DAMPs in immunosenescence and cancer.

Damage-associated molecular patterns (DAMPs) are endogenous molecules released by cells in response to injury or stress, recognized by host pattern recognition receptors that assess the immunological significance of cellular damage. The interaction between DAMPs and innate immune receptors triggers sterile inflammation, which serves a dual purpose: promoting tissue repair and contributing to pathological conditions, including age-related diseases. Chronic inflammation mediated by DAMPs accelerates immunosenescence and influences both tumor progression and anti-tumor immunity, underscoring the critical role of DAMPs in the nexus between aging and cancer. This review explores the characteristics of immunosenescence and its impact on age-related cancers, investigates the various types of DAMPs, their release mechanisms during cell death, and the immune activation pathways they initiate. Additionally, we examine the therapeutic potential of targeting DAMPs in age-related diseases. A detailed understanding of DAMP-induced signal transduction could provide critical insights into immune regulation and support the development of innovative therapeutic strategies.

Kilogram-scale production of strong and smart cellulosic fibers featuring unidirectional fibril alignment.

Multifunctional fibers with high mechanical strength enable advanced applications of smart textiles, robotics, and biomedicine. Herein, we reported a one-step degumming method to fabricate strong, stiff, and humidity-responsive smart cellulosic fibers from abundant natural grass. The facile process involves partially removing lignin and hemicellulose functioning as glue in grass, which leads to the separation of vessels, parenchymal cells, and cellulosic fibers, where cellulosic fibers are manufactured at kilogram scale. The resulting fibers show dense and unidirectional fibril structure at both micro- and nano-scales, which demonstrate high tensile strength of ∼0.9 GPa and Young's modulus of 72 GPa, being 13- and 14-times higher than original grass. Inspired by stretchable plant tendrils, we developed a humidity-responsive actuator by engineering cellulosic fibers into the spring-like structures, presenting superior response rate and lifting capability. These strong and smart cellulosic fibers can be manufactured at large scale with low cost, representing promising a fiber material derived from renewable and sustainable biomass.

ITCH inhibits alkaliptosis in human pancreatic cancer cells through YAP1-dependent SLC16A1 activation.

Alkaliptosis is a type of pH-dependent cell death and plays an emerging role in tumor suppression. However, the key modulation mechanism of alkaliptosis remains largely unknown. In particular, the nucleus, as the centre of genetic and metabolic regulation, is crucial for the regulation of cellular life. It is not known whether nuclear proteins are involved in the regulation of alkaliptosis. Here, we isolated nuclear proteins to perform a proteomics that identified itchy E3 ubiquitin protein ligase (ITCH) as a natural inhibitor of alkaliptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. The downregulation of ITCH protein is associated with the induction of alkaliptosis in three human PDAC cell lines (SW1990, MiaPaCa2, and PANC1). Functionally, increasing ITCH expression reduces JTC801-induced growth inhibition and cell death. In contrast, knocking down ITCH using specific shRNA increases JTC801-induced cell growth inhibition in the short or long term, resulting in increased cell death. Mechanistically, JTC801-induced ITCH inhibition blocks large tumor suppressor kinase 1 (LATS1) ubiquitination, which in turn suppresses Yes1 associated transcriptional regulator (YAP1)-dependent the transcriptional activation of solute carrier family 16 member 1 (SLC16A1), a proton-linked monocarboxylate transporter that inhibits JTC801-induced alkaliptosis. Additionally, decreased expression of ITCH is associated with longer survival times in patients with PDAC. Collectively, our results establish an ITCH-dependent pathway that regulates alkaliptotic sensitivity in PDAC cells and deepen the understanding of alkaliptosis in targeted therapy.

[A comparative study of four combined methods for planning access to the anterior acetabular column for nail placement].

OBJECTIVE: To investigate global optimisation of anterior acetabular column pinning channels can be achieved based on large density point cloud data. METHODS: Data were collected on the CT scans of the normal pelvis in 40 adults from January 2022 to January 2023, including 22 males and 18 females, aged 20 to 54 years old. Medical imaging data from three of the samples were selected for experimental study. In planning access for anterior acetabular column pinning, to address the issue of whether the current CAD planning methods were advanced or not, four combinations of the same point cloud acquisition channels, different directional line creation software, and the same 3D design and virtual experiment software were proposed: Mimics+Imageware+UG, Mimics+3DReshaper+UG, Mimics+ZEISS Quality Suite+UG and Mimics+Design X+UG, and directional lines created based on the centroid point set and solid point cloud of the secondary pruning model, respectively, and it applied to the planning of the left anterior column pinning channel of the three acetabular samples. The maximum internally connected cylinder without acetabular socket and pubic bone penetration was used as a safe passage for nailing of the anterior acetabular column to evaluate the advancement of each method. RESULTS: The fitting effect of the directional line was better than that of the unnoised solid point cloud when the central point set with obvious relevant features was selected as the sample points;and the combination of Mimics+Imageware+UG and Mimics+3DReshaper+UG could efficiently and stably obtain the desirable planning results when planning with the central point set, respectively, in the three acetabular samples 1, 2, 3. The maximum internal joint circle diameters obtained in samples 1, 2, and 3 were 10.35 mm, 9.62 mm, and 9.24 mm;and when the directional lines were based on the solid point cloud the combined methods of Mimics+ZEISS Quality Suite+UG and Mimics+Design X+UG were not applicable;whereas the Mimics+3DReshaper+UG the solid point cloud denoising planning method could stably obtain the maximum value of the safe channel for nail placement, and the maximum internal joint circle diameters obtained in acetabular samples 1, 2, and 3 are 10.66 mm, 10.96 mm, and 9.48 mm, respectively. CONCLUSION: It is recommended that the nail placement channel planners use robust Mimics+Imageware+UG or Mimics+3DReshaper+UG centre point set planning method, and if there is enough time, it is recommended to use the solid point cloud denoising planning method of Mimics+3DReshaper+UG in order to obtain the maximum value of safe channels for nail placement.

Cetylpyridinium chloride triggers paraptosis to suppress pancreatic tumor growth via the ERN1-MAP3K5-p38 pathway.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive solid malignancy with low 5-year survival and limited treatment options. We conducted an unbiased screening using FDA-approved drug and demonstrated that cetylpyridinium chloride (CPC), a component commonly found in mouthwash and known for its robust bactericidal and antifungal attributes, exhibits anticancer activity against human PDAC cells. CPC inhibited PDAC cell growth and proliferation by inducing paraptosis, rather than apoptosis. Mechanistically, CPC induced paraptosis through the initiation of endoplasmic reticulum stress, leading to the accumulation of misfolded proteins. Subsequently, the endoplasmic reticulum stress to nucleus signaling 1 (ERN1)-mitogen-activated protein kinase kinase kinase 5 (MAP3K5)-p38 mitogen-activated protein kinase (MAPK) signaling pathway was activated, ultimately culminating in the induction of paraptosis. In vivo experiments, including those involving patient-derived xenografts, orthotopic models, and genetically engineered mouse models of PDAC, provided further evidence of CPC's effectiveness in suppressing the growth of pancreatic tumors.

Ciprofloxacin is a novel anti-ferroptotic antibiotic.

Cancer patients undergoing chemotherapy are susceptible to various bacterial infections, necessitating prompt and precise antimicrobial treatment with antibiotics. Ciprofloxacin is a clinically utilized broad-spectrum antimicrobial agent known for its robust antiseptic activity. While ferroptosis, an oxidative form of cell death, has garnered attention as a promising avenue in cancer therapy, the potential impact of ciprofloxacin on the anticancer effects of ferroptosis remains unclear. This study seeks to investigate the potential influence of antibiotics on ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Here, we report a previously unrecognized role of ciprofloxacin in inhibiting ferroptosis in human PDAC cells. Mechanistically, ciprofloxacin suppresses erastin-induced endoplasmic reticulum (ER) stress through the activating transcription factor 6 (ATF6) and ER to nucleus signaling 1 (ERN1) pathway. Excessive ER stress activation can trigger glutathione peroxidase 4 (GPX4) degradation through autophagic mechanisms. In contrast, ciprofloxacin enhances the protein stability of GPX4, a crucial regulator that suppresses ferroptosis by inhibiting lipid peroxidation. Thus, our study demonstrates the anti-ferroptotic role of ciprofloxacin, highlighting the importance of careful consideration when contemplating the combination of ciprofloxacin with specific ferroptosis inducers in PDAC patients.

Macropinocytosis inhibits alkaliptosis in pancreatic cancer cells through fatty acid uptake.

Alkaliptosis, a form of regulated cell death, is characterized by lysosomal dysfunction and intracellular pH alkalinization. The pharmacological induction of alkaliptosis using the small molecule compound JTC801 has emerged as a promising anticancer strategy in various types of cancers, particularly pancreatic ductal adenocarcinoma (PDAC). In this study, we investigate a novel mechanism by which macropinocytosis, an endocytic process involving the uptake of extracellular material, promotes resistance to alkaliptosis in human PDAC cells. Through lipid metabolomics analysis and functional studies, we demonstrate that the inhibition of alkaliptosis by fatty acids, such as oleic acid, is not dependent on endogenous synthetic pathways but rather on exogenous uptake facilitated by macropinocytosis. Consequently, targeting macropinocytosis through pharmacological approaches (e.g., using EIPA or EHoP-016) or genetic interventions (e.g., RAC1 knockdown) effectively enhances JTC801-induced alkaliptosis in human PDAC cells. These findings provide compelling evidence that the modulation of macropinocytosis can increase the sensitivity of cancer cells to alkaliptosis inducers.

Biocontrol potential of plant growth-promoting rhizobacteria against plant disease and insect pest.

Biological control is a promising approach to enhance pathogen and pest control to ensure high productivity in cash crop production. Therefore, PGPR biofertilizers are very suitable for application in the cultivation of tea plants (Camellia sinensis) and tobacco, but it is rarely reported so far. In this study, production of a consortium of three strains of PGPR were applied to tobacco and tea plants. The results demonstrated that plants treated with PGPR exhibited enhanced resistance against the bacterial pathogen Pseudomonas syringae (PstDC3000). The significant effect in improving the plant's ability to resist pathogen invasion was verified through measurements of oxygen activity, bacterial colony counts, and expression levels of resistance-related genes (NPR1, PR1, JAZ1, POD etc.). Moreover, the application of PGPR in the tea plantation showed significantly reduced population occurrences of tea green leafhoppers (Empoasca onukii Matsuda), tea thrips (Thysanoptera:Thripidae), Aleurocanthus spiniferus (Quaintanca) and alleviated anthracnose disease in tea seedlings. Therefore, PGPR biofertilizers may serve as a viable biological control method to improve tobacco and tea plant yield and quality. Our findings revealed part of the mechanism by which PGPR helped improve plant biostresses resistance, enabling better application in agricultural production.

Zinc Treatment of Tea Plants Improves the Synthesis of Trihydroxylated Catechins via Regulation of the Zinc-Sensitive Protein CsHIPP3.

The tea plant (Camellia sinensis [L.] O. Kussntze) is a global economic crop. Zinc treatment of tea plants can enhance catechin biosynthesis. However, the underlying molecular mechanism behind catechin formation through zinc regulation remains unclear. This study identified a zinc-responsive protein, C. sinensis heavy metal-associated isoprenylated plant protein 3 (CsHIPP3), from zinc-treated tea seedlings. CsHIPP3 expression was positively correlated with trihydroxylated catechin (TRIC) content. CsF3'5'H1 is a crucial regulator of the TRIC synthesis pathway. The interaction between CsHIPP3 and CsF3'5'H1 was assessed using bimolecular fluorescence complementation, firefly luciferase complementation imaging, and pulldown experiments. CsHIPP3 knockdown using virus-induced gene silencing technology decreased the content of each component of TRICs. Compared with the control, the relative catechin content was reduced by 40.12-55.39%. Co-overexpression of CsHIPP3 and CsF3'5'H1 significantly elevated the TRIC content in tea leaves and calli. Moreover, the TRIC content in transient co-overexpression leaves was 1.44-fold higher than that of the control group, and tea callus was 50.83% higher in transient co-overexpression than in the wild type. Thus, zinc-regulated TRIC synthesis in a zinc-rich environment was mediated by binding CsHIPP3 with CsF3'5'H1 to promote TRIC synthesis and accumulation.

Plant growth-promoting rhizobacteria (PGPR) improve the growth and quality of several crops.

Plant growth-promoting rhizobacteria (PGPR) are known to have the effect of promoting plant growth. In this paper, three PGPR strains were selected from the previous work, which had plant growth-promoting activities such as phosphate solubilization, nitrogen fixation, phosphorus mobilization, etc. These strains named FJS-3(Burkholderia pyromania), FJS-7(Pseudomonas rhodesiae), and FJS-16(Pseudomonas baetica), respectively, were prepared into solid biological agents. Three widely planted commercial crops (tea plant, tobacco, and chili pepper) were selected for PGPR growth promotion verification. The results showed that the new shoots of tea seedlings under PGPR treatment were much more than the control. We also used tobacco, another important crop in Guizhou, to test the growth-promoting effect of individual bacteria, and the results showed that each of them could promote the growth of tobacco plants, and FJS-3(Burkholderia pyrrocinia) had the best effect. In addition, we carried out experiments on tobacco and pepper using multi-strain PGPR, the tobacco plants' height, fresh, and root weight increased by 30.15 %, 37.36 %, and 54.5 %, respectively, and the pepper plants' increased by 30.10 %, 56.38 % and 43.18 %, respectively, which both showed significantly better effects than that of a single strain. To further test the field performance, field trials were carried out in a mature Longjing43 tea plantation in Guizhou. There were four treatments: no fertilization (T1), combined application of PGPR biological agent and compound fertilizer (T2), only application of PGPR (T3), and only application of compound fertilizer (T4). In terms of yield, grouped with or without PGPR, there was a 15.38 % (T2:T4) and 92.31 % (T3:T1) increase between them, respectively. The tea's yield and tea flavor substances such as tea polyphenols, caffeine, and theanine were detected, and the T2 showed the most significant positive effect on both sides. Especially, an important indicator of Matcha green tea is the color, chlorophyll content was then tested, and PGPR application increased it and improved the appearance. All these results demonstrated that the PGPR we screened could significantly promote plant growth and quality improvement, and had good application potential in crop planting, which could contribute to environmental protection and economic growth.