Fibroblasts-specific p16 exacerbates inflammageing-mediated post-infarction ventricular remodelling through interacting with STAT3 to regulate NLRP3 transcription.

Background And Aims: Inflammageing represents both a critical pathophysiological hallmark and independent risk factor for myocardial infarction (MI), with age-related increases observed in MI incidence and severity of post-MI ventricular remodelling. Novel therapeutic strategies targeting inflammageing-driven mechanisms are urgently required to attenuate adverse ventricular remodelling following MI. This investigation was designed to elucidate the impact of fibroblast-specific p16 on inflammageing-associated ventricular remodelling after MI and to develop a targeted nanotherapy to mitigate this process.

Predicting estrogen receptor agonists from plastic additives across various aquatic-related species using machine learning and AlphaFold2.

The absence of effective public databases greatly limits high-throughput prediction of hormonal effects mediated by nuclear receptors in aquatic organisms. In this study, we developed novel strategies for multi-species screening of estrogen receptor (ER) agonists in plastic additives using AlphaFold2. Firstly, Deep Forest (DF), artificial neural network (ANN) and conventional machine learning (ML) models were utilized to screen ERα agonists.

Thymic Bmi-1 hampers γδT17 generation and its derived RORγt-IL-17A signaling to delay cardiac aging.

New immunosenescence targets for preventing senescence-associated pathological cardiac hypertrophy (SA-PCH) need to be explored. In the present study, with physiologically aged human and mouse samples, the IL-17A level increased with physiological aging, heart failure (HF), and SA-PCH and was negatively correlated with thymic Bmi-1 expression. mice and littermates were generated to determine whether Bmi-1 delayed T cell aging by maintaining thymic T cell development to prevent SA-PCH.

New Psychoactive Substance Esketamine Causes Endocrine-Disrupting Effects and Developmental Toxicity.

Esketamine (ESK), a new psychoactive substance known for its strong hallucinogenic effect, has been detected in surface water worldwide. The toxicity of ESK to fish at a certain environmental concentration remains unclear. In this study, zebrafish embryos and ZF4 cells were exposed to ESK (0, 0.

Benzimidazole Fungicide Carbendazim Induces Gut Inflammation through the TLR5/NF-κB Pathway in Grass Carp.

Fungicides have been increasingly used across various sectors, including agriculture and textiles. The biocidal properties of fungicides may negatively impact the stability of intestinal microbiota, thereby posing a threat to intestinal health. In this study, we investigated the mechanisms of intestinal damage and functional abnormalities in grass carp following a 42-day exposure to the widely used fungicide carbendazim at environmentally relevant concentrations (0.

Copper excess induces autophagy dysfunction and mitochondrial ROS-ferroptosis progression, inhibits cellular biosynthesis of milk protein and lipid in bovine mammary epithelial cells.

Excessive copper (Cu) has the potential risk to ecosystems and organism health, with its impact on dairy cow mammary glands being not well-defined. This study used a bovine mammary epithelial cell (MAC-T) model to explore how copper excess affects cellular oxidative stress, autophagy, ferroptosis, and protein and lipid biosynthesis in milk. Results showed the increased intracellular ROS, MDA, and CAT (P < 0.

Estimation and evaluation of usage, loss and ecological risk of neonicotinoid pesticides in a large catchment.

Neonicotinoid pesticides (NNs) are increasingly used in agriculture, which may pose significant threats to aquatic organisms in receiving rivers. However, no studies have explored their entire process from application and transport to receptors within river basins. Here, we estimated the usage and loss of NNs in the Dongting Lake Basin in China using modeling approaches, and assessed NNs-associated aquatic ecological risks.

Antitussive drug dextromethorphan induces developmental impairment in zebrafish.

Dextromethorphan (DXM) is a common ingredient in cough and cold remedies. Despite its widespread presence in aquatic environments, the impact of DXM on fish remains largely unknown. This study evaluated the developmental impairment of zebrafish embryos exposed to DXM from 2 hours post-fertilization (hpf) to 14 days post-fertilization (dpf) at five different exposure concentrations: 0.

Evaluating pulmonary toxicity of PFOS and its alternative OBS using spheroids of A549 cells.

Sodium p-perfluorous nonenoxybenzene sulfonate (OBS) is a prominent alternative to perfluorooctanesulfonic acid (PFOS). Numerous studies have demonstrated hepatotoxicity and neurotoxicity of OBS and PFOS in mammals. The lungs, as a sensitive organ, are among the potential target organs for OBS and PFOS exposure.

Multiomics analysis reveal the impact of 17α-Ethinylestradiol on mortality in juvenile zebrafish.

17α-Ethinylestradiol (EE2) is known for its endocrine-disrupting effects on embryonic and adult fish. However, its impact on juvenile zebrafish has not been well established. In this study, juvenile zebrafish were exposed to EE2 at concentrations of 5 ng/L (low dose, L), 10 ng/L (medium dose, M), and 50 ng/L (high dose, H) from 21 days post-fertilization (dpf) to 49 dpf.

Bmi-1 Epigenetically Orchestrates Osteogenic and Adipogenic Differentiation of Bone Marrow Mesenchymal Stem Cells to Delay Bone Aging.

With the increase in the aging population, senile osteoporosis (SOP) has become a major global public health concern. Here, it is found that Prx1 and Bmi-1 co-localized in trabecular bone, bone marrow cavity, endosteum, and periosteum. Prx1-driven Bmi-1 knockout in bone-marrow mesenchymal stem cells (BMSCs) reduced bone mass and increased bone marrow adiposity by inhibiting osteoblastic bone formation, promoting osteoclastic bone resorption, downregulating the proliferation and osteogenic differentiation of BMSCs, and upregulating the adipogenic differentiation of BMSCs.

Effects of New Psychoactive Substance Esketamine on Behaviors and Transcription of Genes in Dopamine and GABA Pathways in Zebrafish Larvae.

Esketamine (ESK) is the S-enantiomer of ketamine racemate (a new psychoactive substance) that can result in illusions, and alter hearing, vision, and proprioception in human and mouse. Up to now, the neurotoxicity caused by ESK at environmental level in fish is still unclear. This work studied the effects of ESK on behaviors and transcriptions of genes in dopamine and GABA pathways in zebrafish larvae at ranging from 12.

[Water-holding characteristics of litter and soil and the influencing factors after individual rainfall].

To clarify the water-holding characteristics of forest litter and soil, different densities (0, 300, 600, 900 g·m) of litter were covered on the typical soil surface of loess cinnamon and calcareous cinnamon in north China. Based on an artificial simulated rainfall experiment, we observed the variation of litter and soil water content with time, and analyzed the variation process and influencing factors of litter and soil water content after rainfall. The results showed that water content of litter decreased significantly with the increases of duration after the rainfall, and that the range of litter water contents under all treatments was 22.

Screening androgen receptor agonists of fish species using machine learning and molecular model in NORMAN water-relevant list.

Androgen receptor (AR) agonists have strong endocrine disrupting effects in fish. Most studies mainly investigate AR binding capacity using human AR in vitro. However, there is still few methods to rapidly predict AR agonists in aquatic organisms.

An azole fungicide climbazole damages the gut-brain axis in the grass carp.

Azole antifungal climbazole has frequently been detected in aquatic environments and shows various effects in fish. However, the underlying mechanism of toxicity through the gut-brain axis of climbazole is unclear. Here, we investigated the effects of climbazole at environmental concentrations on the microbiota-intestine-brain axis in grass carp via histopathological observation, gene expression and biochemical analyses, and high-throughput sequencing of the 16 S rRNA.

Ephedrine and cocaine cause developmental neurotoxicity and abnormal behavior in zebrafish.

Ephedrine (EPH) and cocaine (COC) are illegal stimulant drugs, and have been frequently detected in aquatic environments. EPH and COC have negative effects on the nervous system and cause abnormal behaviors in mammals and fish at high concentrations, but their mechanisms of neurotoxicity remain unclear in larvae fish at low concentrations. To address this issue, zebrafish embryos were exposed to EPH and COC for 14 days post-fertilization (dpf) at 10, 100, and 1000 ng L.

Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer.

Multitarget HDAC inhibitors capable of simultaneously blocking the BRD4-LIFR-JAK1-STAT3 signaling pathway hold great potential for the treatment of TNBC and other solid tumors. Herein, novel Fedratinib-based multitarget HDAC inhibitors were rationally designed, synthesized, and biologically evaluated, among which compound stood out as a potent HDAC/JAK/BRD4 triple inhibitor. Satisfyingly, compound led to concurrent inhibition of HDACs and the BRD4-LIFR-JAK1-STAT3 signaling pathway, which was validated by hyper-acetylation of histone and α-tubulin, hypo-phosphorylation of STAT3, downregulation of LIFR, MCL-1, and c-Myc in MDA-MB-231 cells.

Climbazole causes cell apoptosis and lipidosis in the liver of grass carp.

Climbazole, an azole, is widely used in personal care products, pharmaceuticals, and pesticides and is frequently detected in surface water. Climbazole has showed endocrine-disrupting effects. However, the effects of climbazole in fish are still largely unclear.

Norethindrone suppress the germ cell development via androgen receptor resulting in male bias.

Progestins are widely used and detected in surface waters, and can affect gonad development and sexual differentiation in fish. However, the toxicological mechanisms of sexual differentiation induced by progestins are not well understood. Here, we investigated the effects of norethindrone (NET) and androgen receptor (AR) antagonist flutamide (FLU) on gonadal differentiation in zebrafish from 21 dpf (days post-fertilization) to 49 dpf.

IFNγ Transcribed by IRF1 in CD4+ Effector Memory T Cells Promotes Senescence-Associated Pulmonary Fibrosis.

Physiologically aged lungs are prone to senescence-associated pulmonary diseases (SAPD). This study aimed to determine the mechanism and subtype of aged T cells affecting alveolar type II epithelial (AT2) cells, which promote the pathogenesis of senescence-associated pulmonary fibrosis (SAPF). Cell proportions, the relationship between SAPD and T cells, and the aging- and senescence-associated secretory phenotype (SASP) of T cells between young and aged mice were analyzed using lung single-cell transcriptomics.

Bmi-1 Overexpression Improves Sarcopenia Induced by 1,25(OH) D Deficiency and Downregulates GATA4-Dependent Rela Transcription.

Sarcopenia increases with age, and an underlying mechanism needs to be determined to help with designing more effective treatments. This study aimed to determine whether 1,25(OH) D deficiency could cause cellular senescence and a senescence-associated secretory phenotype (SASP) in skeletal muscle cells to induce sarcopenia, whether GATA4 could be upregulated by 1,25(OH) D deficiency to promote SASP, and whether Bmi-1 reduces the expression of GATA4 and GATA4-dependent SASP induced by 1,25(OH) D deficiency in skeletal muscle cells. Bioinformatics analyses with RNA sequencing data in skeletal muscle from physiologically aged and young mice were conducted.

A Time-course Transcriptional Kinetics of Genes in Behavior, Cortisol Synthesis and Neurodevelopment in Zebrafish Larvae Exposed to Imidacloprid and Thiamethoxam.

Agricultural use of neonicotinoid insecticides, neuroactive nitroguanidine compounds, has been detected everywhere in the global, posing significant hazard to nontarget organisms. This work studied the developmental neurotoxicity of zebrafish larvae exposed to imidacloprid (IMI) and thiamethoxam (THM), ranging from 0.05 µg L to 50 µg L for 35 days.

Dydrogesterone and levonorgestrel at environmentally relevant concentrations have antagonist effects with rhythmic oscillation in brain and eyes of zebrafish.

Synthetic progestins levonorgestrel (LNG) and dydrogesterone (DDG) are frequency detected in surface water. Combined effects of LNG and DDG on gonad differentiation are similar to LNG single exposure in juvenile zebrafish. However, LNG and DDG mixtures have stronger effects on spermatogenesis in testes of adult zebrafish, which show variable at different life stage.