Ageing and the lymphatic system: Implications for immunity, brain health, and possible therapeutic interventions.

The pathological features of invasion and metastasis in malignant tumors are intricately intertwined with the tumor microenvironment (TME). Recent investigations underscore that, alongside immune cells, blood vessels, and the lymphatic system, the nervous system emerges as a pivotal player within the TME. Tumors possess the remarkable ability to modify and even co-opt the architecture and functions of the nervous system, creating a dynamic interplay. Furthermore, aberrant neuronal activation has the potential to accelerate tumor progression. This review summarizes the emerging field of cancer neuroscience, encompassing both direct neuro-cancer cell communication and indirect interactions mediated through other TME components. It further outlines the commonly used experimental tools, cutting-edge technologies, and potential therapeutic targets identified along neuro-cancer interaction pathways. By elucidating the reciprocal interplay between the nervous system and tumors, this area of research offers new perspectives for understanding tumorigenesis and provides promising molecular targets and strategies for cancer therapy.

Untargeted metabolomic profiling reveals mTORC1-dependent regulation of amino acid utilization in lymphatic endothelial cells.

In recent years, with the continuous development of scientific and technological means, human understanding of previously unknown or insufficiently recognized physiological structures is gradually being decrypted, and the exploration of the causes of disease occurrence and development has become more thorough. As a newly discovered intracranial material transport system, the glymphatic system is named after its similarity to the lymphatic circulatory system. Its structure and function are gradually being understood, and its mechanism of action in central nervous system diseases is constantly being explored. More and more studies have confirmed the important relationship between glymphatic system dysfunction and central nervous system diseases from human, animal, and cell dimensions, and more and more evidence has revealed that regulating glymphatic system function is helpful to treat central nervous system diseases from behavior, imaging, pathology, and molecule. Therefore, this paper will review the glymphatic system from three aspects: structure, function, and mechanism in central nervous system diseases, with the intention of elaborating the mechanism of glymphatic system dysfunction in central nervous system diseases, and then contributing to its further research and exploration.

Pulmonary lymphatics play multiple essential roles in lung homeostasis through interstitial fluid removal, traffic of immune cells, and antigen presentation. This highly branching vascular bed comprises initial capillaries, pre-collecting vessels, and collecting lymphatics, and it is lined by characteristic lymphatic endothelial cells (LECs). These cells are distinct from blood endothelial cells in their structure, molecular markers (e.g., PROX1, LYVE-1, VEGFR-3), and responsiveness to inflammatory and mechanical stimuli. In health, LECs preserve barrier integrity, promote immune surveillance, and support unidirectional lymph flow. However, during pulmonary inflammation or injury, LECs may undergo phenotypic changes that impair function and promote local coagulation. This review consolidates current knowledge on pulmonary lymphatic vessel structure and function and LEC biology, with a focus on their involvement in inflammation and coagulation pathways. We examine how cigarette smoke disrupts LEC homeostasis, leading to endothelial injury, procoagulant factor upregulation [e.g., tissue factor, plasminogen activator inhibitor-1 (PAI-1)], and fibrin-rich thrombosis in lung lymphatics. Although vaping induces oxidative stress and vascular inflammation, its effects on the pulmonary lymphatic system have not been clearly explained. Based on pathological features shared with smoking, we propose potential mechanisms by which e-cigarette aerosols may contribute to lymphatic endothelial dysfunction and altered coagulation in lungs. Given the increasing prevalence of vaping, further research using in vitro, in vivo, and human studies is needed to elucidate how inhaled toxicants alter LEC function and to identify novel targets for preserving lymphatic health in lung disease.

Accurate and early diagnosis of cancer is critical for determining effective treatment strategies and improving patient survival rates. However, automated multi-class cancer detection remains an enormous clinical and computational challenge due to the high visual heterogeneity within specific cancer classes and the morphological similarities across different types of malignancies. Deep convolutional neural networks (CNNs), particularly the VGG-16 architecture, offer robust feature extraction capabilities for medical imaging; yet, their diagnostic performance is heavily restricted by suboptimal hyperparameter tuning and inefficient feature utilization. To solve this problem, this article proposes a comprehensive, dual-strategy deep learning framework that integrates both pre-trained and fine-tuned VGG-16 models with six nature-inspired metaheuristic optimization algorithms. By employing the Whale Optimization Algorithm (WOA), Grey Wolf Optimizer (GWO), Particle Swarm Optimization (PSO), Genetic Algorithm (GA), Ant Colony Optimization (ACO), and Modified PSO (MPSO), the framework autonomously optimizes critical hyperparameters to maximize classification accuracy. The proposed methodology was rigorously evaluated on two complex imaging datasets: a five-class dataset for cervical cancer (a leading global cause of female cancer-related mortality) and a three-class dataset for lymphoma (a complex malignancy of the lymphatic system). The experimental results demonstrated that integrating pre-trained VGG-16 networks with metaheuristic optimizers significantly outperformed baseline models across both datasets. Notably, the Whale Optimization Algorithm (WOA) exhibited superior performance, achieving up to 100% in accuracy, precision, recall, and specificity during the testing phase for both datasets. These findings confirm that optimizing deep CNNs with metaheuristic algorithms provides a highly adaptable, reliable, and precise framework capable of resolving the complexities of high-dimensional multi-class cancer diagnosis.

The lymphatic system plays a fundamental role in cardiovascular physiology by maintaining whole-body fluid balance, facilitating immune trafficking, and enabling lipid transport. Through these functions, lymphatic performance is tightly coupled to cardiovascular health, and disturbances in lymphatic flow, pumping, or lympho-venous return can directly influence the development and progression of heart disease. This review examines the relationship between the lymphatic and cardiovascular systems with an emphasis on systemic lymphatic function and its relevance to cardiovascular pathology. We describe the structure and physiology of the human lymphatic vasculature, including mechanisms governing lymph formation, transport, and return to the venous circulation, and discuss how these processes are challenged in conditions such as heart failure, venous congestion, and altered hemodynamics. Clinical and experimental evidence linking lymphatic dysfunction to edema, inflammation, and impaired organ function across multiple cardiovascular disease states - including heart failure, atherosclerosis, congenital heart disease, and heart transplantation - is considered. In addition, comparative and translational perspectives are presented illustrating how diverse vertebrate lymphatic strategies inform fundamental principles of lymphatic regulation and translational cardiovascular research. Finally, emerging imaging modalities and therapeutic approaches targeting lymphatic structure and function are discussed as potential avenues for improving the diagnosis and treatment of cardiovascular disease. Together, this review positions the lymphatic system as an integral, system-level contributor to cardiovascular physiology and disease, underscoring the need to consider lymphatic function alongside the blood circulation in both research and clinical practice.

Many patients with coronary artery disease are eligible for either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Technical and clinical aspects influence the decision for either treatment. However, biological effects of PCI and CABG on long-term coronary artery anatomy and physiology should be considered but are largely unknown. Eight German landrace swine were used in this study. An artificial atherosclerotic plaque (AAP) was implanted into the left anterior descending coronary artery (LAD) to simulate coronary atherosclerosis. Physiological changes of PCI and surgical CABG in vascular and perivascular tissue were assessed in an ex vivo setting (organ care system OCS). Furthermore, radiological and nuclear imaging was performed using single photon emission computed tomography (SPECT) and computed tomography (CT). Furthermore, interventional (PCI) and surgical (CABG) treatment was evaluated using an ex-vivo setting. Lymphatic flow and myocardial perfusion were improved in pigs in the CABG group compared to the PCI group. The PCI group showed a significantly higher mean count number proximal to the intervention in the LAD area. Stenting experiments showed a significantly higher mean count number proximal to the intervention in the LAD area. This effect could also be demonstrated macroscopically, as myocardial infarct areas were smaller and myocardial function was better after defibrillation in the OCS (organ care system) in the CABG treated hearts. The artificial atherosclerotic plaque model in porcine hearts is a new valuable tool to simulate coronary artery stenosis without damaging other organs. It may serve as a tool for future medical testing and for further specific research on coronary artery physiology. Our data suggest that the cardiac lymphatic vascular system and perfusion capability are partly restricted after PCI as compared to CABG.

Model-guided design of lymphatic drug delivery systems using osmotic pressure, viscosity and lymph node size.

The lymphatic system maintains physiological homeostasis through constant immunosurveillance, immune cell trafficking, and regulation of interstitial fluid flow. Lymphatic dysfunction is associated with a wide range of pathologies, including cancer metastasis and lymphedema. Aberrant lymphatic structure also contributes to chronic wounds and transplanted organ rejection. These functional and structural deficits have inspired strategies for lymphatic vasculature modulation and tissue engineering to regulate immune functions during disease and injury rehabilitation. Lymphangiogenesis-the process of lymphatic vessel growth- is central to the success of these strategies and has broad potential if harnessed for therapeutic intervention and tissue integration. Here we review the opportunities and obstacles for biomolecular pathway modulation, nanotechnology, and tissue engineering to promote or inhibit lymphangiogenesis.

High endothelial venules (HEVs) provide another portal for tumour metastasis. However, whether HEVs and other blood vessels exert different effects on tumour escape remains unknown. Here we show that tumour involvement in HEVs is an independent prognostic marker for patients with lymph node (LN)-positive female breast cancer. Tumour cells that spread via HEVs are less immunogenic and more capable of establishing distant metastases than those that spread through non-HEV blood vessels. Mechanistically, the expression of arachidonate 12-lipoxygenase (ALOX12) in HEVs is promoted by tumour-derived semaphorin 3 C (SEMA3C). Reciprocally, ALOX12-derived metabolite 12-hydroxyeicosatetraenoic acid (12-HETE) promotes ADAR1 p150-dsRNA phase separation in tumour cells by selectively binding to ADAR1 p150. Consequently, the immune recognition of dsRNA is reduced because of the increased adenosine-to-inosine (A-to-I) RNA editing in tumour cells. Collectively, our data indicate that a unique lymphatic anatomical structure mediates specific immune evasion of migrating tumour cells.

Lipedema is a chronic and progressive adipose tissue disorder that is often misdiagnosed and notoriously resistant to weight loss. Liposuction remains the most effective surgical treatment, but it requires precise technique to preserve the fragile lymphatic system. This study investigates the utility ofpre-, intra- and postoperative ultrasound (US) to objectively assess fat reduction and the selective removal of pathological adipose tissuein patients undergoing liposuction for lipedema. A retrospective, single-center study of 24 female patients with lipedema who underwent liposuction of the lower extremities. Perioperative US was used to measure the thickness of the superficial subcutaneous fat (D1) and the deep fat layer (D2) at a standardized anatomical site. Intraoperative US was employed to verify that fat aspiration was performed in the correct superficial plane. A paired t-test was conducted to assess the statistical significance of the change in D1 thickness. The mean patient age was 38 years, with a mean BMI of 25.3 kg/m2. The mean volume of liposuction aspirate was 4.5 L. Statistical analysis showed asignificant reductionin mean D1 thickness from 9.9 mm preoperatively to 6.3 mm immediately postoperatively (p < 0,05). This reduction was sustained at the 3-month follow-up, with a mean D1 thickness of 5.8 mm. Our pilot study suggests that the perioperative use of ultrasound is a valuable tool for objectively documenting the selective fat reduction achieved with liposuction in lipedema patients. Intraoperative US not only enhances surgical precision, but also reduces the risk of complicationsby confirming correct cannula positioning in the superficial plane. This technique enhances surgical precision by allowing for thequantifiable removal of pathological superficial fat, confirming its potential to improve outcomes with a low complication rate. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Lipid Drug Conjugates (LDCs) are the conjugates of drug molecules in which covalently bound lipids are attached, enhancing lipophilicity and altering other pharmaceutical properties. Overall, conjugates show improved oral bioavailability, targeted delivery to the lymphatic system and tumours, and reduced toxicity. The coupling of drugs with lipids can be performed using a variety of techniques and chemical linkers, which are considered crucial for optimal drug delivery and good therapeutic outcomes. The choice of linker and conjugation strategy affects the delivery of the drug from the LDC, thereby influencing the formulation's performance and safety. Such traditional lipid-based drug formulations face challenges, including poor blood circulation, inadequate tumor targeting, and potential toxicities arising from the release of drugs during anticancer therapy from systemic circulation. However, recent advances in bioconjugation strategies have improved the physicochemical properties, pharmacokinetics, and antitumor activity of LDCs. Such improvements have been reported mainly in preclinical models, where LDCs generally exhibit reduced toxicity and enhanced therapeutic efficacy compared to conventional lipid formulations. An exciting new approach is the use of stimuli-responsive linkers in LDCs, which release the drug in response to specific triggers in the tumor microenvironment. These systems have the advantage of releasing a sustained amount of drug at the tumor site while minimizing systemic exposure. Moreover, the amphiphilic nature of most lipid-drug conjugates facilitates the self-assembly of nanoparticles for targeted drug delivery. This review focuses on various stimuli-responsive chemical bonds in lipids, conjugation strategies, and delivery forms used in LDCs, and highlights the prospects they offer for improving cancer treatments.

Tumor vaccines represent a promising strategy for mobilizing the immune system against malignancies, however, their efficacy is limited by poor antigen immunogenicity, inefficient lymph nodes (LNs) accumulation, and inadequate antigen presentation by antigen-presenting cells (APCs), particularly dendritic cells (DCs). Pyroptosis, a pro-inflammatory form of cell death known to enhance immunogenicity, and autophagy, a cellular pathway that promotes MHC class I and II antigen presentation in APCs, have emerged as two compelling mechanisms to address these limitations. Here, we developed a biomimetic hybrid nanovaccine (hDMVac) by repeatedly extruding pyroptotic B16 and DC2.4, followed by loading with beclin-1. The results show that hDMVac exhibited a particle size of approximately 160nm and showed enhanced accumulation in LNs after subcutaneous injection, with time-dependent distribution within the lymphatic system. The incorporation of pyroptotic tumor cells significantly enhanced antigen immunogenicity. Moreover, beclin-1 loading robustly induced autophagy in DCs, facilitating DCs maturation and markedly enhancing cross-presentation of antigens within LNs. The synergistic effect significantly amplified antigen-specific T cell activation. Consequently, hDMVac effectively suppressed tumor growth in both prophylactic and therapeutic melanoma models. This dual strategy represents a synergistic approach to overcoming the limitations of conventional tumor vaccines, representing a clinically translatable platform compatible with existing immunotherapies for improved tumor treatment.

Oral immunization with attenuated Salmonella enterica serovar Enteritidis expressing dual-toxin antigen induces protective immunity against avian necrotic enteritis.

Ginsenoside Rg1 Ameliorates LPS-Induced Sepsis-Associated Lung Injury in Mice via VEGFC/D-VEGFR3 Signaling-Mediated Lymphangiogenesis and Lymphatic Remodeling.

A cancerous tumor harbors millions of genetically mutated cells, which after hyperproliferation are picked up and transported to various sites in the human body by the bloodstream or lymphatic system. These circulating tumor cells (CTCs) become the seeds for the subsequent growth of secondary tumors. Hence, CTCs hold information about a tumor that could be the key to cancer diagnosis and treatment. This work focused on the designing and simulating a microfluidic platform using contactless-dielectrophoresis (cDEP) to separate CTCs from platelets and red blood cells (RBCs) in a viscoelastic fluid flowing through a microfluidic channel. Contactless electrodes with alternating potentials have been used in this microfluidic device. Using the finite element-based solver, the separation in a microfluidic device based on size-based segregation has been simulated. The operating conditions have been varied in this work to determine the optimal conditions for segregation. Under optimal conditions of 150Pa inlet pressure of working fluid, 2.5V of applied voltage, and 50kHz of alternating electric field frequency, the cells were effectively segregation yielding the best results. At these conditions, separation efficiency of 98.5% is achieved for platelets, 97.25% for RBCs, and 98.5% for CTCs for a separation period of 100s. The angle of separation of the particles is suffered by the cells at various applied voltages (2, 2.5, 3, 3.5, and 4V). The study demonstrates the validity of a size-based segregation device using cDEP for the segregation of tumor cells and the advancement of microscale devices in cancer detection and diagnosis.

Imaging of the central lymphatic system enables characterization of patient-specific lymphatic anatomy and accurate localization of leaks. Advancements in CT technology, particularly spectral CT, can enhance CT lymphangiography (CTL) with improved visualization and quantification. This study aimed to assess the feasibility of spectral CTL in both static and dynamic scans. 50% diluted iodinated contrast was injected into the bilateral superficial inguinal lymph nodes of a pig. The pig was scanned with a dual-layer spectral CT every 60 seconds for 10 minutes. To optimize contrast and visualize peristalsis, a second animal was injected with 25% and 10% diluted contrast and scanned dynamically 4 and 6.25 minutes after contrast injection. Conventional images and iodine maps were reconstructed to calculate the contrast-to-noise ratio (CNR). Additionally, the iodine density was measured adjacent to the lymphovenous junction to show fluctuations from peristalsis and contrast washout. Iodine maps, compared to conventional images, separated the contrast-filled central lymphatic system from surrounding soft tissue and increased CNR to 895 compared to 43 with conventional images. 25% diluted contrast provided the best balance between visualization and quantification of the central lymphatic system, showing high and low iodine density regions corresponding to peristalsis. Iodine density peaked at 15.4 ± 0.6 mg/mL and decreased to 2.0 ± 0.1 mg/mL at 10.5 minutes. Spectral CTL not only improves visualization of the central lymphatic system compared to CTL but also provides quantitative information for physiological characterization of lymphatic disease that can enhance current subjective assessment. Iodine maps from spectral CT lymphangiography separated contrast-filled lymphatic structures from surrounding soft tissue and provided better contrast-to-noise compared to conventional images.Spectral CT lymphangiography enabled quantification of contrast in the central lymphatic system that demonstrated contrast washout and may be utilized for physiological characterization of disease.Dynamic spectral CT imaging of the lymphatic system visually showed peristalsis in the thoracic duct and was further reflected in quantitative iodine density measurements.

Cutaneous lymphatic vessels are essential for maintaining tissue homeostasis and coordinating immune defence, making them vital to skin health. Recent advances in molecular biology and immunology have revealed the association between lymphatic dysfunction and various dermatological conditions, including skin aging, psoriasis, systemic lupus erythematosus, and cutaneous squamous cell carcinoma. Lymphatic structure and function alterations influence immune regulation and play active roles in inflammatory responses and tissue repair processes. This study provides a systematic review of the biological characteristics of cutaneous lymphatic vessels, their mechanistic contributions to disease pathogenesis, and current lymphatic imaging methodologies. Emerging therapeutic strategies targeting lymphatic regulation represent a promising direction for dermatological interventions, with prospects for future research and clinical translation. By elucidating the pathophysiological mechanisms underlying cutaneous lymphatic activity, the aim of this review was to provide novel theoretical foundations and strategic insights for the prevention and treatment of related diseases.

The human vascular network is a highly dynamic, complex and organ-specific microenvironment essential for organ homeostasis. Traditional 2D cell cultures fail to capture its complex intercellular interactions, tissue-specific architectures, and mechanobiological cues. Blood vessel organoids (BVOs) generated from human induced pluripotent stem cells (hiPSCs) replicate the structure and function of blood vessels. Because hiPSCs preserve the donor's telomere length and epigenetic memory, BVOs may preserve the genesis memory, opening up a completely new avenue for the study of vascular disorders. In this review, we systematically outline the methods for in vitro blood vessel generation and explore how vascularizing parenchymal organoids actively drives tissue maturation while overcoming hypoxic limitations. We assess the vital transition from biochemical induction to biomechanical integration, highlighting how microfluidic organ-on-a-chip (OoC) platforms resolve the lineage-specific media dilemma and impose the physiological shear stress necessary for definitive vascular maturation. Furthermore, we comprehensively summarize the applications of BVOs as personalized preclinical avatars across diverse pathologies, including diabetic vasculopathy, cerebrovascular and cardiovascular diseases, tumor immune evasion, hereditary anomalies, and infectious vasculotropism. Finally, we address critical current bioengineering constraints-notably incomplete vessel maturation, the absence of functional lymphatic systems, and the lack of immunocompetent microenvironments-providing strategic future perspectives to accelerate the translation of BVOs in precision and regenerative medicine.