The incorporation of acetylated LAP-TGF-ß1 proteins into exosomes promotes TNBC cell dissemination in lung micro-metastasis.

Triple-negative breast cancer (TNBC) stands as the breast cancer subtype with the highest recurrence and mortality rates, with the lungs being the common site of metastasis. The pulmonary microenvironment plays a pivotal role in the colonization of disseminated tumor cells. Herein, this study highlights the crucial role of exosomal LAP-TGF-ß1, the principal form of exosomal TGF-ß1, in reshaping the pulmonary vascular niche, thereby facilitating TNBC lung metastasis. Although various strategies have been developed to block TGF-ß signaling and have advanced clinically, their significant side effects have limited their therapeutic application. This study demonstrates that in lung metastatic sites, LAP-TGF-ß1 within exosomes can remarkably reconfigure the pulmonary vascular niche at lower doses, bolstering the extravasation and colonization of TNBC cells in the lungs. Mechanistically, under the aegis of the acetyltransferase TIP60, a non-canonical KFERQ-like sequence in LAP-TGF-ß1 undergoes acetylation at the K304 site, promoting its interaction with HSP90A and subsequent transport into exosomes. Concurrent inhibition of both HSP90A and TIP60 significantly diminishes the exosomal burden of LAP-TGF-ß1, presenting a promising therapeutic avenue for TNBC lung metastasis. This study not only offers fresh insights into the molecular underpinnings of TNBC lung metastasis but also lays a foundation for innovative therapeutic strategies.

Ginkgolide B targets and inhibits creatine kinase B to regulate the CCT/TRiC-SK1 axis and exerts pro-angiogenic activity in middle cerebral artery occlusion mice.

Promoting angiogenesis in the ischemic penumbra is a well-established method of ischemic stroke treatment. Ginkgolide B (GB) has long been recognized for its neuroprotective properties following stroke. As previously reported, it appears that stroke-induced neurogenesis and angiogenesis interact or are dependent on one another. Although the pharmacodynamic effect of GB on cerebral blood flow (CBF) following ischemic stroke has been reported, the molecular mechanism underlying this effect remains unknown. As such, this study sought to elucidate the pharmacodynamic effects and underlying mechanisms of GB on post-stroke angiogenesis. To begin, GB significantly increased the proliferation, migration, and tube formation capacity of mouse cerebral hemangioendothelioma cells (b.End3) and human umbilical vein endothelial cells (HUVEC). Additionally, GB significantly improved angiogenesis after oxygen-glucose deprivation/reperfusion (OGD/R) in endothelial cells. The dynamics of CBF, brain microvascular neovascularization and reconstruction, and brain endothelial tissue integrity were examined in middle cerebral artery occlusion (MCAO) mice following GB administration. Through label-free target detection techniques, we discovered for the first time that GB can specifically target Creatine Kinase B (CKB) and inhibit its enzymatic activity. Additionally, we demonstrated through network pharmacology and a series of molecular biology experiments that GB inhibited CKB and then promoted angiogenesis via the CCT/TRiC-SK1 axis. These findings shed new light on novel therapeutic strategies for neurological recovery and endothelial repair following ischemic stroke using GB therapy.

Strawberry Yield Improvement by Hydrogen-Based Irrigation Is Functionally Linked to Altered Rhizosphere Microbial Communities.

Molecular hydrogen (H2) is crucial for agricultural microbial systems. However, the mechanisms underlying its influence on crop yields is yet to be fully elucidated. This study observed that H2-based irrigation significantly increased strawberry (Fragaria × ananassa Duch.) yield with/without nutrient fertilization. The reduction in soil available nitrogen (N), phosphorus (P), potassium (K), and organic matter was consistent with the increased expression levels of N/P/K-absorption-related genes in root tissues at the fruiting stage. Metagenomics profiling showed the alterations in rhizosphere microbial community composition achieved by H2, particularly under the conditions without fertilizers. These included the enrichment of plant-growth-promoting rhizobacteria, such as Burkholderia, Pseudomonas, and Cupriavidus genera. Rhizobacteria with the capability to oxidize H2 (group 2a [NiFe] hydrogenase) were also enriched. Consistently, genes related to soil carbon (C) fixation (i.e., rbcL, porD, frdAB, etc.), dissimilar nitrate reduction (i.e., napAB and nrfAH), and P solublization, mineralization, and transportation (i.e., ppx-gppA, appA, and ugpABCE) exhibited higher abundance. Contrary tendencies were observed in the soil C degradation and N denitrification genes. Together, these results clearly indicate that microbe-mediated soil C, N, and P cycles might be functionally altered by H2, thus increasing plant nutrient uptake capacity and horticultural crop yield.

The role of glycemic traits in the mediation of the causal effect of hypothyroidism on coronary heart disease.

Background: Hypothyroidism and coronary heart disease are both common diseases in life and both are increasing in prevalence. Many studies have found a strong association between the two. However, they have not been able to prove a causal relationship. Furthermore, numerous studies have demonstrated that glycemic traits play a role in both. Consequently, the objective of this study was to ascertain the causal estimation of the association between hypothyroidism and coronary heart disease and to quantify the potential mediating role of glycemic traits in this relationship. Methods: We used two-sample Mendelian randomisation (UVMR) to explore causality between hypothyroidism and coronary heart disease. Additionally, multivariate Mendelian randomisation (MVMR) was applied to quantify the potential mediation of glycemic traits in this relationship. A variety of Mendelian randomization methods were employed in this study, including the inverse variance weighting (IVW) method, weighted median method, and MR-Egger test. Heterogeneity and horizontal pleiotropy were evaluated through MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis to ensure the robustness of the study results. Results: The results of the MR analyses indicated that hypothyroidism was associated with an increased risk of coronary heart disease (IVW: OR=2.75, 95% CI: 1.53-4.94). In mediation analyses, the proportion of HbA1c-mediated effects of hypothyroidism on coronary heart disease was 7.3% (2.2%-12.5%). Conclusion: The results of our study indicate a causal relationship between hypothyroidism and coronary heart disease. Furthermore, HbA1c partially mediated the causal effect of hypothyroidism on coronary heart disease. Consequently, intervention in this factor may reduce the risk of coronary heart disease associated with hypothyroidism.

The delayed senescence in harvested blueberry by hydrogen-based irrigation is functionally linked to metabolic reprogramming and antioxidant machinery.

Molecular hydrogen is beneficial for fruits quality improvement. However, the mechanism involved, especially cellular metabolic responses, has not been well established. Here, the integrated widely targeted metabolomics analysis (UPLC-MS/MS) and biochemical evidence revealed that hydrogen-based irrigation could orchestrate, either directly or indirectly, an array of physiological responses in blueberry (Vaccinium spp.) during harvesting stage, especially for the delayed senescence in harvested stage (4 °C for 12 d). The hubs to these changes are wide-ranging metabolic reprogramming and antioxidant machinery. A total of 1208 distinct annotated metabolites were identified, and the characterization of differential accumulated metabolites (DAMs) revealed that the reprogramming, particularly, involves phenolic acids and flavonoids accumulation. These changes were positively matched with the transcriptional profiles of representative genes for their synthesis during the growth stage. Together, our findings open a new window for development of hydrogen-based agriculture that increases the shelf-life of fruits in a smart and sustainable manner.

Exosomes derived from pulmonary metastatic sites enhance osteosarcoma lung metastasis by transferring the miR-194/215 cluster targeting MARCKS.

Osteosarcoma, a prevalent primary malignant bone tumor, often presents with lung metastases, severely impacting patient survival rates. Extracellular vesicles, particularly exosomes, play a pivotal role in the formation and progression of osteosarcoma-related pulmonary lesions. However, the communication between primary osteosarcoma and exosome-mediated pulmonary lesions remains obscure, with the potential impact of pulmonary metastatic foci on osteosarcoma progression largely unknown. This study unveils an innovative mechanism by which exosomes originating from osteosarcoma pulmonary metastatic sites transport the miR-194/215 cluster to the primary tumor site. This transportation enhances lung metastatic capability by downregulating myristoylated alanine-rich C-kinase substrate (MARCKS) expression. Addressing this phenomenon, in this study we employ cationic bovine serum albumin (CBSA) to form nanoparticles (CBSA-anta-194/215) via electrostatic interaction with antagomir-miR-194/215. These nanoparticles are loaded into nucleic acid-depleted exosomal membrane vesicles (anta-194/215@Exo) targeting osteosarcoma lung metastatic sites. Intervention with bioengineered exosome mimetics (anta-194/215@Exo) not only impedes osteosarcoma progression but also significantly prolongs the lifespan of tumor-bearing mice. These findings suggest that pulmonary metastatic foci-derived exosomes initiate primary osteosarcoma lung metastasis by transferring the miR-194/215 cluster targeting MARCKS, making the miR-194/215 cluster a promising therapeutic target for inhibiting the progression of patients with osteosarcoma lung metastases.

Argon-stimulated nitric oxide production and its function in alfalfa cadmium tolerance.

Recent results showed that argon may have great potential in both medicines (especially) and agriculture. However, how argon positively influences crop physiology remains elusive. Here, we observed that the stimulation of nitric oxide (NO) production upon cadmium (Cd) stress in hydroponic alfalfa root tissues was strengthened by argon-rich water and/or a NO-releasing compound. The pharmacological results further indicated that above potential source of NO stimulation achieved by argon might be attributed to NO synthase (NOS) and nitrate reductase (NR). Under hydroponic and pot conditions, the improvement of Cd tolerance elicited by argon, confirmed by the alleviation in the plant growth inhibition, oxidative damage, and Cd accumulation, was sensitive to the scavenger of NO. These results suggested a crucial role of argon-induced NO synthesis in response to Cd stress. Subsequent evidence showed that the improved iron homeostasis and increased S-nitrosylation were also dependent on argon-stimulated NO. Above results were matched with the transcriptional profiles of representative target genes involved in heavy metal detoxification, antioxidant defence, and iron homeostasis. Taken together, our results clearly indicated that argon-stimulated NO production contributes to Cd tolerance by favoring important defense strategies against heavy metal exposure.

Natural products: potential therapeutic agents for atherosclerosis.

Atherosclerosis (AS) is an invisible killer among cardiovascular diseases (CVD), which has seriously threatened the life of quality. The complex pathogenesis of AS involves multiple interrelated events and cell types, such as macrophages, endothelial cells, vascular smooth muscle cells and immune cells. Currently, the efficacy of recommended statin treatment is not satisfactory. Natural products (NPs) have attracted increasing attention with regard to their broad structural diversity and biodiversity, which makes them a promising library in the demand for lead compounds with cardiovascular protective bio-activity. NPs can preclude the development of AS by regulating lipid metabolism, ameliorating inflammation, stabilizing plaques, and remodeling the gut microbiota, which lays a foundation for the application of NPs in clinical therapeutics.

Study of quickly separating water from tunneling slurry waste by combining vacuum with electro-osmosis.

Tunneling slurry waste causes multiple problems, including environmental pollution, and requires transportation and a large landfill space, and therefore, it is important to find a method that can quickly separate water from tunneling slurry waste for metro construction. This paper proposes a practical method to improve the effect of slurry waste separation by implementing five laboratory tests. The results of these tests reflect that vacuum combined electro-osmosis is a suitable and practical method for treating tunneling slurry waste. The water content after treatment by vacuum combined horizontal electric field electro-osmosis method is not only lower than that after other methods but also close to the liquid limit, which fully meets the requirements of engineering transportation. However, vacuum and filter press dewatering cannot give full play to the drainage effect when the slurry permeability coefficient is too low. This combined technique can improve water separation from the slurry and works well in engineering applications.

New radiocarbon and archaeobotanical evidence reveal the timing and route of southward dispersal of rice farming in south China.

The origins and spreads of rice agriculture have been enduring topics, yet the timing and southward dispersal from the Yangtze River Basin have been difficult to trace, due to the scarcity of archaeobotanical data, especially systematic macro-plant remains examination, combined with the poor preservation in the humid climate and acidic soils of China's southern provinces. Here, we report new radiocarbon dating and preserved rice phytolith evidence, derived from three Late Neolithic archaeological sites in south China, dated about 5,000-4,100 cal a BP. Our results demonstrate that rice farming had spread southward through the mountainous regions of Wuyi and Nanling, then entered the areas of Western Fujian and North Guangdong by 5,000 cal a BP, followed by continued expansion into coastal areas of East China Sea and South China Sea, also crossing the Taiwan Strait, around 4,500-4,000 cal a BP. The North River, East River, Min River, and possibly other river systems likely were influential as pathways or conduits.