The global prevalence of food allergies, particularly IgE-mediated responses, is increasing at an alarming rate. This trend is likely driven by environmental factors such as nanoplastics (NPs) ingestion and the westernization of dietary and lifestyle habits. This study examines the impact of polystyrene nanoplastics (PS-NPs) on ovalbumin (OVA)-induced food allergies in mice subjected to either a normal diet (ND) or a high-fat diet (HFD). BALB/c mice were stratified into eight groups based on dietary regimen, NP exposure, and OVA sensitization. Food allergy was induced via OVA administration, and multiple physiological and immunological parameters were evaluated, including body weight, intestinal permeability, cytokine profiles, gut microbiota composition, and small intestinal gene expression. Mice in the HFD + OVA + NP group exhibited significant increases in intestinal permeability, diarrhea severity, and serum OVA-specific IgE levels compared to other groups. Flow cytometric analysis revealed an expansion of innate lymphoid cells (ILC2 and ILC1) within the lamina propria of the small intestine. Shotgun metagenomic sequencing demonstrated gut microbiota dysbiosis, characterized by a reduction in beneficial bacterial populations in the HFD + OVA + NP cohort. Weighted Gene Co-Expression Network Analysis (WGCNA) identified a negative correlation between NPs exposure or OVA sensitization and the expression of Slc1a1, Slc5a8, and Mep1a, while a positive correlation was observed with Aa467197 expression. These findings indicate that oral exposure to PS-NPs exacerbates OVA-induced food allergies, particularly in the context of an HFD, through mechanisms involving increased intestinal permeability, gut microbial dysbiosis, and gene expression modulation. This study highlights the potential health hazards posed by environmental microplastic contamination and its possible contribution to the escalating incidence of food allergies.

Oral supramolecular drug delivery systems (SDDSs) have shown promising potential, along with a rapid increase in the development of polypeptide-based drugs. Biofriendly, biocompatible, and multistimulation-responsive SDDSs achieve their unique deliverability via noncovalent bonds, which can encapsulate drugs and release them at the target site along the oral tract. In this review, we analyze the oral tract from an anatomical perspective and explain the potential physical, microenvironmental, and systematic barriers, as well as the properties of drug delivery. After understanding the specific environment at different oral sites, the application of SDDSs to the mouth, stomach, small intestine, and cell targeting is summarized. Finally, this review summarizes the application of SDDSs for the successful delivery of drugs and describes how to overcome the barriers of SDDSs in drug delivery using a more biofriendly approach.

High fidelity neuronal signaling is enabled by a stable local microenvironment. A high degree of homeostatic regulation of the brain microenvironment, and its separation from the variable and potentially neurotoxic contents of the blood, is brought about by the central nervous system barriers. Evidence from clinical and preclinical studies implicates brain microcirculation, cerebral hypoperfusion, blood-brain barrier dysfunction, and reduced amyloid clearance in Alzheimer pathophysiology. Studying this dysregulation is key to understanding Alzheimer disease (AD), identifying drug targets, developing treatment strategies, and improving prescribing to this vulnerable population. This review has 2 parts: part 1 describes the cerebral microcirculation, cerebral blood flow, extracellular fluid drainage, and the neurovascular unit components with an emphasis on the blood-brain barrier, and part 2 summarizes how each aspect is altered in AD. Discussing the neurovascular unit structures separately allows us to conclude that aberrant pericytes are an early contributor and central to understanding AD pathophysiology. Pericytes have multiple functions including maintenance of blood-brain barrier integrity and the control of capillary blood flow, capillary stalling, neurovascular coupling, intramural periarterial drainage, glia-lymphatic (glymphatic) drainage, and consequently amyloid and tau clearance. Pericytes are vasoactive, express cholinergic and adrenergic receptors, and exhibit apolipoprotein E isoform-specific transport pathways. Hypoperfusion in AD is linked to a pericyte-mediated response. Deficient endothelial cell-pericyte (PDGBB-PDGFRβ) signaling loops cause pericyte dysfunction, which contributes and even initiates AD degeneration. We conclude that pericytes are central to understanding AD pathophysiology, are an interesting therapeutic target in AD, and have an emerging role in regenerative therapy. SIGNIFICANCE STATEMENT: Dysregulation and dysfunction of the neurovascular unit and fluid circulation (including blood, cerebrospinal fluid, and interstitial fluid) occurs in Alzheimer disease. A central player is the aberrant pericyte. This has fundamental implications to understanding disease pathophysiology and the development of therapies.

Flavivirus such as Dengue, Zika, West Nile, Japanese encephalitis, and yellow fever virus, composed of single-stranded positive-sense RNA, predominantly contaminated through arthropods. Flavivirus infection characterises from asymptomatic signs to severe hemorrhagic fever and encephalitis. The host's immune system detects these viruses and provides a defence mechanism to sustain their life and growth. However, flaviviruses through different mechanisms compromise the host's immune defence. The current pharmacotherapeutic strategies against Flavivirus infection target different stages of the Flavivirus life cycle and its proteins. On the contrary, the host's immune defence mechanism is equally important to restrict their growth. It has been suggested that flaviviruses compromise claudins to sustain their life and growth inside the mammalian cells. This review primarily focuses on the effect of Flavivirus on claudins (CLDNs), transmembrane proteins that form tight junctions in mammalian cells. CLDNs are crucial in viral entry and pathogenesis by regulating paracellular permeability, particularly in tissues and the blood-brain barrier. Recent studies indicate that the Dengue and Zika viruses can potentially be treated by targeting specific CLDNs-specifically CLDN 1, CLDN 5, and CLDN 7 to inhibit viral entry and fusion. Additionally, it highlights the current challenges and future prospects in developing claudin-based antiviral agents against Flavivirus infections.

This study investigated the protective effects of Garcinia biflavonoid 1 (GB1) against dextran sulfate sodium (DSS)-induced ulcerative colitis and its underlying mechanisms. Using wild-type (WT) and NLRP3 knockout (Nlrp3-/-) mice, we demonstrated that GB1 administration significantly ameliorated colitis symptoms, as evidenced by improved body weight, disease activity index (DAI) scores, colon length, and histological damage in WT mice. Mechanistically, GB1 downregulated pro-inflammatory mediators (IL-6, NF-κB, and CD11b) while attenuating the expression of NLRP3 inflammasome components (ASC, Caspase-1, and IL-1β). Notably, these protective effects were abolished in Nlrp3-/- mice, confirming the essential role of NLRP3 in GB1-mediated mitigation of colitis. Furthermore, GB1 reinforced intestinal barrier integrity by preserving tight junctions, reducing permeability, and attenuating mucosal inflammation. Collectively, our findings highlight GB1 as a promising therapeutic candidate for colitis treatment, primarily through NLRP3 inflammasome suppression and intestinal barrier restoration.

Water scarcity and rising global temperatures are two of the greatest current and future threats to poultry sustainability. Therefore, selection for water efficiency (WE) and heat resilience are of vital importance. Additionally, intestinal integrity is of critical importance under challenging conditions to maintain nutrient absorption and therefore, growth and performance of broilers. Here, we examined the effect of chronic cyclic heat stress (HS) on the ileal expression profile of tight-junction, gap-junction, adherens, and desmosome genes in the fourth generation of divergently selected low (LWE)- and high water efficient (HWE)-chicken lines. LWE birds exhibited higher levels of gut permeability, regardless of temperature, as measured by fluorescein isothiocyanate-dextran (FITC-D). Among the claudins (CLDN), Cldn1 showed greater expression in the HWE as compared to LWE, regardless of temperature. Cldn5, -16, -20, and -34 genes were all greater in LWE and lower in HWE during HS. Conversely, Cldn25 was decreased in LWE but increased HWE under HS. Cldn4 was increased in the HWE line and decreased by HS. Cingulin (Cgn) gene expression was lower in HWE as compared to LWE and lower in HS as compared to thermoneutral (TN) condition. Gap junction protein α1 (Gja1) and desmoglein 4 (Dsg4) were greater in the HWE as compared to the LWE. Cadherin 1 (Cdh1) gene expression was greatest in the HWE in TN conditions and lowest in HWE under HS, whereas catenin α2 (Ctnna2) and desmocollin 1 (Dsc1) were highest in HWE during HS compared to all other groups. This differential expression of key genes associated with intestinal barrier integrity likely contributes to the water efficiency phenotype and the response of these birds to HS.

The gut-ovary axis involves a complex interplay of various physiological and molecular mechanisms, which significantly impact poultry production and health. This study investigated the effects of betaine (Bet) on the gut-ovary axis of laying hens in aged laying hens. A total of 108 Hy-Line Brown hens, aged 500 days, were randomly divided into three groups (n = 36 per group) and fed diets containing 0, 1000, and 3000 mg/kg of Bet (designated as CON, l-Bet, and H-Bet, respectively) over a 42-day trial. The results indicated that dietary supplementation with Bet improved laying performance. Specifically, H-Bet Supplementation increased villus height (VH) and villus height/crypt depth ratio (VH/CD), and up-regulated the expression of Claudin-1 in the jejunal and ileal mucosa. Additionally, H-Bet enhanced the richness of Bacteroidetes and reduced Firmicutes/Bacterodietes ratio. LEfSe analysis revealed significant enrichment Eubacteriaceae, Merdibacter, Anaerorhabdus_furcosa_group, Syntrophococcus, and Clostridium_innocuum_group in Bet group. Transcriptome sequencing of small yellow follicles (SYFs) showed significant up-regulation of ATP6 and down-regulation of EGR1. KEGG enrichment analysis indicated that H-Bet influenced oxidative phosphorylation, peroxisome, and other pathways, with GESA was primarily enriched in oxidative phosphorylation, and MAPK signaling pathway. Furthermore, H-Bet supplementation increased SOD, CAT, Nrf2, NQO-1, and HO-1 expression in the jejunum, while only HO-1 expression was up-regulated in the ileum. In the ovary, H-Bet differentially affected GPX, and CAT expression. These results demonstrate that dietary supplementation with Bet improves intestinal and ovarian health in aged laying hens, likely due to enhanced antioxidant capacity and improved intestinal morphology.

As a major environmental heavy metal pollutant, hexavalent chromium (Cr(VI)) causes irreversible damage to animals and humans. Nevertheless, how Cr(VI) exposure causes intestinal damage in broilers remains inadequately explored. This study explores Cr(VI)-induced poisoning using potassium dichromate to build a Cr(VI) poisoning model. The results indicate that Cr(VI) exposure evidently reduced the body weight and the functions of liver and kidney in broilers. Histopathological analysis revealed different degrees of structural damage in all three segments of the small intestines by Cr(VI) exposure. Moreover, Cr(VI) exposure downregulated ZO-1, Occludin, and Claudin-1, while altering the diversity of cecal microbiota to impair the intestinal barrier function. Additionally, with increasing Cr(VI) concentration, the contents of Fe2+, ROS, and LPO in all three intestinal segments showed a dose-dependent increase. The levels of GPX4, SLC7A11, FTL, and FTH1 were downregulated by Cr(VI), while the levels of p38-MAPK, phosphorylated p38, TFR1, and HMGB1 were upregulated. This study suggests that Cr(VI)-induced ROS can trigger ferroptosis through the GPX4/HMGB1/p38-MAPK pathway, leading to intestinal barrier dysfunction and ultimately reducing the production performance of broilers. This provides foundation of theory for understanding the effects of Cr(VI) exposure on the small intestine.

Combination therapy of chemotherapy and zolbetuximab demonstrated a significant survival benefit compared to chemotherapy alone in patients with human epidermal growth factor receptor 2 (HER2)-negative, claudin (CLDN) 18.2-positive metastatic gastric cancer (mGC). Consequently, it has been approved as a standard first-line therapy for these patients. Combination therapy of chemotherapy and immune checkpoint inhibitors (ICIs)-either nivolumab or pembrolizumab-is a standard first-line therapy for patients with HER2-negative mGCs that are positive for programmed death-ligand 1 (PD-L1) expression, as defined by a combined positive score (CPS). Although approximately 13-22% of CLDN-positive mGCs are also CPS-positive, optimal treatment for mGC patients expressing both CLDN and PD-L1 remains undetermined due to the absence of direct comparative studies between zolbetuximab and ICIs. Treatment selection under this condition has become a critical issue. In this review, we discuss the appropriate treatment selection for HER2-negative mGC patients who are double-positive for CLDN 18.2 and PD-L1 based on clinical data and differences in the mechanism of action and safety profile between zolbetuximab and ICI.

Claudin18.2 (CLDN18.2) is highly expressed during the development of various malignant tumors, especially gastric cancer, and CAR-T cells targeting CLDN18.2 have therapeutic potential. However, their dependence on the major histocompatibility complex (MHC) for antigen recognition limits their application. Human Gamma Delta (γδ) T cells, with strong MHC-independent cytotoxicity to most solid tumors both in vivo and in vitro, are emerging as ideal cells for the generation of robust universal CLDN18.2 CAR-T cells to treat solid tumors. Our aim was to construct a universal CAR-γδ T cell targeting CLDN18.2.

We constructed novel CAR-CLDN18.2-γδ T cells by lentiviral infection and compared their superior efficacy in the treatment of CLDN18.2-positive solid tumors in vivo and in vitro.

CD3ζ expression was verified in HEK293T cells after lentiviral transfection of CLDN18.2 CAR, and the lentivirus was packaged and concentrated to a titer of 4.90 × 108 TU/mL. Primary γδ T cells and αβ T cells were infected with efficiencies of approximately 31.76 ± 4.122% and 44.13 ± 4.436%, respectively. CAR-CLDN18.2-γδ T cells exhibited specific cytotoxicity against CLDN18.2-positive gastric cancer cells and secreted relatively high levels of Granzyme-B, Perforin-1, and IFN-γ. CAR-γδ T cells also showed superior cytotoxicity to target cells compared to classical CAR-αβ T cells in vitro. Finally, the antitumor activity of γδ T-CAR-CLDN18.2 cells was evaluated in tumor-bearing NSG mice, and CAR-CLDN18.2-γδ T cells significantly inhibited tumor growth and prolonged the survival of the mice.

Our results demonstrate that universal CAR-CLDN18.2-γδ T cell is promising for the treatment of CLDN18.2-positive solid tumor and provide insights for the development of more universal CAR-γδ T-cell strategies for tumor immunotherapy.

Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive tumor with limited treatment options. Zolbetuximab, a monoclonal antibody against the tight junction protein Claudin 18.2 has recently been developed. At present, few and conflicting data have been reported regarding the clinical-pathological features of Claudin 18.2 expression in PDA. The present study investigated the expression of Claudin 18.2 in histological samples from PDA patients with the aim of verifying its utility as a therapeutic biomarker. Claudin 18.2 immunoreactivity was assessed by immunohistochemical staining on 70 formalin-fixed, paraffin-embedded PDA specimens (28 surgical specimens and 42 fine needle aspiration biopsies). The results obtained were associated with the clinicopathological characteristics and the survival rate of patients. Claudin 18.2 was detected only in neoplastic cells, not in normal pancreatic tissue. Claudin 18.2 was positive in 50% of samples and a higher expression was associated with well- and moderately-differentiated tumors and lymph node-negative status. The high expression of Claudin 18.2 in neoplastic tissue and absence in normal cells suggested that this protein had an attractive role in PDA as both a diagnostic and a prognostic-therapeutic marker. High expression of Claudin 18.2 in neoplastic tissue was associated with more favorable prognostic parameters and the high percentage of positive samples obtained suggests that Zolbetuximab may be suitable for a large number of patients.

Infections by enteropathogenic Escherichia coli (EPEC) cause acute diarrheal disease in infants accounting for severe morbidity and mortality. One of the underlying causes of the disease is the breakdown of the intestinal barrier maintained by the tight junctions (TJs). EPEC uses a type 3 secretion system to translocate more than 20 effectors into infected cells, which disrupt several functions of the host cells. The effectors EspF, Map, EspG1/G2 and NleA have been reported to disrupt the TJs causing the leakage of charged ions and uncharged molecules through the barrier. We have previously reported that EspF and Map cause the depletion of TJ proteins claudin-1, claudin-4 and occludin through both transcriptional and post-transcriptional mechanisms. Here, we show that the inhibition of the lysosomal protease cathepsin B, in cells expressing the EPEC effector Map, reduces the depletion of claudin-1, claudin-4 and occludin. Further, we show that the expression of a mutant Map protein lacking the mitochondrial targeting sequence inhibits the depletion of occludin and its delocalization from the TJs and partially rescues claudin-4 levels and its junctional localization. We also identified a novel interaction of Map with the GTPase Rab13. Rab13 has been reported to mediate the recycling of occludin to the plasma membrane. Since occludin regulates the passage of macromolecules through the intestinal TJ barrier, the interaction of Map with Rab13 may have important implications for the loss of TJ integrity and excessive leakage through the intestinal barrier in EPEC pathogenesis.

Claudins (CLDNs) play a crucial and indispensable role as fundamental components within the structure of tight junctions. Due to the distinct and unique distribution pattern exhibited by CLDNs in both normal and malignant tissues, these proteins have garnered significant attention as pivotal targets for systemic anti-cancer therapy and as noteworthy diagnostic markers. This review provides a comprehensive and detailed elucidation of the fundamental understanding surrounding CLDNs, their intricate expression patterns, the potential role they play in cancer diagnosis and therapeutic potentials; all encapsulated within a succinct summary of the cutting-edge advancements and the information derived from various clinical trials.

How tissues develop distinct structures remains poorly understood. We propose herein the Lego hypothesis of tissue morphogenesis, which states that during tissue morphogenesis, the topographical properties of cell surface adhesion molecules can be dynamically altered and polarised by regulating the spatiotemporal expression and localization of orientational cell adhesion (OCA) molecules cell-autonomously and non-cell-autonomously, thus modulating cells into unique Lego pieces for self-assembling into distinct cytoarchitectures. This concept can be exemplified by epithelial morphogenesis, in which cells are coalesced into a sheet by many types of adhesions. Among them, parallel OCAs (pOCAs) at the lateral cell membranes are essential for configuring cells in parallel. Major pOCAs include Na+/K+-ATPase-mediated adhesions, Crumbs-mediated adhesions, tight junctions, adherens junctions, and desmosomes. These pOCAs align in stereotypical orders along the apical-to-basal axis, and their absolute positioning is also regulated. Such spatial organization of pOCAs underlies proper epithelial morphogenesis. Thus, a key open question about tissue morphogenesis is how to regulate OCAs to make compatible adhesive cellular Lego pieces for tissue construction.

Tight junctions (TJs) between adjacent Sertoli cells are believed to form immunological barriers that protect spermatogenic cells expressing autoantigens from autoimmune responses. However, there is no direct evidence that Sertoli cell TJs (SCTJs) do indeed form immunological barriers. Here, we analyzed male mice lacking claudin-11 (Cldn11), which encodes a SCTJ component, and found autoantibodies against antigens of spermatocytes/spermatids in their sera. Defective spermatogenesis in Cldn11-deficient mice was not restored on a recombination activating gene 2 (Rag2) knockout background lacking mature T and B lymphocytes. This suggests that adaptive immune responses to spermatogenic cells are not a cause of defective spermatogenesis in Cldn11-deficient mice. Further analyses showed that Cldn11 knockout impaired Sertoli cell polarization, localization of stem cell factor (SCF) (a key molecule for maintaining differentiating spermatogonia) to the basal compartment of seminiferous tubules, and also proliferation of differentiating spermatogonia. We propose that CLDN11 creates a microenvironment for SCF-mediated spermatogonial proliferation at the basal compartment via Sertoli cell polarization.

The choroid plexus (CP) is a small yet highly active epithelial tissue located in the ventricles of the brain. It secretes most of the CSF that envelops the brain and spinal cord. The epithelial cells of the CP have a high fluid secretion rate and differ from many other secretory epithelia in the organization of several key ion transporters. One striking difference is the luminal location of, for example, the vital Na+-K+-ATPase. In recent years, there has been a renewed focus on the role of ion transporters in CP secretion. Several studies have indicated that increased membrane transport activity is implicated in disorders such as hydrocephalus, idiopathic intracranial hypertension, and posthemorrhagic sequelae. The importance of the CP membrane transporters in regulating the composition of the CSF has also been a focus in research in recent years, particularly as a regulator of breathing and hemodynamic parameters such as blood pressure. This review focuses on the role of the fundamental ion transporters involved in CSF secretion and its ion composition. It gives a brief overview of the established factors and controversies concerning ion transporters, and finally discusses future perspectives related to the role of these transporters in the CP epithelium.

The expression of claudins (CLDNs), major components of tight junctions (TJs), is abnormal in various solid tumors. CLDN14 is highly expressed in human colorectal cancer (CRC) tissues and confers chemoresistance. CLDN14 may become a novel therapeutic target for CRC, but CLDN14-targeting drugs have not been developed. Here, we searched for a CLDN14-targeting peptide, which can suppress CLDN14 expression and chemoresistance using human CRC-derived DLD-1 and LoVo cells. Among some short peptides which mimic the second extracellular loop structure of CLDN14, PSGMK most strongly suppressed the protein expression of CLDN14. The mRNA expression of other endogenous TJ components was unchanged by PSGMK. The PSGMK-induced reduction of CLDN14 protein was inhibited by chloroquine, a lysosome inhibitor, and monodansylcadaverine, a clathrin-dependent endocytosis inhibitor, indicating that PSGMK may enhance endocytosis and lysosomal degradation of CLDN14. In a three-dimensional culture model, the oxidative stress was significantly reduced by PSGMK, whereas hypoxia stress was not. Furthermore, the expression levels of nuclear factor erythroid 2-related factor 2, an oxidative stress response factor, and its target genes were decreased by PSGMK. These results suggest that PSGMK relieves stress conditions in spheroids. The cell viability of spheroids was decreased by anticancer drugs such as doxorubicin and oxaliplatin, which was exaggerated by the cotreatment with PSGMK. Our data indicate that CLDN14-targeting peptide, PSGMK has an anti-chemoresistance effect in CRC cells.

The most critical issue impeding the development of innovative cerebrospinal medications is the blood-brain barrier (BBB). The BBB limits the ability of most medications to penetrate the brain to the CNS. The BBB structure and functions are summarized, with the physical barrier generated by endothelial tight junctions and the transport barrier formed by transporters within the membrane and vesicular processes. The functions of connected cells, particularly the end feet of astrocytic glial cells, microglia, and pericytes, are described. The drugs that cross the blood brain barrier are explained below along with their mechanisms. Some of the associated conditions and problems are given.

The contributions of intestinal barrier loss, that is, increased permeability, to multiple disorders, including inflammatory bowel disease (IBD), have been a topic of speculation for many years, and the literature is replete with conclusions based on correlation and speculation. The goal of this article is to critically review recent advances in mechanistic understanding of barrier regulation and the evidence for and against contributions of intestinal barrier loss to disease pathogenesis.

It is now recognized that intestinal permeability reflects the combined effects of two distinct routes across tight junctions, which form selectively permeable seals between adjacent epithelial cells, and mucosal damage that leads to nonselective barrier loss. These are referred to as pore and leak pathways across the tight junction and an unrestricted pathway at sites of damage. Despite advances in phenotypic and mechanistic characterization of three distinct permeability pathways, development of experimental agents that specifically target these pathways, and remarkable efficacy in preclinical models, pathway-targeted therapies have not been tested in human subjects.

After decades of speculation, therapeutic interventions that target the intestinal barrier are nearly within reach. More widespread use of available tools and development of new tools that discriminate between pore, leak, and unrestricted pathway permeabilities and underlying regulatory mechanisms will be essential to understanding the local and systemic consequences of intestinal barrier loss.

Here, we review key events in the accrual of knowledge about the cortical thick ascending limb (CTAL) of the kidney, starting with its initial characterization by Maurice Burg in 1973. Burg's work showed that the CTAL actively reabsorbs NaCl and that, because its water permeability is virtually zero, it can lower the luminal NaCl concentration to a "static head" level well below blood levels. This process is central to the kidney's ability to excrete dilute urine in states of high water intake. Following Burg's original observations, Greger and Schlatter, working in the 1980s, identified the membrane transport processes responsible for transepithelial NaCl transport in the CTAL. In the 1990s, several investigators identified the key transporter genes and proteins at a molecular level by cDNA cloning. The successful completion of human and mouse genome sequencing projects at the turn of the century led to the development of transcriptomic and proteomic methodologies that allowed the identification of complete transcriptomes and proteomes of CTAL cells. Knowledge accrual was enhanced by the development of differential equation-based models of transport in the CTAL in the 2010s. Here, we used a simplified mathematical model of NaCl ("salt"), urea, and water transport in the CTAL to address three key questions about CTAL function: 1) What is the mechanism of Burg's "static head" phenomenon? 2) How does the kidney compensate for the very short length of the CTALs of juxtamedullary nephrons? 3) Which of the three isoforms of the apical Na-K-2Cl cotransporter (NKCC2) dominates functionally in the CTAL?NEW & NOTEWORTHY Here, we review key events in the accrual of knowledge about the cortical thick ascending limb (CTAL) of the kidney, starting with its initial characterization by Maurice Burg in 1973, and culminating with the application of systems biology techniques including mathematical modeling.

Malignant tumors of the digestive system have had a notoriously dismal prognosis throughout history. Immunotherapy, radiotherapy, surgery, and chemotherapy are the primary therapeutic approaches for digestive system cancers. The rate of recurrence and metastasis, nevertheless, remains elevated. As one of the immunotherapies, chimeric antigen receptor T cell (CAR-T) therapy has demonstrated a promising antitumor effect in hematologic cancer. Despite undergoing numerous clinical trials, the ineffective antitumor effect and adverse effects of CAR-T cell therapy in the treatment of digestive system cancers continue to impede its clinical translation. It is necessary to surmount the restricted options for targeting proteins, the obstacles that impede CAR-T cell infiltration into solid tumors, and the limited survival time in vivo. We examined and summarized the developments, obstacles, and countermeasures associated with CAR-T therapy in digestive system cancers. Emphasis was placed on the regulatory functions of potential antigen targets, the tumor microenvironment, and immune evasion in CAR-T therapy. Thus, our analysis has furnished an all-encompassing comprehension of CAR-T cell therapy in digestive system cancers, which will generate tremendous enthusiasm for subsequent in-depth research into CAR-T-based therapies in digestive system cancers.

In addition to their adhesive properties, cell adhesion molecules such as claudins (CLDNs) exhibit signaling ability to organize diverse cellular events. Although the CLDN-adhesion signaling stimulates or inhibits cancer progression, the underlying mechanism remains poorly established. Here, we verified whether and how CLDN10 promotes intracellular signals and malignant phenotypes in clear cell renal cell carcinoma (ccRCC).

We developed a novel monoclonal antibody that specifically recognizes CLDN10. By immunohistochemistry using this antibody, the clinicopathological significance of aberrant CLDN10 expression in 165 ccRCC patients was determined. We next generated the ccRCC cells (786-O, ACHN, and OS-RC-2) expressing CLDN10, and compared their phenotypes with those of control cells. Immunoprecipitation-mass spectrometry was used to identify a CLDN10-interacting protein, followed by evaluation of its association with CLDN10 and loss-of-functions in ccRCC cells.

High CLDN10 expression predicted poor outcome in ccRCC patients and represented an independent prognostic marker for cancer-specific survival. Cell surface CLDN10 promoted cell viability, proliferation, and migration of ccRCC cells, as well as their tumor growth. CLDN10 also activated mTOR signaling and expression of downstream targets, including MYC target genes. Notably, we found that CLDN10 forms a complex with an amino acid transporter, LAT1, and that CLDN10-LAT1 signaling facilitates malignant phenotypes in ccRCC cells. Structural prediction and immunoprecipitation analysis results strongly suggest an interaction between CLDN10-TM1 (transmembrane domain 1) and LAT1-TM4.

We conclude that CLDN10-LAT1 signaling drives ccRCC progression. Taken together with our previous findings on CLDN-Src-family kinases signaling, CLDNs propagate distinct intracellular signals depending on their association with different binding partners.

Recently, the molecular landscape of gastric and pancreatic cancers has advanced with Claudin 18.2 (CLDN18.2) emerging as a promising therapeutic target. Claudin 18.2, a tight junction protein, is selectively expressed in cancer cells and minimally in normal tissues, making it an attractive candidate for targeted therapy. Therapies like monoclonal antibodies (e.g., zolbetuximab), bispecific antibodies, and antibody-drug conjugates have shown significant potential in improving clinical outcomes. Early-phase clinical trials demonstrate robust antitumor activity, particularly in combination with chemotherapy and immunotherapy regimens. However, challenges such as patient selection, resistance mechanisms, and toxicity management remain critical. This review highlights the therapeutic landscape, clinical advancements, and future directions of targeting Claudin 18.2 in gastric and pancreatic cancer treatment.

Invasive micropapillary carcinoma of the breast is characterized by clusters of cells presenting with inverted polarity. Although the apico-basal polarity is a fundamental property of the epithelium, the biological alterations leading to the inside-out pattern observed in invasive micropapillary carcinoma (IMPC) remain mostly unknown. The regulation of tight junctions in polarity formation and maintenance is acknowledged. By using immunohistochemistry, we have analysed claudin-1, -3, -4, and -7 tight junction proteins expression and their prognostic value on IMPCs and compared them to invasive breast carcinomas of no special type (IBC-NST) tumors. Our cohort consisted of 37 IMPCs, 36 IBC-NST and 9 mixed IMPC/IBC-NST tumors. Two scoring systems were used to quantify protein expression: a 4-tier scoring system and the H-score method. Distant metastasis free survival (DMFS) intervals and overal survival (OS) data were used for prognosis evaluation. The analysed samples were characterized mainly by low or no claudin-1 expression whereas claudins-3, -4 and -7 showed variable positivity. We have found no significant differences in claudin-3 and -4 protein expression between IMPC and IBC-NST groups with either scoring methods, however high claudin-7 expression was found in significantly more IMPCs than IBC-NST tumors according to the H-score system (p = 0.02). The 4-tier scoring method revealed association of claudin-7 expression with molecular tumor subtypes (p = 0.001). IMPC and IBC-NST tumors did not show difference in DMFS (p = 0.70). In the analysis of pure IMPC and IBC-NST tumors, positive/high claudin-4 protein expression was significantly associated with shorter DMFS (p = 0.02/p = 0.008, respectively according to the two scoring methods). Claudin-3 and claudin-7 expression showed no association with DMFS or OS. Changes in epithelial polarity seem not to be related to claudin-1, -3, and -4 expression. Increased claudin-4 expression may have a role in breast cancer progression.

The kidney plays a major role in maintenance of serum calcium concentration, which must be kept within a narrow range to avoid disruption of numerous physiologic processes that depend critically on the level of extracellular calcium, including cell signaling, bone structure, and muscle and nerve function. This defense of systemic calcium homeostasis comes, however, at the expense of the dumping of calcium into the kidney tissue and urine. Because of the large size and multivalency of the calcium ion, its salts are the least soluble among all the major cations in the body. The potential pathologic consequences of this are nephrocalcinosis and kidney stone disease. In this review, we discuss recent advances that have highlighted critical roles for the proximal tubule and thick ascending limb in renal calcium reabsorption, elucidated the molecular mechanisms for paracellular transport in these segments, and implicated disturbances in these processes in human disease.

A considerable amount of NaCl reabsorption in proximal tubules (PTs) occurs via the paracellular transport regulated by the tight junction proteins claudins (Cldns). However, the paracellular transport properties in mouse superficial PTs remain unclear. We characterized these properties in superficial PT S1-S3 segments from mice expressing [wild-type (WT, WTS1-WTS3)] or lacking [knockout (KO, KOS1-KOS3)] claudin-2. We isolated and perfused segments with symmetrical solutions in the presence of bath ouabain and measured the diffusion potential upon changing the salt composition of the lumen or bath. Based on the diffusion potential corrected for the liquid junction potential (dVT), we calculated the paracellular Na+ over Cl- permeability (PNa/PCl) ratio. The PNa/PCl values upon reducing luminal NaCl averaged 1.27, 1.04, and 0.85 in WTS1, WTS2, and WTS3 and 0.34, 0.55, and 0.80 in KOS1, KOS2, and KOS3, respectively. The dVT values exhibited a symmetrical response to bidirectional NaCl concentration gradients in WTS1-WTS3 and KOS1-KOS3. WTS1 and WTS3 were monovalent cation-selective, with WTS1 demonstrating stronger cation selectivity. The order of permeabilities relative to Cl- was K+ > Rb+ > Na+ > Li+, whereas both KOS1 and KOS3 exhibited monovalent cation selectivity loss and, consequently, enhanced anion selectivity, especially in KOS1. Protamine addition to the lumen and bath similarly decreased PNa/PCl values upon reduced luminal NaCl in the order of WTS1 > WTS3 > KOS3 > KOS1. Therefore, this study presents evidence of axial heterogeneity in paracellular transport across superficial PTs in mice.NEW & NOTEWORTHY Research on isolated perfused S2 segments of proximal tubules in mice, both expressing and lacking claudin-2, indicates that claudin-2 forms leaky monovalent cation-selective paracellular channels within the tight junctions of proximal tubules. This study characterized the paracellular transport properties in isolated and perfused superficial proximal tubule S1-S3 segments in both groups of mice. The findings demonstrate, for the first time, functional heterogeneity in the paracellular pathway along the axis of the superficial proximal tubules.

Pseudolipoblastic perineurioma is a very uncommon variant of extraneural perineurioma, with only a limited number of cases documented in the medical literature. The most remarkable histopathologic characteristic is the existence of vacuolated cells that closely resemble lipoblasts; besides the presence of small, spindle shaped, or epithelioid perineurial cells. In this study, we present another case of pseudolipoblastic perineurioma, predominantly characterized by the presence of vacuolated "pseudolipoblastic" cells. The immunohistochemical expression of EMA, Glut-1, claudin-1, collagen type IV, and laminin as well as S-100 negativity is essential for the diagnosis to support the perineurial origin. Simple excision is the best treatment option for these benign tumors that do not recur or metastasize. It is crucial to recognize this rare entity to differentiate it from many other tumors characterized by prominent intracytoplasmic vacuoles.

Regulation of salt and water balance occupies a dominant role in the physiology of many animals and often relies on the function of the renal system. In the mammalian kidney, epithelial ion and water transport requires high degree of coordination between the transcellular and paracellular pathways, the latter being defined by the intercellular tight junctions (TJs). TJs seal the paracellular pathway in a highly specialized manner, either by forming a barrier against the passage of solutes and/or water or by allowing the passage of ions and/or water through them. This functional TJ plasticity is now known to be provided by the members of the claudin family of tetraspan proteins. Unlike mammalian nephron, the renal structures of insects, the Malpighian tubules, lack TJs and instead have smooth septate junctions (sSJs) as paracellular barrier forming junctions. Many questions regarding the molecular and functional properties of sSJs remain open but research on model species have begun to inform our understanding. The goal of this commentary is to highlight key concepts and most recent findings that have emerged from the molecular and functional dissection of paracellular barriers in the mammalian and insect renal epithelia.

Pancreatitis is an inflammatory disease of the pancreas that can arise due to various factors, including environmental risks such as diet, alcohol, and smoking, as well as genetic predispositions. In some cases, pancreatitis may progress and become chronic, leading to irreversible damage and impaired pancreatic function. Genome-wide association studies (GWAS) have identified polymorphisms at the X-linked CLDN2 locus as risk factors for both sporadic and alcohol-related chronic pancreatitis. CLDN2 encodes claudin-2 (CLDN2), a paracellular cation-selective channel localized at tight junctions and expressed in the pancreas and other secretory organs. However, whether and how CLDN2 may modify pancreatitis susceptibility remains poorly understood. We aimed to clarify the potential role of CLDN2 in the onset and progression of pancreatitis. We employed multiple methodologies to examine the role of CLDN2 in human pancreatic tissue, caerulein-induced experimental pancreatitis mouse model, and pancreatic ductal epithelial organoids. In both human chronic pancreatitis tissues and caerulein-induced experimental pancreatitis, CLDN2 protein was significantly upregulated in pancreatic ductal epithelial cells. Our studies using pancreatic ductal epithelial organoids and mice demonstrated the inflammatory cytokine IFNγ upregulates claudin-2 expression at both RNA and protein levels. Following caerulein treatment, Ifng KO mice had diminished upregulation of CLDN2 relative to WT mice, indicating that caerulein-induced claudin-2 expression is partially driven by IFNγ. Functionally, Cldn2 knockout mice developed more severe caerulein-induced experimental pancreatitis, indicating CLDN2 plays a protective role in pancreatitis development. Pancreatic ductal epithelial organoid-based studies demonstrated that CLDN2 is critical for sodium-dependent water transport and necessary for cAMP-driven, CFTR-dependent fluid secretion. These findings suggest that functional crosstalk between CLDN2 and CFTR is essential for fluid transport in pancreatic ductal epithelium, which may protect against pancreatitis by adjusting pancreatic ductal secretion to prevent worsening autodigestion and inflammation. In conclusion, our studies suggest CLDN2 upregulation during pancreatitis may play a protective role in limiting disease development, and decreased CLDN2 function may increase pancreatitis severity. These results point to the possibility of modulating pancreatic ductal CLDN2 function as an approach for therapeutic intervention of pancreatitis.

A 12-year-old female, resident of western India, presented with a history of pruritus associated with jaundice for two months. On presentation, she had icterus with mild palpable hepatomegaly. Investigations revealed direct hyperbilirubinemia and elevated transaminases, while gamma-glutamyl transferase levels were normal. Serology for anti-hepatitis A, E, B, and C were negative. Autoimmune markers such as antinuclear antibody, smooth muscle antibody, and anti-liver kidney microsomal antibody were negative. Serum IgG levels were within the normal range. A normal magnetic resonance cholangiopancreatography ruled out any ductal abnormalities. A liver biopsy was also conducted but proved to be inconclusive. Despite extensive workup, the diagnosis remained unclear. However, genetic testing through whole exome sequencing identified a novel compound heterozygous variation, a novel in exon 5 and exon 4 of the Tight-Junction Protein 2 gene, and confirmed the diagnosis of cholestatic liver disease as progressive familial intrahepatic cholestasis type 4. This case highlights the importance of genetic testing for diagnosing cholestatic liver diseases, especially when conventional tests do not provide a clear diagnosis. Whole exome sequencing revealed a novel mutation in the TJP2 gene, ultimately confirming the diagnosis of PFIC4.

Tumor development and progression is a long and complex process influenced by a combination of intrinsic (eg, gene mutation) and extrinsic (eg, environmental pollution) factors. As a detoxification organ, the liver plays an important role in human exposure and response to various environmental pollutants including nanomaterials (NMs). Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and remains a serious threat to human health. Whether NMs promote liver cancer progression remains elusive and assessing long-term exposure to subtoxic doses of nanoparticles (NPs) remains a challenge. In this study, we focused on the promotional effects of nano zinc oxide (nZnO) on the malignant progression of human HCC cells HepG2, especially aged nZnO that has undergone physicochemical transformation.

In in vitro experiments, we performed colony forming efficiency, soft agar colony formation, and cell migration/invasion assays on HepG2 cells that had been exposed to a low dose of nZnO (1.5 μg/mL) for 3 or 4 months. In in vivo experiments, we subcutaneously inoculated HepG2 cells that had undergone long-term exposure to nZnO for 4 months into BALB/c athymic nude mice and observed tumor formation. ZnCl2 was administered to determine the role of zinc ions.

Chronic low-dose exposure to nZnO significantly intensified the malignant progression of HCC cells, whereas aged nZnO may exacerbate the severity of malignant progression. Furthermore, through transcriptome sequencing analysis and in vitro cellular rescue experiments, we demonstrated that the mechanism of nZnO-induced malignant progression of HCC could be linked to the activation of Claudin-2 (CLDN2), one of the components of cellular tight junctions, and the dysregulation of its downstream signaling pathways.

Long-term exposure of fresh and aged nZnO promotes hepatocellular carcinoma malignancy by up-regulating CLDN2. The implications of this work can be profound for cancer patients, as the use of various nanoproducts and unintentional exposure to environmentally transformed NMs may unknowingly hasten the progression of their cancers.

Hepatobiliary and pancreatic diseases are becoming increasingly common worldwide and associated cancers are prone to recurrence and metastasis. For a more accurate treatment, new therapeutic strategies are urgently needed. The claudins (CLDN) family comprises a class of membrane proteins that are the main components of tight junctions, and are essential for forming intercellular barriers and maintaining cellular polarity. In mammals, the claudin family contains at least 27 transmembrane proteins and plays a major role in mediating cell adhesion and paracellular permeability. Multiple claudin proteins are altered in various cancers, including gastric cancer (GC), esophageal cancer (EC), hepatocellular carcinoma (HCC), pancreatic cancer (PC), colorectal cancer (CRC) and breast cancer (BC). An increasing number of studies have shown that claudins are closely associated with the occurrence and development of hepatobiliary and pancreatic diseases. Interestingly, claudin proteins exhibit different effects on cancer progression in different tumor tissues, including tumor suppression and promotion. In addition, various claudin proteins are currently being studied as potential diagnostic and therapeutic targets, including claudin-3, claudin-4, claudin-18.2, etc. In this article, the functional phenotype, molecular mechanism, and targeted application of the claudin family in hepatobiliary and pancreatic diseases are reviewed, with an emphasis on claudin-1, claudin-4, claudin-7 and claudin-18.2, and the current situation and future prospects are proposed.

Ischemic stroke is a leading cause of morbidity and mortality in older adults. Therefore, in this study, we sought to understand the interplay between the microbiota, gut, and brain in the context of stroke in older adults.

To determine whether gut microbiota from younger individuals promotes recovery through angiogenesis in both elderly stroke patients and aged stroke mice, we explored the changes in gut microbiota and the correlation between short-chain fatty acids (SCFAs) and angiogenesis in the aged stroke population. Then, we altered the gut microbiome in aged mice by transplanting microbiota from younger donors before inducing experimental stroke to explore the mechanism by which gut microbiota-derived SCFAs promote angiogenesis.

Part I: We conducted a single-center, double-blind trial to compare gut microbiota diversity and SCFA levels in fecal samples from older stroke patients with those from younger stroke patients. Additionally, we measured levels of vascular endothelial growth factor (VEGF) and VEGFC levels in plasma to assess their correlation with SCFA levels. Part II: We performed fecal microbiota transplantation (FMT) 3 days before inducing ischemic stroke in aged male mice (16-18) via distal middle cerebral artery occlusion (dMCAO). The FMT was conducted using gut microbiomes from either young donors (2-3 months) or aged donors (16-18 months).

In older stroke patients, gut microbiota diversity was significantly reduced compared to that in younger stroke patients. Furthermore, levels of acetate, a bacterially derived SCFA, were lower and positively correlated with angiogenesis markers (VEGF and VEGF-C). In aged stroke mice, transplantation of young microbiota improved stroke outcomes by promoting angiogenesis, which was facilitated by lymphatic ingrowth into the cortex. This protective effect was linked to gut microbiota-derived acetate, which enhanced lymphangiogenesis by replenishing acetyl coenzyme A.

(a) Gut microbiota-derived acetate promotes angiogenesis post-stroke and (b) lymphatic ingrowth into the cerebral cortex was observed in post-dMCAO mice. These findings suggest that selectively promoting SCFA-producing bacteria, particularly acetate-producers, could be a promising therapeutic strategy to reduce functional impairments in older stroke subjects.

Reflux esophagitis (RE) is a disease in which inflammation of the esophageal mucosa owing to the reflux of gastric contents into the esophagus results in cytokine damage. Britannilactone 1-O-acetate (Brt) has anti-inflammatory effects, significantly inhibiting the activation of the NLRP3 inflammasome, leading to a decrease in inflammatory factors including IL-1 β, IL-6, and TNF-α. However, the mechanism underlying its protective effect against RE-induced esophageal injury remains unclear. In the present study, we investigated the protective mechanism of TRIM31 against NLRP3 ubiquitination-induced RE both in vivo and in vitro.

A model of RE was established in vivo in rats by the method of "4.2 mm pyloric clamp + 2/3 fundoplication". In vitro, the mod was constructed by using HET-1A (esophageal epithelial cells) and exposing the cells to acid, bile salts, and acidic bile salts. The 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay was used to screen the concentration of administered drugs, and the viability of HET-1A cells in each group. HE staining was used to assess the degree of pathological damage in esophageal tissues. Toluidine blue staining was used to detect whether the protective function of the esophageal epithelial barrier was damaged and restored. The enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of IL-1 β, IL-6, and TNF-α factors in serum. Immunohistochemistry (IHC) was used to detect the expression level of NLRP3 in esophageal tissues. The molecular docking and Co-immunoprecipitation assay (Co-IP assay) were used to detect the TRIM31 interacts with NLRP3. Western blotting detected the Claudin-4, Claudin-5, The G-protein-coupled receptor calcium-sensitive receptor (CaSR), NLRP3, TRIM31, ASC, C-Caspase1, and Caspase1 protein expression levels.

Brt could alleviate RE inflammatory responses by modulating serum levels of IL-1 β, IL-6, and TNF-α. It also activated the expression of NLRP3, ASC, Caspase 1, and C-Caspase-1 in HET-1A cells. Brt also attenuated TRIM31/NLRP3-induced pathological injury in rats with RE through a molecular mechanism consistent with the in vitro results.

Brt promotes the ubiquitination of NLRP3 through TRIM31 and attenuates esophageal epithelial damage induced by RE caused by acidic bile salt exposure. This study provides valuable insights into the mechanism of action of Brt in the treatment of RE and highlights its promising application in the prevention of NLRP3 inflammatory vesicle-associated inflammatory pathological injury.

We aimed to investigate the impact of heat stress (HS) on the expression of tight junction (TJ) proteins and the interaction between genes affecting intestinal barrier function using transcriptomics in the porcine jejunum. Twenty-four barrows (crossbred Yorkshire × Landrace × Duroc; average initial body weight, 56.71 ± 1.74 kg) were placed in different temperatures (normal temperature [NT]; HS) and reared for 56 days. At the end of the experiment, jejunal samples were collected from three pigs per treatment for transcriptome and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) analyses. We identified 43 differentially expressed genes, involving five Kyoto Encyclopedia of Genes and Genomes pathways, eight molecular functions, seven cellular components (CCs), and nine biological processes, using gene ontology enrichment analysis. Genes associated with the actin cytoskeleton, filament-binding pathways, and TJ proteins were selected and analyzed by RT-qPCR. Significant differences in relative mRNA expression showed that downregulated genes in the HS group included ZO1, CLDN1, OCLN, PCK1, and PCK2, whereas ACTG2, DES, MYL9, MYLK, TPM1, TPM2, CNN1, PDLIM3, and PCP4 were upregulated by HS (p < 0.05). These findings indicate that HS in growing-finishing pigs induces depression in gut integrity, which may be related to genes involved in the actin cytoskeleton and filaments of CC.

Tight junctions are cell-cell adhesion complexes that act as gatekeepers of the paracellular space. Formed by several transmembrane proteins, the claudin family performs the primary gate-keeping function. The claudin proteins form charge and size-selective diffusion barriers to maintain homeostasis across endothelial and epithelial tissue. Of the 27 known claudins in mammals, some are known to seal the paracellular space, while others provide selective permeability. The differences in permeability arise due to the varying expression levels of claudins in each tissue. The tight junctions are observed as strands in freeze-fracture electron monographs; however, at the molecular level, tight junction strands form when multiple claudin proteins assemble laterally (cis assembly) within a cell and head-on (trans assembly) with claudins of the adjacent cell in a zipper-like architecture, closing the gap between the neighboring cells. The disruption of tight junctions caused by changing claudin expression levels or mutations can lead to diseases. Therefore, knowledge of the molecular architecture of the tight junctions and how that is tied to tissue-specific function is critical for fighting diseases. Here, we review the current understanding of the tight junctions accrued over the last three decades from experimental and computational biophysics perspectives.

Protein-protein interaction (PPI) networks provide valuable insights into the function of biological systems. Aligning multiple PPI networks may expose relationships beyond those observable by pairwise comparisons. However, assessing the biological quality of multiple network alignments is a challenging problem.

We propose two new measures to evaluate the quality of multiple network alignments using functional information from Gene Ontology (GO) terms. When aligning multiple real PPI networks across species, we observe that both measures are highly correlated with objective quality indicators, such as common orthologs. Additionally, our measures strongly correlate with an alignment's ability to predict novel GO annotations, which is a unique advantage over existing GO-based measures.

The scripts and the links to the raw and alignment data can be accessed at https://github.com/kimiayazdani/GO_Measures.git.

An exceptional expression of claudins (CLDNs), tight junction (TJ) proteins, is observed in various solid cancer tissues. However, the pathophysiological roles of CLDNs have not been clarified in detail. CLDN14 is highly expressed in human colorectal cancer (CRC) tissues and cultured cancer epithelial cells. We found CLDN14 silencing decreased cell viability without affecting spheroid size in the three-dimensional (3D) spheroid model of DLD-1 cells derived from human CRC. Mitochondria activity and oxidative stress level were reduced by CLDN14 silencing. Furthermore, CLDN14 silencing decreased the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target antioxidative genes. CLDN14 was colocalized with ZO-1, a scaffolding protein in the TJ. CLDN14 silencing induced the disruption of TJ barrier such as the reduction of transepithelial electrical resistance and elevation of fluxes of small molecules including glucose in two-dimensional (2D) cultured model,. The depletion of glucose induced the elevation of ROS generation, mitochondria activity, and Nrf2 expression. These results suggest that CLDN14 increases Nrf2 expression in spheroids mediated via the formation of paracellular barrier to glucose. The cytotoxicities of doxorubicin, an anthracycline anticancer drug, and oxaliplatin, a platinum-based agent, were augmented by an Nrf2 activator in 2D cultured cells. The anticancer drug-induced toxicity was enhanced by CLDN14 silencing in 3D spheroids. We suggest that CLDN14 may potentiate chemoresistance mediated by the suppression of paracellular glucose permeability and activation of the Nrf2 signaling pathway in CRC cells.

Obesity stands as a formidable global health challenge, predisposing individuals to a plethora of chronic illnesses such as cardiovascular disease, diabetes, and cancer. A confluence of genetic polymorphisms, suboptimal dietary choices, and sedentary lifestyles significantly contribute to the elevated incidence of obesity. This multifaceted health issue profoundly disrupts homeostatic equilibrium at both organismal and cellular levels, with marked alterations in gut permeability as a salient consequence. The intricate mechanisms underlying these alterations have yet to be fully elucidated. Still, evidence suggests that heightened inflammatory cytokine levels and the remodeling of tight junction (TJ) proteins, particularly claudins, play a pivotal role in the manifestation of epithelial barrier dysfunction in obesity. Strategic targeting of proteins implicated in these pathways and metabolites such as short-chain fatty acids presents a promising intervention for restoring barrier functionality among individuals with obesity. Nonetheless, recognizing the heterogeneity among affected individuals is paramount; personalized medical interventions or dietary regimens tailored to specific genetic backgrounds and allergy profiles may prove indispensable. This comprehensive review delves into the nexus of obesity, tight junction remodeling, and barrier dysfunction, offering a critical appraisal of potential therapeutic interventions.

Gastric cancer remains a formidable challenge in oncology with high mortality rates and few advancements in treatment. Claudin-18.2 (CLDN18.2) is a tight junction protein primarily expressed in the stomach and is frequently overexpressed in certain subsets of gastric cancers. Targeting CLDN18.2 with monoclonal antibodies, such as zolbetuximab (IMAB362), has shown promising efficacy results in combination with chemotherapy.

The molecular cell biology of CLDN18.2 is discussed along with studies demonstrating the utility of CLDN18.2 expression as a biomarker and therapeutic target. Important clinical studies are reviewed, including Phase III trials, SPOTLIGHT and GLOW, which demonstrate the efficacy of zolbetuximab in combination with chemotherapy in patients with CLDN18.2-positive advanced gastric cancer.

CLDN18.2 is involved in gastric differentiation through maintenance of epithelial barrier function and coordination of signaling pathways, and its expression in gastric cancers reflects a 'gastric differentiation' program. Targeting Claudin-18.2 represents the first gastric cancer specific 'targeted' treatment. Further studies are needed to determine its role within current gastric cancer treatment sequencing, including HER2-targeted therapies and immunotherapies. Management strategies will also be needed to better mitigate zolbetuximab-related treatment side effects, including gastrointestinal (GI) toxicities.

Claudin18.2 is a tight junction protein, highly selective, generally expressed only in normal gastric mucosal epithelial cells, which can effectively maintain the polarity of epithelial and endothelial cells, thus effectively regulating the permeability and conductance of the paracellular pathway. Abnormal expression of Claudin18.2 can occur in various primary malignant tumors, especially gastrointestinal tumors, and even in metastatic foci. It regulates its expression by activating the aPKC/MAPK/AP-1 pathway, and therefore, the Claudin18.2 protein is a pan-cancer target expressed in primary and metastatic lesions in human cancer types. Zolbetuximab (IMAB362), an antibody specific for Claudin18.2, has been successfully tested in a phase III clinical trial, and the results of the study showed that combining Zolbetuximab with chemotherapy notably extends patients' survival and is expected to be a potential first-line treatment for patients with Claudin18.2(+)/HER-2(-) gastric cancer. Here, we systematically describe the biological properties and oncogenic effects of Claudin18.2, centering on its clinical-pathological aspects and the progress of drug studies in gastric cancer, which can help to further explore its clinical value.