Pharmacological approaches for targeting lysosomes to induce ferroptotic cell death in cancer.

Lysosomes are crucial organelles responsible for the degradation of cytosolic materials and bulky organelles, thereby facilitating nutrient recycling and cell survival. However, lysosome also acts as an executioner of cell death, including ferroptosis, a distinctive form of regulated cell death that hinges on iron-dependent phospholipid peroxidation. The initiation of ferroptosis necessitates three key components: substrates (membrane phospholipids enriched with polyunsaturated fatty acids), triggers (redox-active irons), and compromised defence mechanisms (GPX4-dependent and -independent antioxidant systems). Notably, iron assumes a pivotal role in ferroptotic cell death, particularly in the context of cancer, where iron and oncogenic signaling pathways reciprocally reinforce each other. Given the lysosomes' central role in iron metabolism, various strategies have been devised to harness lysosome-mediated iron metabolism to induce ferroptosis. These include the re-mobilization of iron from intracellular storage sites such as ferritin complex and mitochondria through ferritinophagy and mitophagy, respectively. Additionally, transcriptional regulation of lysosomal and autophagy genes by TFEB enhances lysosomal function. Moreover, the induction of lysosomal iron overload can lead to lysosomal membrane permeabilization and subsequent cell death. Extensive screening and individually studies have explored pharmacological interventions using clinically available drugs and phytochemical agents. Furthermore, a drug delivery system involving ferritin-coated nanoparticles has been specifically tailored to target cancer cells overexpressing TFRC. With the rapid advancements in understandings the mechanistic underpinnings of ferroptosis and iron metabolism, it is increasingly evident that lysosomes represent a promising target for inducing ferroptosis and combating cancer.

Microbial mechanisms in nitrogen fertilization: Modulating the re-mobilization of clay mineral-bound cadmium in agricultural soils.

Soil cadmium (Cd) can affect crop growth and food safety, and through the enrichment in the food chain, it ultimately poses a risk to human health. Reducing the re-mobilization of Cd caused by the release of protons and acids by crops and microorganisms after stabilization is one of the significant technical challenges in agricultural activities. This study aimed to investigate the re-mobilization of stabilized Cd within the clay mineral-bound fraction of soil and its subsequent accumulation in crops utilizing nitrogen ammonium nitrogen (NH4+-N) and nitrate nitrogen (NO3--N), at 60 and 120 mg kg-1. Furthermore, the study harvested root exudates at various growth stages to assess their direct influence on the re-mobilization of stabilized Cd and to evaluate the indirect effects mediated by soil microorganisms. The results revealed that, in contrast to the NO3--N treatment, the NH4+-N treatment significantly enhanced the conversion of clay mineral-bound Cd in the soil to NH4NO3-extractable Cd. It also amplified the accumulation of Cd in edible amaranth, with concentrations in roots and shoots rising from 1.7-6.0 mg kg-1 to 4.3-9.8 mg kg-1. The introduction of NH4+-N caused a decrease in the pH value of the rhizosphere soil and stimulated the production and secretion organic and amino acids, such as oxalic acid, lactic acid, stearic acid, succinic acid, and l-serine, from the crop roots. Furthermore, compared to NO3--N, the combined interaction of root exudates with NH4+-N has a more pronounced impact on the abundance of microbial genes associated with glycolysis pathway and tricarboxylic acid cycle, such as pkfA, pfkB, sucB, sucC, and sucD. The effects of NH4+-N on crops and microorganisms ultimately result in a significant increase in the re-mobilization of stabilized Cd. However, the simulated experiments showed that microorganisms only contribute to 3.8-6.6 % of the re-mobilization of clay mineral-bound Cd in soil. Therefore, the fundamental strategy to inhibit the re-mobilization of stabilized Cd in vegetable cultivation involves the regulation of proton and organic acid secretion by crops.

Plastic does not simply flow into the sea: River transport dynamics affected by tides and floating plants.

Plastic pollution is ubiquitous in aquatic environments worldwide. Rivers connect terrestrial and marine ecosystems, playing a key role in the transport of land-based plastic waste towards the sea. Emerging research suggests that in estuaries and tidal rivers, tidal dynamics play a significant role in plastic transport and retention dynamics. To date, observations in these systems have been limited, and plastic transport dynamics during single tidal cycles remain poorly understood. Here, we investigated plastic transport, trapping, and re-mobilization of macroplastics (> 0.5 cm) in the Saigon River, focusing on short-term dynamics of individual tidal cycles. We used GPS trackers, released at different stages of the tidal cycle (ebb, flood, neap, spring). Plastic items demonstrated dynamic and intermittent transport behavior. Items spent almost half of the time (49%) temporarily stopped, mainly due to their entrapment in vegetation, infrastructure, or deposition on riverbanks. Items were almost always re-mobilized within 10 h (85%), leading to successive phases of stopping and transport. Tidal dynamics also resulted in bidirectional transport of plastic items, with median daily total transport distance within the 40 km study reach (8.9 km day-1) over four times larger than the median daily net distance (2.0 km day-1). The median retention time of plastic items within the reach was 21 days (mean = 202 days). In total, 81% of the retrieved items were trapped within water hyacinths, emphasizing the important role of floating vegetation on river plastic transport dynamics. With this paper, we aim to provide data-driven insights into macroplastic transport and retention dynamics in a tropical tidal river. These are crucial in the design of effective intervention and monitoring strategies, and estimating net plastic emission from rivers into the sea.

Nitrogen fertilizer affects rhizosphere Cd re-mobilization by mediating gene AmALM2 and AmALMT7 expression in edible amaranth roots.

In-situ stabilization of Cd-contaminated farmland is a commonly used remediation technology. Yet, rhizosphere metabolites (e.g., organic acids) during crop cultivation may cause Cd re-mobilization and over-accumulation. Here, we identified four pivotal cytomembrane-localized genes underlying Cd accumulation difference between two contrasting edible amaranth cultivars based on root gene expression profile, studied their subcellular localization and functional characteristics, and then investigated effects of nitrogen fertilizer on their expression and rhizosphere Cd re-mobilization. Results showed that more Cd accumulated by edible amaranth was due to rhizosphere Cd mobilization by mediating high expression of AmALMT2 and AmALMT7 genes, not Cd transporters in roots. This was confirmed by heterologous expression of AmALMT2 and AmALMT7 genes in Arabidopsis thaliana, since they mediated malic, fumaric, succinic, and aspartic acids efflux. Furthermore, nitrogen influencing rhizosphere acidification might be closely associated with organic acids efflux genes. Compared with N-NO3- application, N-NH4+ was massively assimilated into glutamates and oxaloacetates through up-regulating glutamine synthetase and alanine-aspartate-glutamate metabolic pathways, thereby enhancing TCA cycle and organic acids efflux dominated by binary carboxylic acids via up-regulating AmALMT2 and AmALMT7 genes, which finally caused Cd re-mobilization. Therefore, N-NO3--dominated nitrogen retarded rhizosphere Cd re-mobilization via inhibiting organic acids efflux function of AmALMT2 and AmALMT7 proteins.

Effects of Immobilization and Re-Mobilization on Knee Joint Arthrokinematic Motion Quality.

BACKGROUND: Knee immobilization is a common intervention for patients with traumatic injuries. However, it usually leads to biomechanical/morphological disturbances of articular tissues. These changes may contribute to declining kinetic friction-related quality of arthrokinematics; however, this phenomenon has not been analyzed in vivo and remains unrecognized. Thus, the aim of the present study is to investigate the effect of immobilization and subsequent re-mobilization on the quality of arthrokinematics within the patellofemoral joint, analyzed by vibroarthrography (VAG). METHODS: Thirty-four patients after 6-weeks of knee immobilization and 37 controls were analyzed. The (VAG) signals were collected during knee flexion/extension using an accelerometer. Patients were tested on the first and last day of the 2-week rehabilitation program. RESULTS: Immobilized knees were characterized by significantly higher values of all VAG parameters when compared to controls (p < 0.001) on the first day. After 2 weeks, the participants in the rehabilitation program that had immobilized knees showed significant improvement in all measurements compared to the baseline condition, p < 0.05. However, patients did not return to normal VAG parameters compared to controls. CONCLUSION: Immobilization-related changes within the knee cause impairments of arthrokinematic function reflected in VAG signal patterns. The alterations in joint motion after 6 weeks of immobilization may be partially reversible; however, the 2-week physiotherapy program is not sufficient for full recovery.

Participation of Green Organs to Grain Filling in Triticum turgidum var durum Grown under Mediterranean Conditions.

In wheat, flag leaf, stem, chaff and awns contribute to grain filling through photosynthesis and/or re-mobilization. Environmental and genetic effects on the relative contribution of each organ were examined by analyzing the consequences of sink-source manipulations (shading and excision) and by comparing carbon isotope discrimination (Δ) values in dry matter (at maturity) and sap (two weeks after anthesis) in six durum wheat genotypes grown in two contrasting seasons. The contribution of flag leaf, stem, chaff and awns to grain filling, estimated by sink-source manipulations, highly varied with the season. The contribution of ear photosynthesis and re-mobilization from the stem increased with post-anthesis water stress. They showed a large genetic variation that was, however, not clearly associated to morphological characteristics of ear and stem. Isotopic imprints of chaff on grain Δ were identified as a possible surrogate of the destructive and cumbersome sink-source manipulations to evaluate the contribution of carbon assimilated in ears or re-mobilized from stem. This might facilitate screening of genetic resources and allow the combining of favourable drought tolerance mechanisms in wheat.

Effects of nitrogen supply on the seasonal re-mobilization of nitrogen in Ulex europaeus.

Nodulated plants of Ulex europaeus L. (gorse) were grown over two seasons in sand. Nutrients were supplied as solutions containing either 0-25 mol m-3 NO3 -> , 5·0 mol m-3 NO3 , 0·25 mol m-3 NH4 -+ or 5·0 mol m-3 NH4 + , as Ca(NO3 )2 or (NH4 )2 SO4 . In the first season all nitrogen (N) was enriched with 15 N to 5 atom %. In the second season half the plants received the same solution, while the remaining plants received a similar solution in terms of form and amount of nitrogen but at natural abundance. Throughout the second season eight destructive harvests were performed. Plants were separated into roots, nodules, previous season's shoot, new shoot and flowers, and then analysed for total N and 15 N content. This allowed estimates to be made of total root N uptake, N2 fixation and the contribution of re-mobilization to the nitrogen content of new shoot growth in the second season. The main source of N was N2 fixation for plants receiving a low supply of N and root uptake for plants receiving a high supply of N. Plants supplied high NH4+ stored more N over winter than did plants given other treatments. The proportion of over-wintering stores that were re-mobilized to support spring shoot growth was unaffected by the capacity of the plants for N2 fixation.