth factor-ß (TGF-ß), lysozyme (LYS), and insulin-like growth factor-I (IGF-I) significantly decreased with H treatment (P < 0.05). The results also revealed that intestinal microbial community was changed following nitrate exposure and could alter the α-diversity and ß-diversity. Specifically, the proportion of intrinsic flora decreased, whereas that of the potential pathogens significantly increased with M and H treatments (P < 0.05). In conclusion, chronic nitrate exposure could weaken the barrier function and disturb the composition of intestinal microbiota in marine teleosts, thereby harming their health condition.

Telomerase: Key regulator of inflammation and cancer.

The telomerase holoenzyme, which has a highly conserved role in maintaining telomere length, has long been regarded as a high-profile target in cancer therapy due to the high dependency of the majority of cancer cells on constitutive and elevated telomerase activity for sustained proliferation and immortality. In this review, we present the salient findings in the telomerase field with special focus on the association of telomerase with inflammation and cancer. The elucidation of extra-telomeric roles of telomerase in inflammation, reactive oxygen species (ROS) generation, and cancer development further complicated the design of anti-telomerase therapy. Of note, the discovery of the unique mechanism that underlies reactivation of the dormant telomerase reverse transcriptase TERT promoter in somatic cells not only enhanced our understanding of the critical role of TERT in carcinogenesis but also opens up new intervention ideas that enable the differential targeting of cancer cells only. Despite significant effort invested in developing telomerase-targeted therapeutics, devising efficacious cancer-specific telomerase/TERT inhibitors remains an uphill task. The latest discoveries of the telomere-independent functionalities of telomerase in inflammation and cancer can help illuminate the path of developing specific anti-telomerase/TERT therapeutics against cancer cells.

Modulation of Macrophage Polarization by Phospholipids on the Surface of Titanium.

Macrophage polarization has become increasingly important for the improvement of the biocompatibility of biomaterials. In this study, we coated Ti discs with phospholipids (phosphatidylserine/phosphatidylcholine [4:1 mole/mole]) by evaporating the solvent under vacuum, and observed the polarization of RAW 264.7 cells cultured on the discs. The coated discs were hydrated before cell culture was added. The shape of the hydrated phospholipids varied with the concentration of loaded phospholipids: a perforated layer (0.1 mM), tubules and spheres (1 mM), and spheres (10 mM). RAW 264.7 cells exhibited different morphologies, depending on the concentration of phospholipids. On the coated discs, the gene expression and protein release of TGF-ß1, VEGF, Arg-1, and TNF-α were downregulated, especially with 10 mM phospholipids. The stimulation of mRNA expression and the protein release of those genes by IL-4 and LPS were also disturbed on the phospholipid-coated discs. In conclusion, the polarization of RAW 264.7 cells was prevented by hydrated phospholipids on Ti discs.

Transcriptional repressor GATA binding 1-mediated repression of SRY-box 2 expression suppresses cancer stem cell functions and tumor initiation.

Cancer stem cells (CSCs) have been reported in a variety of cancers. SRY-box 2 (SOX2) is a member of the SOX family of transcription factors and has been shown to play a critical role in maintaining the functions of CSCs and promoting tumor initiation. However, the underlying mechanisms for the transcriptional regulation of the SOX2 gene in CSCs are unclear. In this study, using in silico and experimental approaches, we identified transcriptional repressor GATA binding 1 (TRPS1), an atypical GATA-type transcription factor, as a critical transcriptional regulator that represses SOX2 expression and thereby suppresses cancer stemness and tumorigenesis. Mechanistically, TRPS1 repressed SOX2 expression by directly targeting the consensus GATA-binding element in the SOX2 promoter as elucidated by ChIP and luciferase reporter assays. Of note, in vitro mammosphere formation assays in culture and in vivo xenograft tumor initiation experiments in mouse models revealed that TRPS1-mediated repression of SOX2 expression suppresses CSC functions and tumor initiation. Taken together, our study provides detailed mechanistic insights into CSC functions and tumor initiation by the TRPS1-SOX2 axis.

Effect of flow velocity on the growth, stress and immune responses of turbot (Scophthalmus maximus) in recirculating aquaculture systems.

Land-based recirculating aquaculture systems (RAS) are widely utilized for turbot (Scophthalmus maximus) culture. Flow velocity in the tank is essential to maintain water quality, conservation of energy and fish welfare. However, little is known about how turbot respond to different velocities in the long term. In this study, water quality was kept constant, allowing the effect of flow velocity on the feeding intake, growth, plasma biochemical indexes, innate (non-specific) immunity and immune-related stress gene expressions in the skin to be examined in isolation in RAS. Turbot (average body length 20.10 cm) were reared for 60 days in RAS under three velocities, 0.06 m s-1, 0.18 m s-1, and 0.36 m s-1, corresponding to approximately 0.3 body length per second (bl s-1), 0.9 bl s-1 and 1.8 bl s-1, respectively. The results showed that at velocities of 0.36 m s-1 (1.8 bl s-1), juvenile turbot were subject to stress accompanied by a reduced growth rate. A velocity of 0.36 m s-1 was also found to significantly reduce SOD and GSH activity, and the concentration of total protein in plasma, while concentrations of urea nitrogen (BUN) and total bilirubin (TBIL) increased. There was an up-regulation of cathepsin D and lysozyme (LZM) in the skin at the highest velocity, implying the activation of stress and immune responses. At the medium velocity of 0.18 m s-1 (0.9 bl s-1), turbot increased their feed intake, obtained an elevated special growth rate (SGR), and exhibited significantly higher AKP and ACP activity in plasma. Overall, the results suggest that excessively high velocities are a stressor for turbot inducing an immune response in the skin, which is sensitive to environmental changes. A velocity of approximately 0.9 bl s-1 is suggested to promote growth and obtain better innate immunity of cultured turbot.

Effects of different light spectra on embryo development and the performance of newly hatched turbot (Scophthalmus maximus) larvae.

Light is a key environmental factor that synchronizes various life stages from embryo development to sexual maturation in fish. For turbot, light spectra have the most influence at the larval and juvenile stages. In the current study, differences in the development of embryos and the performance of newly hatched turbot larvae exposed to five different spectra: full spectrum (LDF), blue (LDB, peak at 450 nm), green (LDG, peak at 533 nm), orange (LDO, peak at 595 nm) and red (LDR, peak at 629 nm), were examined. At 62.8 h post fertilization, a higher number of embryos exposed to short-wavelengths (LDG and LDB) had developed a heartbeat in comparison with embryos exposed to other wavelengths. Larvae exposed to the green spectrum had higher malformation rates than larvae exposed to the other spectra, indicating that larvae exposed to green light may have significantly reduced survival rates. The results of non-specific immunity parameters showed that the mRNA expression levels of cathepsin D (CTSD), cathepsin F (CTSF), catalase (CAT) and metallothionein (MT) in larvae exposed to LDB were significantly higher than those exposed to other spectra, but CAT activity in larvae exposed to LDB was significantly lower than larvae exposed to the other spectra. There was no significant difference in MT activity in larvae exposed to the five different spectra. The mRNA expression level of lysozyme (LZM) in larvae exposed to LDR was significantly higher than other spectra, while there was no significant difference in LZM activity observed in larvae exposed to LDR, LDG, LDB and LDF. The difference of the enzyme activity of total superoxide dismutase (T-SOD) was not significant among larvae exposed to the five spectra. mRNA expression of the heat shock protein 70 (HSP70) was significantly higher in newly hatched larvae exposed to LDB, LDR and LDG, indicating that larvae exposed to LDB, LDG and LDR exhibited a stress response. The mRNA expression level of the insulin-like growth factor-1 (IGF-1) and growth parameters in the newly hatched larvae exposed to the different spectra were not significantly different. The results of the present study indicate that LDO and LDF should be used for embryo incubation and newly hatched larvae when rearing turbot. This study provides a theoretical basis for optimizing the incubation light environment for fertilized turbot eggs, promoting immunity and reducing stress responses in newly hatched larvae.

Apelin/APJ system: A novel potential therapy target for kidney disease.

Apelin is an endogenous ligand of seven-transmembrane G protein-coupled receptor APJ. Apelin and APJ are distributed in various tissues, including the heart, lung, kidney, and even in tumor tissues. Studies show that apelin mRNA is highly expressed in the inner stripe of kidney outer medulla, which plays an important role in process of water and sodium balance. Additionally, more studies also indicate that apelin/APJ system exerts a broad range of activities in kidney. Therefore, we review the role of apelin/APJ system in kidney diseases such as renal fibrosis, renal ischemia/reperfusion injury, diabetic nephropathy, polycystic kidney disease, and hemodialysis (HD). Apelin/APJ system can improve renal interstitial fibrosis by reducing the deposition of extracellular matrix. Apelin/APJ system significantly reduces renal ischemia/reperfusion injury by inhibiting renal cell death. Apelin/APJ system involves the progression of diabetic nephropathy (DN). Apelin/APJ system also predicts the process of polycystic kidney disease. Besides, apelin/APJ system prevents some dialysis complications in HD patients. And apelin/APJ system alleviates chronic kidney disease (CKD) by inhibiting vascular calcification (VC). Overall, apelin/APJ system plays diversified roles in kidney disease and may be a potential target for the treatment of kidney disease.

ROS-Autophagy pathway mediates monocytes-human umbilical vein endothelial cells adhesion induced by apelin-13.

Apelin is the endogenous ligand of APJ receptor. Both monocytes (MCs) and human umbilical vein endothelial cells (HUVECs) express apelin and APJ, which play important roles in the physiological processes of atherosclerosis. Our previous research indicated that apelin-13 promoted MCs-HUVECs adhesion. Here, we further explore the mechanism responsible for MCs-HUVECs adhesion induced by apelin-13. Apelin-13 promoted reactive oxygen species (ROS) generation and NOX4 expression in HUVECs. Apelin-13 inducedautophagy, increased proteins beclin1 and LC3-II/I expression and induced autophagy flux in HUVECs, which was blocked by NAC, catalase and DPI. Autophagy flux induced by apelin-13 was inhibited by NAC and catalase but not hydroxychloroquine (HCQ). NAC, catalase, and DPI prevented apelin-13 induced ICAM-1 expression in HUVECs. Rapamycin enhanced MCs-HUVECs adhesion that was reversed by NAC, catalase, and DPI. Down-regulation of beclin1 and LC3 by siRNA blocked MCs-HUVECs adhesion. Apelin-13 induced atherosclerotic plaque and increased NOX4, LC3-II/I expression in ApoE-/-(HFD) mouse model. Our results demonstrated that apelin-13 induced MCs-HUVECs adhesion via a ROS-autophagy pathway.

Tricho-rhino-phalangeal syndrome 1 protein functions as a scaffold required for ubiquitin-specific protease 4-directed histone deacetylase 2 de-ubiquitination and tumor growth.

BACKGROUND: Although numerous studies have reported that tricho-rhino-phalangeal syndrome type I (TRPS1) protein, the only reported atypical GATA transcription factor, is overexpressed in various carcinomas, the underlying mechanism(s) by which it contributes to cancer remain unknown. METHODS: Both overexpression and knockdown of TRPS1 assays were performed to examine the effect of TRPS1 on histone deacetylase 2 (HDAC2) protein level and luminal breast cancer cell proliferation. Also, RT-qRCR, luciferase reporter assay and RNA-sequencing were used for transcription detection. Chromatin immunoprecipitation (ChIP) using H4K16ac antibody in conjunction with qPCR was used for determining H4K16ac levels in targeted genes. Furthermore, in vitro cell proliferation assay and in vivo tumor xenografts were used to detect the effect of TRPS1 on tumor growth. RESULTS: We found that TRPS1 scaffolding recruits and enhances interaction between USP4 and HDAC2 leading to HDAC2 de-ubiquitination and H4K16 deacetylation. We detected repression of a set of cellular growth-related genes by the TRPS1-USP4-HDAC2 axis indicating it is essential in tumor growth. In vitro and in vivo experiments confirmed that silencing TRPS1 reduced tumor growth, whereas overexpression of HDAC2 restored tumor growth. CONCLUSION: Our study deciphered the TRPS1-USP4-HDAC2 axis as a novel mechanism that contributes to tumor growth. Significantly, our results revealed the scaffolding function of TPRS1 in USP4-directed HDAC2 de-ubiquitination and provided new mechanistic insights into the crosstalk between TRPS1, ubiquitin, and histone modification systems leading to tumor growth.

Long Non-Coding RNA Expression Signature Hallmarks Promising Efficacy in Identification of Human Non-Small Cell Lung Cancer: a Meta-Analysis Study.

BACKGROUND: The long non-coding RNAs (lncRNAs) are significantly altered in an expanding list of malignant neoplasms, suggesting that they might be popularized as potential biomarkers for cancer detection. This study sought to validate the diagnostic efficacy of lncRNA expression signature(s) as potential biomarker(s) for non-small cell lung cancer (NSCLC) diagnosis. METHODS: We conducted the online databases search for all eligible studies. A quantitative meta-analysis was performed using Stata 12.0 and Meta-Disc 1.4 statistical programs. Sensitivity analysis and a meta-regression test were applied to deeply trace the underlying heterogeneity sources. RESULTS: Eight cohorts comprised 775 NSCLC patients and 630 matched controls were included. Our data manifested that lncRNA expression profiling harbored a pooled sensitivity of 0.77 (95% CI: 0.71 - 0.82) and specificity of 0.86 (95% CI: 0.80 - 0.90) in discriminating NSCLC cases from cancer-free individuals, along with an AUC (area under the curve) value of 0.88. Further subgroup analysis revealed that paralleled testing of lncRNAs (sensitivity, specificity, and AUC of 0.90, 0.80 and 0.96, respectively) substantially strengthened the diagnostic efficacy as compared with the single testing pattern (sensitivity, specificity, and AUC of 0.71, 0.77 and 0.82, respectively). Other stratified analysis of ethnicity, histology type, and test matrix also presented robust results. CONCLUSIONS: Altogether, our results indicate that lncRNA expression signature(s) might be applicable as complementary biomarker(s) for the identification of NSCLC.

Comparative transcriptome analysis reveals growth and molecular pathway of body color regulation in turbot (Scophthalmus maximus) exposed to different light spectrum.

Fish body color changes play vital roles in adapting to ecological light environment and influencing market value. However, the initial mechanisms governing the changes remain unknown. Here, we scrutinized the impact of light spectrum on turbot (Scophthalmus maximus) body coloration, exposing them to red, blue, and full light spectra from embryo to 90 days post hatch. Transcriptome and quantitative real-time PCR (qRT-PCR) analyses were employed to elucidate underlying biological processes. The results showed that red light induced dimorphism in turbot juvenile skin pigmentation: some exhibited black coloration (Red_Black_Surface, R_B_S), while others displayed lighter skin (Red_White_Bottom, R_W_B), with red light leading to reduced skin lightness (L*) and body weight, particularly in R_B_S group. Transcriptomic and qRT-PCR analyses showcased upregulated gene expressions related to melanin synthesis in R_B_S individuals, notably tyrosinase (tyr), tyrosinase-related protein 1 (tyrp1), and dopachrome tautomerase (dct), alongside solute carrier family 24 member 5 (slc24a5) and oculocutaneous albinism type II (oca2) as pivotal regulators. Nervous system emerged as a critical mediator in spectral environment-driven color regulation. N-methyl d-aspartate (NMDA) glutamate receptor, and calcium signaling pathway emerged as pivotal links intertwining spectral conditions, neural signal transduction, and color regulation. The individual differences in NMDA glutamate receptor expression and subsequent neural excitability seemed responsible for dichromatic body coloration in red light-expose juveniles. This study provides new insights into the comprehending of fish adaptation to environment and methods for fish body color regulation and could potentially help enhance the economic benefit of fish farming industry.

Eupatilin inhibits xanthine oxidase in vitro and attenuates hyperuricemia and renal injury in vivo.

Uric acid (UA) is the final metabolite of purines in the liver that can cause hyperuricemia at high levels. The kidneys are the main excretory organs for UA. The excessive accumulation of UA in the kidneys causes the development of hyperuricemia that often leads to renal injury. Eupatilin (Eup) is a flavonoid natural product that possesses various pharmacological properties such as antioxidant, anti-cancer, and anti-inflammatory. We were interested in exploring the potential role of Eup in lowering UA and nephroprotective. We initially investigated the effects of Eup on xanthin oxidase (XOD) activity in vitro, followed by investigating its ability to lower UA levels, anti-inflammatory effects, nephroprotective effects, and the underlying mechanisms using hyperuricemia rats sustained at high UA level. The results showed that Eup had an inhibitory effect on XOD activity in vitro and significantly reduced serum UA, creatinine, BUN, IL-1ß and IL-6 levels in hyperuricemic rats, ameliorating inflammation, renal oxidative stress and pathological injury. Furthermore, Eup inhibited ADA and XOD enzyme activities in the liver and serum and modulated GLUT9, URAT1 and ABCG2 protein expression in the kidneys and ileum. Our findings provide a scientific basis for suggesting Eup as an option for a potential treatment for hyperuricemia.

Silicon fractionations in coastal wetland sediments: Implications for biogeochemical silicon cycling.

Coastal wetland sediment is important reservoir for silicon (Si), and plays an essential role in controlling its biogeochemical cycling. However, little is known about Si fractionations and the associated factors driving their transformations in coastal wetland sediments. In this study, we applied an optimized sequential Si extraction method to separate six sub-fractions of non-crystalline Si (Sinoncry) in sediments from two coastal wetlands, including Si in dissolved silicate (Sidis), Si in the adsorbed silicate (Siad), Si bound to organic matter (Siorg), Si occluded in pedogenic oxides and hydroxides (Siocc), Si in biogenic amorphous silica (Siba), and Si in pedogenic amorphous silica (Sipa). The results showed that the highest proportion of Si in the Sinoncry fraction was Siba (up to 6.6 % of total Si (Sitot)), followed by the Sipa (up to 1.8 % of Sitot). The smallest proportion of Si was found in the Sidis and Siad fractions with the sum of both being <0.1 % of the Sitot. We found a lower Siocc content (188 ± 96.1 mg kg-1) when compared to terrestrial soils. The Sidis was at the center of the inter-transformation among Si fractions, regulating the biogeochemical Si cycling of coastal wetland sediments. Redundancy analysis (RDA) combined with Pearson's correlations further showed that the basic biogenic elements (total organic carbon and total nitrogen), pH, and sediment salinity collectively controlled the Si fractionations in coastal wetland sediments. Our research optimizes sediment Si fractionation procedure and provides insights into the role of sedimentary Si fractions in controlling Si dynamics and knowledge for unraveling the biogeochemical Si cycling in coastal ecosystems.

Tumour microenvironment programming by an RNA-RNA-binding protein complex creates a druggable vulnerability in IDH-wild-type glioblastoma.

Patients with IDH-wild-type glioblastomas have a poor five-year survival rate along with limited treatment efficacy due to immune cell (glioma-associated microglia and macrophages) infiltration promoting tumour growth and resistance. To enhance therapeutic options, our study investigated the unique RNA-RNA-binding protein complex LOC-DHX15. This complex plays a crucial role in driving immune cell infiltration and tumour growth by establishing a feedback loop between cancer and immune cells, intensifying cancer aggressiveness. Targeting this complex with blood-brain barrier-permeable small molecules improved treatment efficacy, disrupting cell communication and impeding cancer cell survival and stem-like properties. Focusing on RNA-RNA-binding protein interactions emerges as a promising approach not only for glioblastomas without the IDH mutation but also for potential applications beyond cancer, offering new avenues for developing therapies that address intricate cellular relationships in the body.

Organic matter composition and stability in estuarine wetlands depending on soil salinity.

Coastal wetlands are key players in mitigating global climate change by sequestering soil organic matter. Soil organic matter consists of less stable particulate organic matter (POM) and more stable mineral-associated organic matter (MAOM). The distribution and drivers of MAOM and POM in coastal wetlands have received little attention, despite the processes and mechanisms differ from that in the upland soils. We explored the distribution of POM and MAOM, their contributions to SOM, and the controlling factors along a salinity gradient in an estuarine wetland. In the estuarine wetland, POM C and N were influenced by soil depth and vegetation type, whereas MAOM C and N were influenced only by vegetation type. In the estuarine wetland, SOM was predominantly in the form of MAOM (> 70 %) and increased with salinity (70 %-76 %), leading to long-term C sequestration. Both POM and MAOM increased with SOM, and the increase rate of POM was higher than that of MAOM. Aboveground plant biomass decreased with increasing salinity, resulted in a decrease in POM C (46 %-81 %) and N (52 %-82 %) pools. As the mineral amount and activity, and microbial biomass decreased, the MAOM C (2.5 %-64 %) and N pool (8.6 %-59 %) decreased with salinity. When evaluating POM, the most influential factors were microbial biomass carbon (MBC) and dissolved organic carbon (DOC). Key parameters, including MBC, DOC, soil salinity, soil water content, aboveground plant biomass, mineral content and activity, and bulk density, were identified as influencing factors for both MAOM abundance. Soil water content not only directly controlled MAOM, but together with salinity also indirectly regulated POM and MAOM by controlling microbial biomass and aboveground plant biomass. Our findings have important implications for improving the accumulation and increased stability of soil organic matter in coastal wetlands, considering the global sea level rise and increased frequency of inundation.