Normal Pathway Research Articles

Purposed potential Alzheimer’s Disease treatment based on the results from current primary research models

Alzheimer’s Disease is one of the most known neurodegenerative diseases that causes over 100,000 deaths till now. The pathology of Alzheimer’s Disease is still not fully clear, but the most widely accepted pathology is the chronic endoplasmic reticulum (ER) stress caused by neurotoxicity via amyloid beta (Aß) plaques and intracellular tau tangles. In Alzheimer's patients, the abnormal Aß plaques and tau tangles cause oxidative stress and induce chronic ER stress, which can hardly be relieved by the normal UPR pathway. One potential treatment for rescuing the excessive ER stress caused by Aß accumulation in human neural cells is the Salubrinal (Sal) treatment. Amentoflavone (AF) treatment is a plausible treatment to alleviate cell death stress due to pyroptosis in Alzheimer's patients. Latrepirdine (LAT) is a treatment that can induce autophagy with the help of ATG5. Mitophagy is a special form of autophagy that degrades dysfunctional mitochondria and does not function well in Alzheimer's patients. Treatment like NMN, UA, and AC can effectively induce mitophagy, decrease memory loss, and relieve common Alzheimer’s pathology like Aß plaques and tau tangles. In this review, the primary research on four key mechanisms in Alzheimer's etiology - UPR pathway(apoptosis), pyroptosis, autophagy and mitophagy - will be discussed and some potential treatments targeting these four mechanisms will be briefly introduced with the primary research results.

Cellular Labeling of Phosphatidylserine Using Clickable Serine Probes.

Phosphatidylserine (PS) is a key lipid that plays important roles in disease-related biological processes, and therefore, the means to track PS in live cells are invaluable. Herein, we describe the metabolic labeling of PS in Saccharomyces cerevisiae cells using analogues of serine, a PS precursor, derivatized with azide moieties at either the amino (N-l-SerN3) or carbonyl (C-l-SerN3) groups. The conservative click tag modification enabled these compounds to infiltrate normal lipid biosynthetic pathways, thereby producing tagged PS molecules as supported by mass spectrometry studies, thin-layer chromatography (TLC) analysis, and further derivatization with fluorescent reporters via click chemistry to enable imaging in yeast cells. This approach shows strong prospects for elucidating the complex biosynthetic and trafficking pathways involving PS.

Neurophysiology of Vestibular Compensation

Vestibular compensation is the process by which patients achieve functional recovery after vestibular lesions, and can be divided into static compensation and dynamic compensation. The first stage, static static compensation, consists of eliminating static symptoms (i.e., spontaneous nystagmus and skew deviation) by rebalancing the tonic neural activity in the vestibular nuclei. The second stage, dynamic compensation is much more subtle, takes longer, and involves a central recalibration of the response properties of the vestibulo-ocular reflex (VOR) (i.e., timing and gain) in order to restore the compensatory actions of the VOR to pre-impairment levels. This review is to introduce the normal vestibular function in humans to understand the neurophysiology of vestibular compensation after vestibular lesions, and to review the effects of various types of lesions and the clinical findings in various stages of compensation after each type of lesion. Vestibular compensation is most effective for unilateral vestibular dysfunctions in which tonic neural activity of the vestibular nucleus is rebalanced to achieve static compensation. Adaptive changes in tonic neural activity occur in the normal vestibular pathways to achieve dynamic compensation. In other types of vestibular lesions, vestibular compensation is possible, but not as effective.

A pictorial review of the radiographic skeletal findings in Morquio syndrome (mucopolysaccharidosis type IV).

Morquio syndrome, also known as Morquio-Brailsford syndrome or mucopolysaccharidosis type IV (MPS IV), is a subgroup of mucopolysaccharidosis. It is an autosomal recessive lysosomal storage disorder. Two subtypes of Morquio syndrome have been identified. In MPS IVA, a deficiency in N-acetylgalactosamine-6-sulfate sulfatase interrupts the normal metabolic pathway of degrading glycosaminoglycans. Accumulated undigested glycosaminoglycans in the tissue and bones result in complications leading to severe skeletal deformity. In MPS IVB, a deficiency in beta-galactosidase results in a milder phenotype than in MPS IVA. Morquio syndrome presents a variety of clinical manifestations in a spectrum of mild to severe. It classically has been considered a skeletal dysplasia with significant skeletal involvement. However, the extraskeletal features can also provide valuable information to guide further work-up to assess the possibility of the disorder. Although the disease involves almost all parts of the body, it most commonly affects the axial skeleton, specifically the vertebrae. The characteristic radiologic findings in MPS IV, such as paddle-shaped ribs, odontoid hypoplasia, vertebral deformity, metaphyseal and epiphyseal bone dysplasia, and steep acetabula, are encompassed in the term "dysostosis multiplex," which is a common feature among other types of MPS and storage disorders. Myelopathy due to spinal cord compression and respiratory airway obstruction are the most critical complications related to mortality and morbidity. The variety of clinical features, as well as overlapping of radiological findings with other disorders, make diagnosis challenging, and delays in diagnosis and treatment may lead to critical complications. Timely imaging and radiologic expertise are important components for diagnosis. Gene therapies may provide robust treatment, particularly if genetic variations can be screened in utero.

Interrupted Nef and Meyer Reactions: A Growing Point for Diversity-Oriented Synthesis Based on Nitro Compounds.

The Nef reaction (nitro to carbonyl group conversion) and related Meyer reaction are among the key transformations of aliphatic nitro compounds. The interrupted versions of these reactions in which the normal pathway is redirected to a different end product by an external nucleophile are much less common, albeit these processes substantially increase the synthetic potential of nitro compounds. In this review, examples of interrupted Nef and Meyer reactions are summarized, and the prospects of this methodology in diversity-oriented organic synthesis are analyzed. The bibliography contains 90 references.

Stoichioproteomics study of differentially expressed proteins and pathways in head and neck cancer.

Hypoxia is a prominent feature of head and neck cancer. However, the oxygen element characteristics of proteins and how they adapt to hypoxia microenvironments of head and neck cancer are still unknown. Human genome sequences and proteins expressed data of head and neck cancer were retrieved from pathology atlas of Human Protein Atlas project. Then compared the oxygen and carbon element contents between proteomes of head and neck cancer and normal oral mucosa-squamous epithelial cells, genome locations, pathways, and functional dissection associated with head and neck cancer were also studied. A total of 902 differentially expressed proteins were observed where the average oxygen content is higher than that of the lowly expressed proteins in head and neck cancer proteins. Further, the average oxygen content of the up regulated proteins was 2.54% higher than other. None of their coding genes were distributed on the Y chromosome. The up regulated proteins were enriched in endocytosis, apoptosis and regulation of actin cytoskeleton. The increased oxygen contents of the highly expressed and the up regulated proteins might be caused by frequent activity of cytoskeleton and adapted to the rapid growth and fast division of the head and neck cancer cells. The oxygen usage bias and key proteins may help us to understand the mechanisms behind head and neck cancer in targeted therapy, which lays a foundation for the application of stoichioproteomics in targeted therapy and provides promise for potential treatments for head and neck cancer.

Identifying key multifunctional components shared by critical cancer and normal liver pathways via SparseGMM

Despite the abundance of multimodal data, suitable statistical models that can improve our understanding of diseases with genetic underpinnings are challenging to develop. Here, we present SparseGMM, a statistical approach for gene regulatory network discovery. SparseGMM uses latent variable modeling with sparsity constraints to learn Gaussian mixtures from multiomic data. By combining coexpression patterns with a Bayesian framework, SparseGMM quantitatively measures confidence in regulators and uncertainty in target gene assignment by computing gene entropy. We apply SparseGMM to liver cancer and normal liver tissue data and evaluate discovered gene modules in an independent single-cell RNA sequencing (scRNA-seq) dataset. SparseGMM identifies PROCR as a regulator of angiogenesis and PDCD1LG2 and HNF4A as regulators of immune response and blood coagulation in cancer. Furthermore, we show that more genes have significantly higher entropy in cancer compared with normal liver. Among high-entropy genes are key multifunctional components shared by critical pathways, including p53 and estrogen signaling.

Fierul, feroptoza şi asocierea cu evoluţia tumorală şi potenţialul impact terapeutic

This article aims at presenting the modern tendencies to redefine the role of iron into the normal and pathological metabolic processes, reminding the normal metabolic pathways of iron, and then compare the normal findings with pathological ones, mostly in cancers. One relatively new concept is ­“ferroptosis”, a different type of (cancer) death cell, intensely researched, at least in the past 11 years. All of these results could potentially have an impact in the better understanding of the metabolism of cancer cells and in the therapeutic area, as a practical ultimate endpoint.

The best of both worlds: mastering nerve regeneration combining biological and nanotechnological tools.

The best of both worlds: mastering nerve regeneration combining biological and nanotechnological tools.

Analysis of Hormonal Profile in Women with Benign Breast Diseases and Women without Breast Pathology at a Tertiary Care Hospital in Lucknow, India: A Cross-sectional Study

Introduction: Disruptions in normal hormonal pathways contribute to the development of various benign breast conditions. Having a general understanding of specific hormonal interactions, such as estradiol, progesterone, and prolactin, among breast tissue, the hypothalamus, the pituitary, and the gonads, can enhance understanding of the causes and manifestations of benign breast conditions such as fibroadenoma, fibroadenosis, breast cyst, abscess, mastitis, galactocele, and phyllodestumour. However, there is limited available information regarding the hormonal environment associated with Benign Breast Disease (BBD). Aim: To compare serum levels of estradiol, progesterone, and prolactin between women with BBD and those without breast pathology. Materials and Methods: This cross-sectional study was conducted in the Department of General Surgery, Era Lucknow Medical College and Hospital (ELMC and H), Lucknow, Uttar Pradesh, India, from January 2021 to January 2023. A total of 80 female subjects were enrolled and divided into two groups: Group A (40 subjects diagnosed with BBD by triple assessment) and Group B (40 subjects with no breast pathology). Serum levels of estradiol, progesterone, and prolactin were tested during the follicular phase and compared between the two groups. Student t-test and Spearman’s correlation with a 95% confidence interval were used for mean comparison between the groups. Receiver Operating Characteristic (ROC) analysis was performed to determine cut-off values, sensitivity, and specificity for the hormones. A p-value of <0.05 was considered as significant. Results: The mean age showed no statistical differences between Group A (26.5 years) and Group B (28.8 years). The mean levels of estradiol and progesterone hormones were significantly higher in Group A (188.38±96.06 pg/mL; 4.34±5.05 ng/mL) than in Group B (103.21±39.52 pg/mL; 0.38±0.30 ng/mL) with a p-value of 0.001. The sensitivity of estradiol was found to be 80% with a specificity of 75% based on ROC analysis when the cut-off was set to <139.5. Furthermore, progesterone showed a sensitivity of 92.50% and specificity of 80% at a cut-off <0.8560. Prolactin showed a sensitivity of 52.50% and specificity of 62.50% at a cut-off <18.96. Conclusion: Authors concluded that steroidal harmones have a significant effect on the development of BBD. The present study had demonstrated that women with BBD exhibit higher levels of estradiol and progesterone compared to women without breast pathology.

Medical ozone. Pharmacological mechanisms as basis of its effectiveness on the autoimmune response, vascular disorders, surgery and COVID-19/sars-CoV-2

Medical ozone is a therapeutic concept of proven pleiotropy. This means that it will have different effects on multiple pharmacological targets, which have been identified in hundreds of studies (experimental and clinical) on disease models and patients. These targets are closely connected to each other and can occur in different diseases. A good example is the “cytokine storm” in rheumatoid arthritis as well as in COVID-19/SARS-CoV-2. Therefore, the aim of this presentation is to highlight the therapeutic targets of medical ozone in different diseases, their interrelationship, and ozone application in pathological processes with an oxidative etiology.
 In animal models and in patients with rheumatoid arthritis, medical ozone has been shown to reduce proinflammatory cytokines (TNF-? and IL-1?) that contribute to “cytokine storm,” to synovitis, cartilage- and bone damaging autoantibodies and oxidative stress. Vascular complications in patients with diabetes were reduced when superoxide radical scavengers increased, mediated by medical ozone, restoring normal metabolic pathway functions and pancreatic integrity. Ozone prevented ischemic reperfusion injury and improved the systemic condition and quality of life of patients with knee osteoarthritis before and after arthroscopy.
 The integration of the above and other results was the basis for the introduction of medical ozone as a successful treatment in a new disease: COVID-19.

The Effect of Taheri Consciousness Fields on the ATP Production in HEK-293 Cell Line by Measuring Luciferase Activity

Various T-Consciousness Fields with different functions have been introduced by Mohammad Ali Taheri. Not only has the existence of these fields been investigated in the initial phase through various experiments, but also the empirical evidence of Mohammad Ali Taheri’s theories, such as the existence of the “mind in the matter”, has been observed. This study aimed to explore the effect of Taheri Consciousness Fields (TCFs) 1, 2, and 3 in the production process of ATP or biological energy in the human cell lines. In this experiment, a human HEK 293 cell line was used in a cell culture medium at the 24th hour of growth. The luciferase enzyme, the concentration of ATP in the sample under the influence of TCFs and control was measured and evaluated. Our findings showed that TCF 1, 2, and 3 resulted respectively in a 5, 11 and 7-fold increase in the number of ATP molecules, compared to the control samples. Due to the limited fuel cell resources and the brief treatment time (one hour) with TCFs, this increase in ATP levels cannot be attributed to the normal cytosolic and mitochondrial glucose oxidation pathways. Thus, there seems to be an alternative pathway. It is possible that TCFs influenced the ionization of water molecules in the mitochondrial intermembrane space and led to more ATP production by maintaining the proton gradient. The factor that makes this possible is nothing but the existence of a type of mind in the cells. According to Taheri’s theory, transmitted information through TCFs has been received by the mind of the cells, and as a result, has led to the ionization of water molecules in the mitochondrial intermembrane space. In conclusion, it seems that regardless of the biological system, under the influence of TCFs, there is an alternative way to increase ATP at the immediate time, which is associated with an increase in information and a decrease in the entropy of the system.

Pharmacokinetics, distribution, metabolism, and excretion of body-protective compound 157, a potential drug for treating various wounds, in rats and dogs.

Body-protective compound (BPC) 157 demonstrates protective effects against damage to various organs and tissues. For future clinical applications, we had previously established a solid-phase synthesis process for BPC157, verified its biological activity in different wound models, and completed preclinical safety evaluations. This study aimed to investigate the pharmacokinetics, excretion, metabolism, and distribution profiles of BPC157. After a single intravenous (IV) administration, single intramuscular (IM) administrations at three doses in successive increments along with repeated IM administrations, the elimination half-life (t1/2) of prototype BPC157 was less than 30min, and BPC157 showed linear pharmacokinetic characteristics in rats and beagle dogs at all doses. The mean absolute bioavailability of BPC157 following IM injection was approximately 14%-19% in rats and 45%-51% in beagle dogs. Using [3H]-labeled BPC157 and radioactivity examination, we proved that the main excretory pathways of BPC157 involved urine and bile. [3H]BPC157 was rapidly metabolized into a variety of small peptide fragments in vivo, thus forming single amino acids that entered normal amino acid metabolism and excretion pathways. In conclusion, this study provides the first analysis of the pharmacokinetics of BPC157, which will be helpful for its translation in the clinic.

Testosterone Deficiency in the Older Male

Testosterone deficiency (TD) in the older male is a difficult diagnosis to make with potentially life changing treatment. Awareness of the normal hormonal pathways, and an understanding of the corrective homeostatic mechanisms, can help in understanding the downstream effects of potential physiologic disturbances. Depending on age, the signs and symptoms of TD can vary from under developed external genitalia in the fetus, to lack of normal pubertal changes in the young adolescent up to an alteration in certain masculine physical characteristics present in the normal adult male. For the adult male, multiple treatment options are available, with newer ones being refined and developed. Monitoring for effective response to Testosterone Replacement Therapy (TRT) and screening for complications is not an onerous task and has the potential to improve the lives of many men.

Knowledge-driven design and optimization of potent symmetric anticancer molecules: A case study on PKM2 activators

BackgroundPyruvate kinase M2 (PKM2) is preferentially expressed as a low-activity dimer over the active tetramer in proliferating tumor cells, resulting in metabolic reprogramming to achieve high energy requirements and nutrient uptake. This leads to a shift from the normal glycolytic pathway causing tumor cells to proliferate uncontrollably. This study utilizes knowledge-based drug discovery to determine the critical features from experimentally known PKM2 activators and design compounds that would significantly confer a stable structural and functional edge over the known compounds which are still at the preclinical stage. MethodsConscientious molecular modeling studies were carried out and critical structural features were identified and validated from the knowledge of experimentally known PKM2 activators to confer high-binding affinities. A virtual library of 200 palindromic and non-palindromic activators was designed based on these identified critical features to target a distinct activator binding-site. This binding would favor specific dimer-dimer association and subsequent protein tetramerization. The resultant compounds strongly correlated with identified structural features and binding affinities which further strengthened our findings. The designed activators were then subjected to pharmacokinetic profiling and toxicity prediction, followed by free-binding energy calculations and MD simulations. ResultsAll the virtually designed activators comprising the identified critical features were observed to confer high-binding affinities ranging from −9.1 to −15.0 kcal/mol to the receptor protein. The designed activators also demonstrated optimum pharmacokinetic and toxicity profiles. ConclusionThe best activators selected for MD simulations studies were conclusively observed to stabilize the required tetrameric conformation suggesting that these activators could potentially target PKM2 tetramerization that might restore the normal glycolytic pathway and suppress tumor progression.

POSSIBLE IMMUNE ALTERATION AFTER COCHLEAR IMPLANTATION

Aims:Cochlear implant (CI) is a widely accepted device to patients with severe to profound sensorineural hearing loss to replace the normal hearing pathway. Since a portion of the device is implanted under the skin, possible immune alteration may occur. Our aim was to assess the production of some selected pro-inflammatory and anti-inflammatory cytokines in patients with cochlear implants and their impact on hearing outcomes. Material and Methods: Our study was conducted on 25 cochlear implanted patients who were subjected to IL-1β, IL2, IFN-γ and IL6 laboratory assessment preoperatively, postoperatively, 6 months after CI and 2 years after CI. Simultaneously, impedance and neural response telemetry (NRT) were measured and the data were analyzed statistically in relation to the laboratory findings. Results:No statistically significant difference was found between the levels of cytokines at different times of assessment except a significant increase of IL-1β at first fitting postoperatively in comparison to preoperative sample. Also, no statistically significant difference was found as regards values of impedance and NRT except a significant decrease of postoperative measures of NRT in comparison to intraoperative measures without any malfunction. Conclusion:There is a minimal immune alteration immediately after CI without any functional affection which may be attributed to the trauma of the implantation surgery rather than foreign body immune response.

The pericontused cortex can support function early after TBI but it remains functionally isolated from normal afferent input

Traumatically injured brain functional connectivity (FC) is altered in a region-dependent manner with some regions functionally disconnected while others are hyperconnected after experimental TBI. Remote, homotopic cortical regions become hyperexcitable after injury, and we hypothesize that this results in increased trans-hemispheric cortical inhibition, preventing reorganization of the primary injured hemisphere. Previously we have shown that temporary silencing the contralesional cortex at 1wk normalizes affected forelimb behavioral use, but not at 4wks. To investigate the potential mechanism for this and to determine whether this occurs due to restoration of afferent pathway FC, and/or reorganization of brain circuits, we probed forelimb circuit function with sensorimotor task-evoked-fMRI, resting state fMRI seed-based analysis, and exploratory structural equation modelling (SEM) of directed causal connections due to forelimb task at 1 and 4wks post-injury after temporary, contralateral silencing with intraparenchymal injection of muscimol versus vehicle, as well as from sham rats. As predicted, silencing at 1wk and 4wks post-injury decimated the contralesional cortical forelimb map evoked by stimulation of the opposite, unaffected forelimb compared to vehicle-injected injured rats indicating the success of the intervention. Surprisingly however, this also resulted in activation of the pericontused cortex ipsilateral to the stimulated forelimb at 1wk, yet this same region could not be activated by directly stimulating the opposite, injury-affected forelimb. Underpinning this were significant increases in interhemispheric FC at the level of the cortex but decreases within subcortical regions. Causal SEM analysis confirmed increased corticothalamic connectivity and suggested changes from and to bilateral thalamus are important for the effect. At 4wks post-injury only cortical increases in FC were found in response to silencing indicating a less flexible brain, and ipsilesional cortex evoked activity was mostly absent. The absence of a reinstatement of ipsilesional evoked activity through normal pathways by temporary neuromodulation despite prior data showing behavioral improvements under the same conditions, indicates that while the pericontused cortex does retain function initially after injury, it is too functionally disconnected to be controlled by normal afferent input. More significant alterations in cross-brain FC during neuromodulation at 1wk compared to 4wk post-injury, suggest that more distributed brain activity accounts for prior behavior improvements in sensorimotor function, and that hemispheric imbalance in function is causally involved in early loss of sensorimotor function in this TBI model.

Biomarkers of autoimmunity and beta cell metabolism in type 1 diabetes.

Posttranslational protein modifications (PTMs) are an inherent response to physiological changes causing altered protein structure and potentially modulating important biological functions of the modified protein. Besides cellular metabolic pathways that may be dictated by PTMs, the subtle change of proteins also may provoke immune attack in numerous autoimmune diseases. Type 1 diabetes (T1D) is a chronic autoimmune disease destroying insulin-producing beta cells within the pancreatic islets, a result of tissue inflammation to specific autoantigens. This review summarizes how PTMs arise and the potential pathological consequence of PTMs, with particular focus on specific autoimmunity to pancreatic beta cells and cellular metabolic dysfunction in T1D. Moreover, we review PTM-associated biomarkers in the prediction, diagnosis and in monitoring disease activity in T1D. Finally, we will discuss potential preventive and therapeutic approaches of targeting PTMs in repairing or restoring normal metabolic pathways in pancreatic islets.

The Efficacy of Ozonized Water Versus Ringer Lactate Arthrocentesis for the Treatment of Temporomandibular Joint Internal Derangement.

Temporomandibular disorders are musculoskeletal conditions characterized by facial pain and impaired temporomandibular joint function, limited mouth opening, joint and muscular pain, and noises during mandibular movements are some of the most common symptoms. The most frequent cause of temporomandibular joint dysfunction is internal derangement (ID), which refers to an alteration in the normal pathways of motion of the joint that largely involves the function of the articular disc, therefore, these alterations have been also referred to as disc derangement. Arthrocentesis is a minimally invasive technique, less expensive than surgical treatment. Adhesions are released after arthrocentesis of the upper joint space under sufficient hydraulic pressure. Intra-articular ozone gas injection is used as conservative treatment modalities for ID of the temporomandibular as it possesses anti-inflammatory, analgesic effects, enhancement the host defense mechanism and accelerates the healing process of the damaged cells. The aim of this study was to compare the effectiveness of ozonized water against lactated ringer solution in the arthrocentesis of the temporomandibular joint. Sixty patients were used in this study, suffered from ID of the temporomandibular joint treated by arthrocentesis under hydraulic pressure and were allocated into 2 groups; the study group (A), which included 30 patients, managed by arthrocentesis utilizing ozonized water and the control group (B) with 30 patients also treated by the same procedure using ringer lactate solution. Visual analog scale pain scores, temporomandibular joint sounds, and maximal mouth opening were assessed preoperatively and at different intervals postoperatively. The age in this study ranged from 14 to 66 years. The mean age of group A was 29.93 years with an SD of ±11.79. For group B, the mean age was 27.56 years and the SD was ±10.80, the prominent percentage in both groups was < 30 years. Regarding sex, 45 patients were females, whereas the males were 15 with a ratio of 3:1. Group A registered the highest reduction in the visual analog scale at all postoperative intervals. With respect to the mouth opening, there was no significant difference in maximal mouth opening between the 2 groups after 1 week and 12 weeks in comparison with the preoperative measurements. The temporomandibular joint sounds improved in all patients in group A after 12 weeks, whereas in group B the sounds dropped to 33.3%. The data from the present study suggested more favorable treatment outcomes for ozonized water lavage and it is a promising new treatment modality for the relief of symptoms associated with the ID of the temporomandibular joint.

Obesity-associated mesenteric lymph leakage impairs the trafficking of lipids, lipophilic drugs and antigens from the intestine to mesenteric lymph nodes

Dietary lipids, highly lipophilic drugs, antigens and immune cells are transported from the intestine to the mesenteric lymph nodes (MLNs) via mesenteric lymphatic vessels. Recently our lab reported that the mesenteric lymphatic vessels become highly branched and leak lymph to the surrounding mesenteric adipose tissue (MAT) in mice and humans with obesity, promoting insulin resistance. This study aimed to investigate the impact of obesity-associated mesenteric lymph leakage on the trafficking of a dietary lipid (oleic acid), lipophilic drug (cyclosporin A) and antigen (ovalbumin) from the intestine to MLNs. C57BL/6J mice were fed a control fat diet (CFD), or a high fat diet (HFD) for up to 35 weeks leading to obesity and impaired glucose tolerance. 14C-oleic acid, 3H-cyclosporin or Cy5.5-ovalbumin were administered orally, and blood plasma and tissues collected to measure radioactivity or fluorescence levels. The accumulation of 14C-oleic acid, 3H-cyclosporin and Cy5.5-ovalbumin in MAT was significantly increased in HFD compared to CFD fed mice, whereas in the MLNs there was less accumulation (3H-cyclosporin and Cy5.5-ovalbumin) or no significant difference (for 14C-oleic acid). The mass ratio of these molecules in MLNs compared to MAT was thus significantly decreased. Obesity-associated mesentery lymph leakage appears to divert dietary lipids, lipophilic drugs and antigens away from their normal lymphatic trafficking pathways from the intestine to MLNs and instead results in leakage into MAT. This is likely to contribute to known detrimental changes to lipid metabolism, immunotherapy and mucosal immunity in obesity.