Gastric cancer is a leading cause of cancer death worldwide. Targeted therapy is shifting from blocking signaling pathways to precise gene regulation. This review covers three key areas: antibody drugs, RNAi, and nanocarriers. Anti-HER2 agents, VEGFR2 inhibitors, Claudin 18.2-directed therapies and PD-1/PD-L1 inhibitors improve survival in biomarker-selected patients-but resistance and low response rates (ORR < 20% in unselected groups) limit their use. RNAi silences key oncogenes to reverse chemoresistance and reprogram the immunosuppressive tumor microenvironment, but it suffers from rapid degradation, poor endosomal escape, off-target effects, and weak tumor penetration. Nanocarrier systems-including lipid nanoparticles (LNPs), stimuli-responsive micelles, and mesoporous silica-combined with aptamers enable targeted delivery of therapeutic antibodies and siRNA, penetration across stromal barriers, and controlled, tumor microenvironment-triggered cargo release. Altogether, the future of gastric cancer therapy is moving beyond monotherapy to a five-part strategy: antibody targeting, RNA silencing, nanocarrier delivery, AI-guided decisions, and immune remodeling.

Poly(lactic-co-glycolic acid) (PLGA) microspheres are a clinically established platform for sustained and controlled drug delivery, offering tunable degradation and reduced dosing frequency. This review critically appraises PLGA microsphere technology, linking materials science with clinical translation. We examine how molecular parameters-molecular weight, lactide-to-glycolide ratio, and terminal group chemistry-affect degradation and release kinetics. Key fabrication methods (emulsion-solvent evaporation, spray drying, membrane emulsification, and microfluidics) are compared for their control over encapsulation efficiency, particle size, and scalability. Release mechanisms, including diffusion, swelling, and erosion, are discussed alongside strategies to mitigate burst release. The review also addresses in vivo pharmacokinetics, recent clinical progress in oncology and vaccine delivery, regulatory challenges, manufacturing hurdles, and future directions such as stimuli-responsive microspheres and AI-guided formulation design.

Hepatic fibrosis, a hallmark of chronic liver diseases, arises from persistent activation of hepatic stellate cells (HSCs). Golgi protein 73 (GP73) is a recognized fibrosis biomarker, yet its active role in driving fibrogenesis and the underlying molecular mechanisms remain poorly defined. Using wild-type, GP73 knockout, and knock-in mouse models, we demonstrate that GP73 expression is not merely a marker but a key functional modulator of fibrotic progression, correlates strongly with fibrosis severity. While these genetic models do not develop spontaneous hepatic fibrosis under basal conditions—notwithstanding the potential metabolic roles of GP73—our results demonstrate that GP73 expression levels significantly dictate the severity of CCl4-induced fibrotic progression. Mechanistically, endogenous co-immunoprecipitation (Co-IP) revealed that GP73 physically interacts with TGF-β receptor 1 (TGFBR1), mTOR, and the recycling endosome marker Rab11. GP73 enhances HSC activation by amplifying TGF-β and mTOR signaling through the inhibition of key fibrotic factors' degradation, such as TGFBR1 and mTOR. Protein half-life and rescue experiments confirmed that GP73 prevents the lysosomal degradation of TGFBR1 and mTOR; notably, re-introducing GP73 into knockdown cells successfully restored receptor stability and downstream signaling. Furthermore, pharmacological disruption of endocytic trafficking with Brefeldin A (BFA) abolished the protective effect of GP73, leading to accelerated receptor degradation. Suppressing GP73 reduced HSC activation and attenuated collagen deposition in vivo. Our findings identify GP73 as a molecular scaffold that reroutes fibrotic signaling complexes into the recycling pathway and away from degradation. Consequently, our results position GP73-mediated endocytic recycling as a potential therapeutic target and a viable adjunctive strategy for managing chronic liver diseases.

Hepatocellular carcinoma (HCC) poses significant therapeutic challenges due to its high heterogeneity and immunosuppressive tumor microenvironment (TME). Immunogenic cell death (ICD) represents a promising strategy in cancer therapy by eliciting antitumor immune responses through the controlled release of damage-associated molecular patterns (DAMPs). However, its therapeutic efficacy remains substantially limited by the immunosuppressive TME and the lack of selective targeting of conventional ICD-inducing agents. MicroRNAs (miRNAs) regulate immune checkpoints (e.g., PD-L1), TME populations (e.g., tumor-associated macrophages and regulatory T cells), and DAMPs-related pathways, positioning them to both enhance ICD and relieve its constraints. Clinical translation, however, is hindered by delivery and off-target effects. Emerging nanotechnologies, including pH-responsive and photoresponsive carriers, enable spatiotemporal co-delivery of ICD inducers (e.g., oxaliplatin) and miRNA modulators (e.g., anti-miR-21), thereby augmenting DAMP release, reprogramming the TME, and targeting competing endogenous RNA networks (e.g., lncRNA H19) to overcoming resistance. In this Review, with a focus on clinical translation, we argue that combining ICD, immune checkpoint blockade, and miRNA modulation offers a coherent framework to turn cold HCC tumors into responsive ones, thereby increasing treatment precision and sustaining benefit.

As an essential carrier for drug delivery systems, the stability of liposomes directly influences the efficiency and safety of drug delivery. In the complex and challenging process of in vivo delivery, the stability of liposomes is affected by both their inherent properties and external environmental factors. This paper first introduces the in vivo journey of liposomes, encompassing blood circulation, tissue distribution, metabolism, and excretion. It then summarizes the biological factors affecting liposome stability, including immune recognition, protein-lipid interactions, enzyme-catalyzed degradation, and physiological changes. Additionally, the paper explores effective strategies to enhance liposome stability, such as optimizing lipid composition and surface modification. Finally, it discusses future research directions and existing challenges, focusing on AI-assisted liposome development, and the development of biocompatible materials. The study emphasizes the critical factors affecting liposome stability, uncovers current limitations, and highlights future potential in this field, providing a theoretical foundation and practical guidance for the design and application of liposomes.

Targeted therapeutics for liver fibrosis (LF) are unavailable. PU.1 is a pioneer transcription factor (TF) that promotes hepatic stellate cell (HSC) activation and LF. PU.1 decoy oligodeoxynucleotides (ODNs) can potentially repress LF by capturing PU.1. In this study, we used Apt-Tan, a hepatic stellate cell (HSC)-internalizing DNA aptamer selected through the cell systematic evolution of ligands by exponential enrichment (Cell-SELEX), and validated the anti-LF effect of a combination of Apt-Tan and PU.1 decoy ODN in mice. Furthermore, intravenous injection of Apt-Tan- PU.1 decoy ODN repressed the expression of PU.1 downstream pro-fibrotic genes such as TIMP1, alleviated liver injury, and reduced extracellular matrix deposition in mice model of LF induced by CCL4. Apt-Tan- PU.1 decoy ODN demonstrated anti-fibrosis potential and warranted further investigation.

Aptamers, as a kind of small-molecule nucleic acid, have attracted much attention since their discovery. Compared with biological reagents such as antibodies, aptamers have the advantages of small molecular weight, low immunogenicity, low cost, and easy modification. At present, aptamers are mainly used in disease biomarker discovery, disease diagnosis, treatment, and targeted drug delivery vectors. In the process of screening and optimizing aptamers, it is found that there are still many problems need to be solved such as the design of the library, optimization of screening conditions, the truncation of screened aptamer, and the stability and toxicity of the aptamer. In recent years, the incidence of liver-related diseases is increasing year by year and the treatment measures are relatively lacking, which has attracted the people's attention in the application of aptamers in liver diseases. This article mainly summarizes the research status of aptamers in disease diagnosis and treatment, especially focusing on the application of aptamers in liver diseases, showing the crucial significance of aptamers in the diagnosis and treatment of liver diseases, and the use of Discovery Studio software to find the binding target and sequence of aptamers, and explore their possible interaction sites.

The activation of hepatic stellate cells play a pivotal role in the pathogenesis of hepatic fibrosis. However, the current lack of specifically identified targets on these cells poses a significant challenge in developing targeted delivery tools for effective anti-hepatic fibrosis therapeutics in clinical practice. Cell-systematic evolution of ligands by exponential enrichment method was conducted on HSC-T6 cell line to screen out activated hepatic stellate cell-specific aptamers. The specificity of the selected aptamers in targeting hepatic stellate cells was confirmed after truncation optimization. Furthermore, the optimal aptamer was conjugated with miR-23b-5p via C6 linkage to evaluate the targeting specificity of this complex and assess its potential in downregulating liver fibrosis-related proteins and slowing down the progression of liver fibrosis. The present study successful identified 11 highly enriched single-stranded DNA sequences (APT1-11) that specifically target activated hepatic stellate cells. Subsequent affinity detection and optimization truncation led to the selection of APT8(16-34), which effectively targeted activated hepatic stellate cells both in vivo and in vitro. Moreover, when conjugated with miR-23b-5p, APT8(16-34) also exhibited internalization ability into activated hepatic stellate cells. The delivered cargo miR-23b-5p by APT8 (16-34) effectively targeted to mRNA, leading to translational inhibition and subsequent downregulation of related proteins. We have identified APT8 (16- 34), which exhibits specific targeting and internalization capabilities into activated hepatic stellate cells. Moreover, when conjugated with miR-23b-5p, APT8 (16-34) also internalizes into activated hepatic stellate cells, enabling miR-23b-5p exert their respective functions. Schematic representation of aptamer selection for activated hepatic stellate cells using Cell-SELEX technology. Initially, the DNA library was incubated with the cells isolated from rats liver, including primary hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells, and Kupffer cell, as negative controls to eliminate negative cell-binding sequences. The unbound DNAs were collected and subsequently incubated with pcDNA3.1-ALK5 treated HSC-T6 cell line for positive selection. Following thorough washing, the bound DNAs were eluted and subjected to PCR amplification for subsequent rounds of selection. After five rounds of selection, DNA sequencing was conducted to identify individual aptamer sequences. The top 11 sequences, named APT1-11, exhibiting significant enrichment were selected using high-throughput sequencing techniques. APT8(16–34) was finally identified after two rounds of truncation, followed by specificity and affinity analysis. Subsequently, miR-23b-5p was conjugated with APT8(16–34) using C6 as the linker and the resulting APT8(16–34)-miR-23b-5p complex was administered intravenously into hepatic fibrosis mice. The experimental evidence demonstrated the effective delivery of miR-23b-5p into activated HSC-T6 cells by APT8(16–34). Furthermore, the delivered miR-23b-5p downregulated the expression of related proteins.

BACKGROUND:Aptamers, consisting of single-stranded DNA or RNA, have secondary and tertiary structures which could bind specifically to target molecules. They are characterized by strong specificity, high affinity, low molecular weight, and low immunogenicity; therefore, the current research focuses on their potential as a targeted drug carrier, a diagnostic probe for diseases, or as a direct therapeutic drug.OBJECTIVE:In this review, how to improve the success rate of adaptor screening and the optimization after screening is described.RESULTS:For aptamer screening, an efficient selection strategy is needed. In this article, by analyzing key aspects of SELEX such as initial library design, screening procedures, truncation and modification after screening, a comprehensive analysis of each step that might meet obstacles in SELEX is provided.CONCLUSION:Aptamers, which possess the specificity and affinity with the target, can serve as targeted drug carriers or biosensors for diagnosing a disease. If the problems in the screening process in cell-SELEX technology, truncation, and modification after screening are solved, it will have a broader range of applications.

BACKGROUND & AIMS: Hepatic fibrosis is characterized by hepatic stellate cell (HSC) activation and transdifferentiation-mediated extracellular matrix (ECM) deposition, which both contribute to cirrhosis. However, no antifibrotic regimen is available in the clinic. microRNA-23b/27b/24-1 cluster inhibition of transforming growth factor-/5 (TGF-/5) signaling during hepatic development prompted us to explore whether this cluster inhibits HSC activation and hepatic fibrosis. METHODS: Experimental fibrosis was studied in carbon tet-rachloride (CCl4)-treated C57BL/6 mice. After administration of miR-23b/27b/24-1 lentivirus or vehicle, animals were eutha-nized for liver histology. In primary rat HSC and HSC-T6, the anti-fibrotic effect of miR-23b/27b/24-1 cluster was furtherly investigated by RNA-sequencing, luciferase reporter assay, western blotting and bioinformatic means. RESULTS: In this study, we showed that increasing the miR-23b/27b/24-1 level through intravenous delivery of miR-23b/27b/24-1 lentivirus ameliorated mouse hepatic fibrosis. Mechanistically, the miR-23b/27b/24-1 cluster directly tar-geted messenger RNAs, which reduced the protein expression of 5 secretory profibrotic genes (TGF-/52, Gremlin1, LOX, Itga2, and Itga5) in HSCs. Suppression of the TGF-/5 signaling pathway by down-regulation of TGF-/52, Itga2, and Itga5, and activation of the bone morphogenetic protein signaling pathway by inhi-bition of Gremlin1, decreased extracellular matrix secretion of HSCs. Furthermore, down-regulation of LOX expression soft-ened the ECM. Moreover, a reduction in tissue inhibitors of metalloproteinase 1 expression owing to weakened TGF-/5 signaling increased ECM degradation. CONCLUSIONS: Hepatic overexpression of the miR-23b/27b/ 24-1 cluster blocked hepatic fibrosis and may be a novel therapeutic regimen for patients with hepatic fibrosis. (Cell Mol Gastroenterol Hepatol 2022;13:1393-1412; https://doi.org/ 10.1016/j.jcmgh.2022.01.016)

肝纤维化(hepatic fibrosis,HF)是细胞外基质过度沉积引起的慢性肝脏疾病,如不及早发现、治疗,后期会发展成肝硬化甚至肝癌.目前,HF的各种诊断方法都有其不足之处,并且对HF的治疗也尚未有特异有效的药物.适配体是短单链DNA或RNA寡核苷酸序列,可以特异性地识别分子靶点并调节其生物活性,从而对疾病进行诊断和治疗.研究表明,适配体能与促HF发生的细胞因子TGF-β1、OPN和引发HF的乙型和丙型肝炎病毒,以及活化肝星状细胞(hepatic stellate cells,HSCs)上过表达的膜蛋白IGFIIR等特异性地结合,在HF的诊断、治疗中发挥重要作用,预示着其在HF方面广阔的发展前景.因此,本文就适配体在HF中的研究进展作一综述,希望为HF的临床诊断和治疗提供新的研究方向.

E proteins are transcriptional regulators that regulate many developmental processes in animals and lymphocytosis and leukemia in Homo sapiens. In particular, E2A, a member of the E protein family, plays a major role in the transcriptional regulatory network that promotes the differentiation and development of B and T lymphocytes. E2A-mediated transcriptional regulation usually requires the formation of E2A dimers, which then bind to coregulators. In this review, we summarize the mechanisms by which E2A participates in transcriptional regulation from a structural perspective. More specifically, the C-terminal helix-loop-helix (HLH) region of the basic HLH (bHLH) domain first dimerizes, and then the activation domains of E2A bind to different coactivators or corepressors in different cell contexts, resulting in histone acetylation or deacetylation, respectively. Then, the N-terminal basic region (b) of the bHLH domain binds to or dissociates from a specific DNA motif (E-box sequence). Last, trans-activation or trans-repression occurs. We also summarize the properties of these E2A domains and their interactions with the domains of other proteins. The feasibility of developing drugs based on these domains is discussed.

Objective To investigate the effect of honokiol on demyelination after compressed spinal cord injury (CSCI) and it's possible mechanism. Design Animal experiment study. Setting Institute of Neuroscience of Chongqing Medical University. Interventions Total of 69 Sprague-Dawley (SD) rats were randomly divided into 3 groups: sham group (n=15), honokiol group (n=27) and vehicle group (n=27). After established CSCI model by a custom-made compressor successfully, the rats of sham group were subjected to the limited laminectomy without compression; the rats of honokiol group were subjected to CSCI surgery and intraperitoneal injection of 20 mg/kg honokiol; the rats of vehicle group were subjected to CSCI surgery and intraperitoneal injection of an equivalent volume of saline. Outcome measures: The locomotor function of each group was assessed using the Basso, Beattie and Bresnahan (BBB) rating scale. The pathological changes of myelinated nerve fibers of spinal cord in 3 groups were detected by osmic acid staining and transmission electron microcopy (TME). Immunofluorescence and Western blot were used to research the experessions of active caspase-3, caspase-12, cytochrome C and myelin basic protein (MBP) respectively. Results In the vehicle group, the rats became paralyzed and spastic after injury, and the myelin sheath became swollen and broken down along with decreased number of myelinated nerve fibers. Western blot analysis manifested that active caspase-3, caspase-12 and cytochrome C began to increase 1 d after injury while the expression of MBP decreased gradually. After intervened with honokiol for 6 days, compared with the vehicle group, the locomotor function and the pathomorphological changes of myelin sheath of the CSCD rats were improved with obviously decreased expression of active caspase-3, caspase-12 and cytochrome C. Conclusions Honokiol may improve locomotor function and protect neural myelin sheat from demyelination via prevention oligodendrocytes (OLs) apoptosis through mediate endoplasmic reticulum (ER)-mitochondria pathway after CSCI.

整合素家族是一类拥有细胞黏附、信号通路传导枢纽和机械力信号传感功能的跨膜二聚体蛋白.整合素广泛分布于肝星状细胞和其他多种类型的肝内细胞中,其中,含有αV亚基的整合素αVβ3和αVβ5,以及含β1亚基的整合素α4β1、α5β1、α8β1、α9β1和α11β1能促进肝纤维化.miR-125b通过靶向下调整合素α8β1中α8亚基的表达抑制肝纤维化,miR-29和miR-152等也具有抑制肝纤维化的潜能.因此,针对整合素αV和β1亚基与肝纤维化形成的机制研究,以及探究微小RNA对这2个亚基的负调控,有可能成为抗肝纤维化治疗的新策略.

Objective To analyze differentially expressed genes (DEGs) related to liver fibrosis, and clarify the key genes and the possible targets in the progression of liver fibrosis. Methods Using microarray datasets, GSE38199 was extracted from Gene Expression Omnibus (GEO), and a bioinformatics method was performed to find DEGs and transcription factors related to liver fibrosis. Results A total of 58 DEGs were screened out according to GEO2R online analysis tool, which included 49 up-regulated and 9 down-regulated genes. These DEGs were mainly involved in formation with the extracellular region and extracellular exosome through gene ontology (GO) enrichment analysis. Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis showed that DEGs mainly participated in the PI3K-Akt signaling pathway, focal adhesion, ECM-receptor interaction, and metabolic pathways. Based on the results of the Protein-Protein Interaction (PPI) network and Molecular Complex Detection (MCODE) analysis, 9 key genes (COL1A1, FBN1, BGN, COL6A3, MMP2, FBLN5, LUM, PDGFRB, LOXL1) were screened out. A total of 30 transcription factors were found according to these 9 key genes, of which 4 transcription factors (Stat3, Trp53, NF-κB1, Sp1) were enriched. Conclusion Stat3, Trp53, NF-κB1, and Sp1 were all related to the development of liver fibrosis, and FBLN5 might be a target for liver fibrosis.

IntentionLong noncoding RNAs, transcribed from a recently discovered class of noncoding genes, may play a critical role in regulating cellular processes, such as cell proliferation and apoptosis, as well as in cancer progression and metastasis. We previously detected the induction of growth arrest–specific 5 (GAS5) during glioma cell death. However, the function and underlying mechanism of GAS5 in human gliomas remain to be elucidated.MethodsCell proliferation was detected using CellTiter 96® AQueous Non‐Radioactive Cell Proliferation Assay (MTS) and tumorigenicity assay in nude mice. Wound‐healing assay and transwell assay were utilized to examine the effects of GAS5 expression on glioma cells migration and invasion. In situ hybridization (ISH) was performed to evaluate GAS5 and microRNA (miR)‐18a‐5p levels in tissue microarrays. The relationship between GAS5 and miR‐18a‐5p was evaluated by quantitative reverse‐transcription polymerase chain reaction and RNA precipitation.ResultsIn this study, we demonstrated that overexpression of GAS5 inhibits malignant phenotypes in glioma cells, including proliferation, migration, and invasion, whereas GAS5 knockdown enhances these phenotypes. We further observed Argonaute 2–dependent reciprocal repression between GAS5 and miR‐18a‐5p in glioma cells. Downregulation of GAS5 and upregulation of miR‐18a‐5p were observed in glioma tissue microarrays relative to normal brain tissue by ISH. By deletion analysis, we identified one miR‐18a‐5p‐binding site within exon 2 of GAS5 that is partially responsible for the tumor‐suppressor functions of GAS5.ConclusionTaken together, our findings suggest that GAS5 is a tumor suppressor in human gliomas that acts in part by repressing miR‐18a‐5p.

Oligodendrocyte apoptosis mediated demyelination is a pathological change characteristic of compressed spinal cord injury (CSCI). However, the mechanism of demyelination due to oligodendrocyte apoptosis is not known. In this study, after successfully establishing a rat CSCI model using a custom-made compressor, we investigated the pathological changes, MBP expression, as well as apoptosis-related protein (p53, active caspase-3) expression to determine whether or not apoptosis and demyelination occurred after injury. To understand the possible mechanism of oligodendrocyte apoptosis, caspase-12 and cytochrome C were analyzed to explore the relationship between oligodendrocyte apoptosis and endoplasmic reticulum(ER)-mitochondria interaction. The transcription factor, E2F1, was also detected by immunofluorescence and Western blot assays. The results showed that CSCI increased the expression levels of p53, E2F1 and active caspase-3 followed by the swelling and breakdown of myelin sheaths. The number of myelinated nerve fibers also decreased with down-regulated expression of MBP. Expression levels of caspase-12 and cytochrome C were enhanced along with a reduction in the number of oligodendrocytes. After treatment of CSCI in rats with Pifithrin-μ(PFT-μ), a specific inhibitor of p53, pathomorphological changes of myelin sheath improved significantly. Expression levels of E2F1, active caspase-3, caspase-12 and cytochrome C were down-regulated, consistent with reduced the number of apoptotic oligodendrocytes. These results demonstrated that over-expression of p53 could mediate oligodendrocyte apoptosis thus resulting in demyelination in two ways; by enhancing ER-mitochondria interaction and by triggering the E2F1 mediated apoptosis pathway.

Oligodendrocyte apoptosis is the leading cause of demyelination in the central nervous system after compressed spinal cord injury (CSCI).Curcumin, which belongs to the curcuminoid family, is a phenolic yellow pigment derived from the powdered rhizome of Curcuma longa.It has been proved that curcumin exhibits neuroprotective effects against traumatic spinal cord injury by inhibiting neuronal apoptosis.However, whether curcumin has a protective effect on demyelination after CSCI by inhibiting the apoptosis of oligodendrocytes has not been reported.Therefore this study was designed to investigate whether curcumin has a reparative effect on CSCI-induced demyelination and, if so, how it does so.First, we found that the administration of 100 mg/kg curcumin intraperitoneally (IP) 60 minutes after CSCI at days 1, 3, and 7 could significantly relieve neurological deficits.After staining with osmic acid, we found that the swelling of myelin sheaths in the treated group was milder than that in the vehicle group.The results of luxol fast blue staining also indicated that the number of remaining myelin sheaths was significantly higher in the treated group.Next we detected the expressions of active caspase-3, caspase-12, cytochrome C, and myelin basic protein (MBP) by Western blot.This revealed that the expression of MBP was significantly enhanced in the curcumin-treated group, consistent with the number of remaining myelin sheaths found on luxol fast blue staining.But the expression of caspase-12, cytochrome C, and active caspase-3 was reduced; in addition, double immunofluorescence showed that active caspase-3-positive oligodendrocytes in the treatment group were fewer in number as compared with the vehicle group.These results suggested that curcumin did have a protective effect on demyelination-mainly through its mediating effects on the endoplasmic reticulum-mitochondrial pathway-to significantly reduce the expression of active caspase-3.In this way cucurmin reduced both the apoptosis of oligodendrocytes and demyelination, thus ameliorating the consequences of CSCI.

Background Aquaporin 5 (AQP5) is a water-specific channel protein. It is thought to be a key participant in fluid secretion and a rate-limiting barrier to the secretion seen during allergic inflammation. We sought to determine the effect of histamine on AQP5 expression in human nasal epithelial cells (HNEpC). Methods HNEpC cells were cultured with four concentrations of histamine in vitro. The phosphorylation of cyclic adenosine monophosphate-responsive element binding protein (CREB) at serine 133 and the AQP5 protein were measured by using immunocytochemistry and Western blotting. Real-time polymerase chain reaction was used to detect AQP5 messenger ribonucleic acid (mRNA). Results Concentration-dependent histamine induced-inhibition of CREB phosphorylation at serine 133 in HNEpC cells was observed, and AQP5 mRNA and protein were also downregulated in a concentration-dependent fashion. Conclusion Histamine downregulates AQP5 production in HNEpC cells by inhibiting CREB phosphorylation at serine 133.