Cell Migration Activity Research Articles

KLF5 promotes esophageal squamous cell carcinoma radioresistance by targeting the Keap1-Nrf2 pathway

ObjectiveEsophageal squamous cell carcinoma (ESCC) has high morbidity and mortality in developing countries. The purpose of this article is to study the mechanism of KLF5's effect on ESCC radiosensitivity.MethodsWGCNA gene expression profiling identified core genes associated with ESCC radiosensitivity. KLF5 expression was detected by RT-qPCR. The effects of overexpression or downregulation of KLF5 on anti-irradiated cells' proliferation, migration, invasion, and apoptotic activity were studied through colony formation assay, Transwell assay, and flow cytometry. Western blot can detect the activity of Nrf2 signaling pathway in cells and tissues. The enrichment of KLF5 at the Keap1 promoter was analyzed by ChIP-base, and the binding of KLF5 to Keap1 was analyzed by ChIP and dual-luciferase. They then injected ESCC cells into mice and used radiation to monitor tumor progression.ResultsKLF5 is a core gene in ESCC and is significantly associated with radiosensitivity. KLF5 expression is upregulated in drug-resistant ESCC cells. Overexpression of KLF5 significantly increased cell viability and attenuated cellular responses to radiation. KLF5 knockdown reduces radioresistance. After KLF5 overexpression, the Nrf2 signaling pathway was significantly up-regulated, and after KLF5 was up-regulated, the Keap1 signaling pathway was down-regulated. KLF5 inhibits the transcriptional activity of Keap1. Upregulation of Keap1 inhibits the effect of KLF5 overexpression on radioresistance of ESCC cells. KLF5/Keap1 regulates the effects of ESCC on in vivo radiotherapy.ConclusionKLF5 promotes ESCC radioresistance by inhibiting Keap1 transcription and activating the Nrf2 pathway.

Visualization of Apical-Basal Stress Polarity Regulating Directed Cell Migration with a FRET-Based Biosensor.

Intracellular morphological apical-basal polarity, regulated by conserved polarity proteins, plays a crucial role in cell migration and metastasis. In this study, using a genetically encoded Förster resonance energy transfer (FRET) biosensor to visually present the spatiotemporal stress state between the lipid rafts on the membrane and the linked actin, we first provide the evidence for the existence of intrinsic apical-basal stress polarity in tumor cells and demonstrate that this polarity is a prerequisite for the formation of flow-induced front-back stress polarity. Interestingly, our study revealed that the front-back stress polarity disappeared upon the disruption of intrinsic apical-basal stress discrepancy, resulting in a large attenuated cell migration activity reduced from 76.2 ± 3.5% to 10 ± 4.9%. This unexpected discovery not only highlights the significance of apical-basal stress polarity as another factor influencing cell migration but also indicates that the disruption of apical-basal polarity in stress might be a novel therapeutic approach for tumor metastasis.

Three-dimensional genome architecture in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a common primary hepatic tumors with a 5-year survival rate of less than 20%. Therefore, it is crucial to elucidate the molecular mechanisms of ICC. Recently, the advance of high-throughput chromosome conformation capture (Hi-C) technology help us look insight into the three-dimensional (3D) genome structure variation during tumorigenesis. However, its function in ICC pathogenesis remained unclear. Hi-C and RNA-sequencing were applied to analyze 3D genome structures and gene expression in ICC and adjacent noncancerous hepatic tissue (ANHT). Furthermore, the dysregulated genes due to 3D genome changes were validated via quantitative real-time PCR and immunohistochemistry. Primarily, the intrachromosomal interactions of chr1, chr2, chr3, and chr11 and the interchromosomal interactions of chr1-chr10, chr13-chr21, chr16-chr19, and chr19-chr22 were also significantly distinct between ANHT and ICC, which may potentially contribute to the activation of cell migration and invasion via the upregulation of WNT10A, EpCAM, S100A3/A6, and MAPK12. Interestingly, 56 compartment regions from 23 chromosomes underwent A to B or B to A transitions during ICC oncogenesis, which attenuated the complement pathway through the downregulation of C8A/C8B, F7, F10, and F13B. Notably, topologically associated domain (TAD) rearrangements were identified in the region containing HOPX (chr4: 57,514,154-57,522,688) and ACVR1 (chr2:158,592,958-158,732,374) in ICC, which may contribute to the hijacking of remote enhancers that were previously outside the TAD and increased expression of HOPX and ACVR1. This study reveals relationship between 3D genome structural variations and gene dysregulation during ICC tumorigenesis, indicating the molecular mechanisms and potential biomarkers.

Extracellular Regucalcin: A Potent Suppressor in the Cancer Cell Microenvironment.

The regucalcin gene is located on the X chromosome, comprising seven exons and six introns. This gene and protein are expressed in various tissues and cells and is predominantly expressed in human liver, kidney, and adrenal tissues. Regucalcin gene expression is enhanced via a mechanism mediated by several signaling molecules and transcription factors. Regucalcin plays a multifunctional role in cellular regulation in maintaining cell homeostasis. In addition, regucalcin has been implicated in several metabolic disorders and diseases. In particular, regucalcin plays a role as a novel suppressor in several types of cancer patients. Increased expression of regucalcin suppresses the growth of human cancer cells, suggesting its pivotal role in suppressing tumor development. The survival time of cancer patients is prolonged with increased expression of regucalcin in the tumor tissues. The adhesion, migration, invasion, and bone metastatic activity of cancer cells are blocked by the overexpression of regucalcin, promoting dormancy in cancer patients. Interestingly, regucalcin is also found in human serum, suggesting its character as a novel biomarker in various diseases. This extracellular regucalcin has been shown to suppress human cancer cells' growth and bone metastatic activity. Thus, extracellular regucalcin may play a vital role as a suppressor of human cancer activity. Alteration of the serum regucalcin levels in physiological and pathophysiological conditions may influence the activity of cancer cells in the microenvironment. This review will discuss the potential role of extracellular regucalcin in cancer cell activity as a critical suppressor in the cancer microenvironment.

Anti-Migratory Activity of Brazilin Chemodiversification on Breast Cancer Cells

Breast cancer is the most common and the leading cause of cancer death in women worldwide; treating invasive breast carcinomas is challenging due to the side effects of chemotherapeutics. Compounds isolated from natural sources have been proposed as potential molecules for cancer therapy; for instance, the homoisoflavonoid brazilin has shown pharmacological properties, including anti-tumoral and anti-inflammatory activities. In this study, we isolated brazilin from the heartwood of Haematoxylum brasiletto; then, we performed a semi-synthesis by adding three methyl or acetyl groups to the core structure of brazilin. We confirmed the identity of brazilin and its derivatives by spectroscopic data (1H NMR and 13C NMR) and measured their purity by optical rotation. Then, we analyzed the effects of brazilin and its derivatives in three mammary gland-derived cell lines: the TNBC MDA-MB-231, the ERα(+) MCF7, and the non-tumorigenic MCF10A. We evaluated the cell viability by MTT assays, cell migration by wound-healing assays, and focal adhesion kinase (FAK) activation by Western blot. Regarding biological assays, the MTT assay showed that these compounds showed cytotoxic effects on the MCF7 and MDA-MB-231 breast cancer cells at 20 µM but was not toxic in non-tumorigenic MCF10A mammary epithelial cells. Specifically, the greatest effects found from treatment with the compounds were in the MDA-MB-231 cell line, where the IC50 of brazilin was 49.92 μM, and for MCF7, the brazilin-(OAc)3 was 49.97 μM. These effects were dose- and time-dependent, as well as being associated with a decrease in the levels of cell migration and FAK activation.

FN1 shapes the behavior of papillary thyroid carcinoma through alternative splicing of EDB region

Papillary thyroid cancer (PTC) is often characterized by indolent behavior, small tumors with slow cell proliferation and a tendency to metastasize to cervical lymph node simultaneously, and the molecular mechanisms underlying that remain poorly understood. In this study, FN1 was the hottest gene of PTC and distinctive expression in PTC cells. FN1 deficiency severely inhibited the p53 signaling pathway, especially cyclin proteins, resulting in increased cell growth but hampered invasion. The alternatively splicing EDB region of FN1 was exclusively expressed in tumors, which impacted integrin β1 (ITGB1) bonding FN1 and its secretion process, resulting in completely distinct roles of two isoforms that FN1 including and skipping EDB domain. The isoform EDB(–)FN1 intracellularly inhibited tumor proliferation by upregulating p21 expression, whereas extracellular EDB(+)FN1 promoted lymph node metastasis via the VEGF signaling pathway in vitro and in vivo. Moreover, the alternative splicing EDB region of FN1 was modulated by p53-targeted protein ZMAT3 which activated cell migration and lymphoangiogenesis. Collectively, combined with p53-induced proteins, FN1 played both anti- and pro-cancer roles owing to EDB domain alternative splicing. FN1 is a potential determinant behind the characteristic behavior of PTC, which may contribute to a deeper understanding of the peculiarity of PTC and provide a promising target for regional lymph node metastasis.

Effects of intentionally-treated water on cell migration of human glioblastoma cells.

This study investigated if human glioblastoma cancer cells (U87MG cell line) cultured in intentionally treated water could reduce cell migration, a prerequisite for metastasis, as compared to the same cells cultured in untreated (control) water. Three Buddhist monks entered a meditative state and directed their awareness to bottles of ultrapure water while holding the intention that the water would cause beneficial changes in U87MG. The study was conducted double-blind whereby all aspects of the study involving cell growth and migration measures, as well as all subsequent statistical evaluations, were performed without knowledge of the type of water being used. Cell cultures were incubated in growth mediums prepared with treated and untreated water, and a wound healing assay was employed to measure cell migration. U87MG cells incubated with treated water migrated less efficiently than the same cells in untreated water. A repeated measures ANOVA, spanning four time periods (0, 3, 6, and 9 h), determined that the time × water condition interaction was associated with p < 0.005. Intentioned awareness appeared to change as-yet unknown properties of ultrapure water, resulting in a reduction of U87MG cells migration activity. Further research is warranted to replicate these results and to investigate the underlying protein expression mechanisms in influencing cell migration.

Influence of a new combined production based on dense carrot root extract and quercetin on the morphological and proliferative properties of l929 line fibroblasts in cell culture

At the first stage of studying the pharmacological properties of substances, the general cytotoxic effect is determined based on the assessment of viability, morphological integrity and functional activity of cells. One of the standard cell lines often used in cytotoxicity tests is the L929 line. Studying the ability of a combined lipid-lowering agent based on dense carrot root extract and quercetin to influence the morphological and functional properties of fibroblasts of the L929 line in cell culture was the aim of this study. Materials and methods: Determination of the cytotoxicity of the drug under study was carried out in a cell culture of the L929 line at a concentration of 40, 100, and 200 mg/ml. The safety of cells in the resulting suspension was assessed using staining with a 0,4% trypan blue solution. Cell morphology and nuclear-cytoplasmic ratio were assessed in fixed culture preparations stained with hematoxylin-eosin. To assess the migration and proliferative activity of a monolayer culture, the “scratch” test was used. Results: When L929 cells were incubated in a nutrient medium with the addition of the product, their viability and morphological properties were preserved; images of a monolayer of the culture of these cells under phase-contrast microscopy coincided with the quantitative analysis data. The absence of changes in the nuclear-cytoplasmic ratio was further evidence of the absence of toxic effects of the studied drug in relation to fibroblast culture. According to the experiment results, the migration and proliferative activity of L929 cells under the influence of the drug did not differ significantly from intact cells. Conclusions: The results of the toxicological study showed that the combined product based on dense carrot root extract and quercetin does not have a cytotoxic effect on the L929 cell line culture and can be recommended for further preclinical research.

High expression of AURKB promotes malignant phenotype of osteosarcoma cells by activating nuclear factor-κB signaling via DHX9

To investigate the regulatory mechanism of aurora kinase B (AURKB) for promoting malignant phenotype of osteosarcoma cells. HA-Vector or HA-AURKB was transfected in 293T cells to identify the molecules interacting with AURKB using immunoprecipitation combined with liquid chromatography-tandem mass spectrometry followed by verification with co-immunoprecipitation and Western blotting. In cultured osteosarcoma cells with lentivirus-mediated RNA interference of AURKB or DHX9 or their overexpression, the changes in cell proliferation, migration, and invasion activities were observed with EDU and Transwell assays. Mechanistic analysis was performed using Co-IP and in vivo ubiquitination experiments to detect the interaction between AURKB and DHX9 and the phosphorylation and ubiquitination levels of DHX9. Western blotting was used to detect the effect of AURKB and DHX9 on activation of nuclear factor-κB (NF-κB) signaling. AURKB was highly expressed in osteosarcoma cell lines, and in osteosarcoma 143B cells, AURKB silencing significantly reduced cell proliferation, migration and invasion abilities. Interactions between AURKB and DHX9 were detected, and they were both highly expressed in osteosarcoma tissues; silencing AURKB reduced the protein expression of DHX9, and AURKB overexpression increased DHX9 phosphorylation. Silencing AURKB did not significantly affect the transcription and translation of DHX9 but accelerated its degradation and ubiquitination. Overexpression of DHX9 effectively reversed the effects of AURKB silencing on IKBα protein and phosphorylated p65, promoted nuclear translocation of p65 to activate the NF-κB signaling pathway, and enhanced the proliferation, migration, and invasion abilities of cultured osteosarcoma cells. AURKB overexpression promotes the malignant phenotype of osteosarcoma cells by activating the NF-κB signaling pathway via regulating DHX9.

Wound healing potential of mouth gel containing isopimarane diterpene from Kaempferia galanga rhizomes for treatment of oral stomatitis.

Oral ulcers have an impact on 25% of the global population including patients who are suffering from chemotherapy and radiotherapy treatments. Kaempferia galanga L. has been traditionally used for treatment of mouth sores and tongue blisters. However, the wound healing study of isopimarane diterpenes isolated from K. galanga is still limited. This study aims to evaluate the wound healing potential of 6β-acetoxysandaracopimaradiene-1α,9α-diol (KG6), a compound isolated from Kaempferia galanga, by examining its biological activities. Additionally, we investigate the physicochemical and biological properties of (KG6) in formulated mouth gels. The KG6 mouth gels at 0.10%, 0.25% and 0.50% w/w were formulated using sodium carboxymethylcellulose as a gelling agent, and their physicochemical and biological stabilities were assessed through a heating-cooling acceleration test. The quantification of KG6 contents in KG6 mouth gels was determined using gas chromatography. Both KG6 and KG6 mouth gels were evaluated for their wound healing properties including cell proliferation, cell migration, and antioxidant activity (H2O2-induced oxidative stress) in human gingival fibroblast (HGF-1-ATCC CRL-2014) (HGF-1). In addition, the anti-inflammatory activity against nitric oxide (NO) production was investigated in macrophage cells (RAW 264.7). After KG6 mouth gels were incubated under heating-cooling acceleration condition, the physicochemical properties of the KG6 mouth gels remain stable across various parameters, including appearance, color, smell, texture, pH, viscosity, separation, and KG6 content. The biological studies indicated that the KG6 compound possessed good wound healing potential. The 0.50% KG6 mouth gel exhibited marked anti-inflammatory effect by inhibiting NO production with an IC50 of 557.7 µg/ml, comparable to that of Khaolaor mouth gel, a positive control. The 0.25% KG6 mouth gel increased HGF-1 cell proliferation to 101.7-103.5%, whereas all formulations of KG6 mouth gel enhanced HGF-1 cell migration to 94.7-98.9%, higher than Khaolaor mouth gel (73.5%). Moreover, 0.50% KG6 mouth gel also showed a good antioxidant effect under H2O2-induced oxidative stress. This study substantiates the significant biological activities related to the wound healing property of 0.50% KG6 mouth gel for treatment of aphthous ulcers and oral stomatitis from chemotherapy and radiotherapy treatments.

Injectable Nanocomposite Hydrogel with Synergistic Biofilm Eradication and Enhanced Re-epithelialization for Accelerated Diabetic Wound Healing.

Diabetic wounds remain a critical clinical challenge due to their harsh microenvironment, which impairs cellular function, hinders re-epithelialization and tissue remodeling, and slows healing. Injectable nanocomposite hydrogel dressings offer a promising strategy for diabetic wound repair. In this study, we developed an injectable nanocomposite hydrogel dressing (HDL@W379) using LAP@W379 nanoparticles and an injectable hyaluronic acid-based hydrogel (HA-ADH-ODEX). This dressing provided a sustained, pH-responsive release of W379 antimicrobial peptides, effectively regulating the wound microenvironment to enhance healing. The HDL@W379 hydrogel featured multifunctional properties, including mechanical stability, injectability, self-healing, biocompatibility, and tissue adhesion. In vitro, the HDL@W379 hydrogel achieved synergistic biofilm elimination and subsequent activation of basal cell migration and endothelial cell tube formation. Pathway analysis indicated that the HDL@W379 hydrogel enhances basal cell migration through MEK/ERK pathway activation. In methicillin-resistant Staphylococcus aureus (MRSA)-infected diabetic wounds, the HDL@W379 hydrogel accelerated wound healing by inhibiting bacterial proliferation and promoting re-epithelialization, regenerating the granulation tissue, enhancing collagen deposition, and facilitating angiogenesis. Overall, this strategy of biofilm elimination and basal cell activation to continuously regulate the diabetic wound microenvironment offers an innovative approach to treating chronic wounds.

Bicistronic Vector Expression of Recombinant Jararhagin-C and Its Effects on Endothelial Cells.

Jararhagin-C (JarC) is a protein from the venom of Bothrops jararaca consisting of disintegrin-like and cysteine-rich domains. JarC shows a modulating effect on angiogenesis and remodeling of extracellular matrix constituents, improving wound healing in a mouse experimental model. JarC is purified from crude venom, and the yield is less than 1%. The aim of this work was to obtain the recombinant form of JarC and to test its biological activity. For this purpose, the bicistronic vector pSUMOUlp1 was used. This vector allowed the expression of the recombinant toxin JarC (rJarC) in fusion with the small ubiquitin-related modifier (SUMO) as well as the SUMO protease Ulp1. After expression, this protease was able to efficiently remove SUMO from rJarC inside the bacteria. rJarC free from SUMO was purified at the expected molecular mass and recognized by polyclonal anti-jararhagin antibodies. In terms of biological activity, both the native and recombinant forms showed no toxicity to the HUVEC cell line CRL1730 and were effective in modulating cell migration activity in the experimental in vitro model. These results demonstrate the successful production of rJarC and the preservation of its biological activity, which may facilitate further investigations into the therapeutic potential of this snake venom-derived protein.

Microgravity’s effects on miRNA-mRNA regulatory networks in a mouse model of segmental bone defects

Rehabilitation from musculoskeletal injuries (MSKI) complicate healing dynamics typically by sustained disuse of bone and muscles. Microgravity naturally allows limb disuse and thus an effective model to understand MSKI. The current study examined epigenetic changes in a segmental bone defect (SBD) mouse model in a prolonged unloading condition after spaceflight (FLT). We further connected potential miRNA–mRNA regulatory pathways impacting bone healing. Here, SBD surgery was performed on nine-week-old male mice that were launched into space for approximately 4 weeks. Sham with no surgery and ground controls were included in the study. The midshaft of the ipsilateral femur (with callus on the surgical mice) as well as the ipsilateral quadriceps tissue were used for analysis. Femur and quadriceps had a distinct miRNA profile. There was a stronger surgery effect as observed by miRNA expression when compared to microgravity effects. Leukopoiesis, granulopoiesis, myelopoiesis of leukocytes, differentiation of myeloid leukocytes, and differentiation of progenitor cells were all altered because of surgery in the femur. The biological functions such as apoptosis, necrosis, and activation of cell migration and viability were altered because of surgery in quadriceps. Integrating the transcriptome and microRNA data indicated pronounced changes because of microgravity. According to pathway analysis, microgravity had a greater impact on the quadriceps tissue than the bone tissue in the absence of surgery. The altered biological functions resulting from microgravity were validated by integrating limited proteomics data to miRNA-mRNA. Thus, this study highlights the importance of dynamic interplay of gene-epigene regulations as they appear to be intrinsically interconnected and influence in combination for the biological outcome.

Depinning transition of self-propelled particles.

For self-propelled particles in a corrugated potential landscape, we describe a discontinuous change of the classical depinning transition and a host of unique behaviors sensitive to the persistence of the propulsion direction. Exact and semianalytic results for active Brownian particles corroborate a creep regime with a superexponentially suppressed drift velocity upon lowering the force towards the threshold value. This unusual nonlinear response emerges from the competition of two critical scaling laws with exponents of 1/2 for rapidly reorienting particles and d/2 for particles with a persistent orientation; the latter case depends on the dimensionality d of rotational motion and also includes run-and-tumble particles. Additionally, different giant diffusion phenomena occur in the two regimes. Our findings extend to random dynamics with bounded noise near a saddle-node bifurcation and have potential applications in various nonequilibrium problems, including arrested active matter and cell migration.

Tumor Protein D53 (TPD53): Involvement in Malignant Transformation of Low-Malignant Oral Squamous Cell Carcinoma Cells.

Background/Objectives: The tumor protein D52 (TPD52) family includes TPD52, TPD53, TPD54, and TPD55. The balance between TPD52 and TPD54 expression plays an important role in high-malignant oral squamous cell carcinoma (OSCC) cells. However, the relationship between TPD53 and OSCC cells (particularly low-malignant OSCC cells) remains unclear. In the present study, we investigated the role of TPD53 in the malignant transformation of low-malignant OSCC cells. Methods: Temporal changes in the expression of TPD52 family members at the protein and mRNA levels in OSCC cells and normal human epidermal keratinocytes (NHEK) were examined. Results: The mRNA expression of TPD53 increased in HSC-3 and HSC-4 cells in a time-dependent manner. Similar results for protein expression were observed. The effects of TPD53 on anchorage-dependent and anchorage-independent proliferation, cell cycle, invasion and migration, epithelial-mesenchymal transition (EMT), and matrix metalloproteinase (MMP) activities in HSC-3 and HSC-4 cells were assayed. Finally, using the HSC-3-xenograft-nude-mice model, these effects were examined in vivo. Overexpression of TPD53 increased cell viability and the percentage of cells in the S phase. Furthermore, overexpression of TPD53 increased cell invasion, migration, and MMP activities, regardless of its effect on EMT. Notably, these effects were more pronounced in HSC-3 than in HSC-4 cells. Overexpression of TPD53 enhanced tumor formation and growth in mouse xenografts, corroborating the results of in vitro experiments. Conclusions: The present study revealed novel and important functions of TPD53 in the proliferation and invasion of low-malignant OSCC cells.

PKN2 Promotes Peripheral Nerve Repair by Regulating Autophagy via Activation of the AKT-mTOR Pathway: An In Vitro Study.

This study aims to explore the role of Protein Kinase N2 (PKN2) in peripheral nerve injury (PNI) and evaluate its potential as a therapeutic target. The study employed a PC12 cell model to assess the effects of PKN2 overexpression on cell proliferation, migration, synaptic growth, and autophagic activity, with a focus on the regulatory role of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. The results demonstrated that PKN2 overexpression significantly promoted PC12 cell proliferation and cell migration, while also enhancing synaptic growth. Additionally, a significant suppression of autophagy was observed. Mechanistic analysis revealed that PKN2 inhibited autophagic activity through the activation of the AKT/mTOR pathway. In summary, PKN2 plays a significant role in peripheral nerve repair by promoting cell proliferation, migration, and synaptic growth, while inhibiting autophagy through the AKT/mTOR pathway. These findings suggest that targeting PKN2 may represent an effective therapeutic strategy for the treatment of PNI.

Co-targeting TMEM16A with a novel monoclonal antibody and EGFR with Cetuximab inhibits the growth and metastasis of esophageal squamous cell carcinoma.

The chloride channel transmembrane protein 16A (TMEM16A) possesses a calcium-activated property linked to tumor-promoting malignant phenotype and electrophysiological stability. Numerous studies have shown that TMEM16A exhibits aberrant amplification in various squamous cell carcinomas such as esophageal squamous cell carcinoma (ESCC) and is correlated with unfavorable outcomes of ESCC patients. Therefore, TMEM16A is considered as a promising therapeutic target for ESCC. Because of its intricate structure, the development of therapeutic antibodies directed against TMEM16A has not been documented. In this study, we produced a series of novel monoclonal antibodies targeting TMEM16A and identified mT16#5 as an antibody capable of inhibiting ESCC cells migration, invasion and TMEM16A ion channel activity. Additionally, based on the validation that TMEM16A was positively correlated with expression of EGFR and the interaction between them, the mT16#5 exhibited a synergistic inhibitory effect on ESCC metastasis and growth when administered in combination with Cetuximab in vivo. In terms of mechanism, we found that mT16A#5 inhibited the phosphorylation of PI3K, AKT and JNK. These results highlight the anti-growth and anti-metastasis capacity of the combination of mT16A#5 and Cetuximab in the treatment of ESCC by targeting TMEM16A and EGFR, and provide a reference for combinational antibody treatment in ESCC.

N-Aryl Benzimidazole and Benzotriazole Derivatives and Their Hybrids as Cytotoxic Agents: Design, Synthesis and Structure-Activity Relationship Studies.

The era of chemotherapy began in the 1940s, which is the basis of traditional antitumor approaches and, being one of the most high-tech treatment methods, is still widely used to treat various types of cancer. A promising direction in modern medicinal chemistry is currently the creation of hybrid molecules containing several pharmacophore fragments of different structures. This strategy is successfully used to increase the therapeutic efficacy of cytotoxic agents and reduce side effects. In this work, we synthesized 10 1-aryl derivatives of benzimidazole and benzotriazole and 11 hybrids based on them. Among the compounds obtained, the most promising hybrid molecules were diphenylamines, containing an amino group and a benzotriazole cycle in the ortho position to the bridging NH group, which showed significant cytotoxic activity, excellent antioxidant properties and the ability to suppress the migration activity of tumor cells. Taken together, our results demonstrate that substituted diphenylamine-based bipharmacophoric compounds may serve as a promising platform for further optimization to obtain effective antitumor compounds.

Promising Pharmacological Interventions for Posterior Capsule Opacification: A Review.

Phacoemulsification combined with intraocular lens implantation is the primary treatment for cataract. Although this treatment strategy benefits patients with cataracts, posterior capsule opacification (PCO) remains a common complication that impairs vision and affects treatment outcomes. The pathogenesis of PCO is associated with the proliferation, migration, and fibrogenesis activity of residual lens epithelial cells, with epithelial-mesenchymal transition (EMT) serving as a key mechanism underlying the condition. Transforming growth factor-beta 2 (TGF-β2) is a major promotor of EMT, thereby driving PCO development. Most studies have shown that drugs and miRNAs mitigate EMT by inhibiting, clearing, or eliminating LECs. In addition, targeting EMT-related signaling pathways in TGF-β2-stimulated LECs has garnered attention as a research focus. This review highlights potential treatments for PCO and details the mechanisms by which drugs and miRNAs counter EMT.

Bilayer Scaffolds Synergize Immunomodulation and Rejuvenation via Layer-Specific Release of CK2.1 and the "Exercise Hormone" Lac-Phe for Enhanced Osteochondral Regeneration.

Repairing osteochondral defects necessitates the intricate reestablishment of the microenvironment. The cartilage layer consists of a porous gelatin methacryloyl hydrogel (PGelMA) covalently crosslinked with the chondroinductive peptide CK2.1 via a "linker" acrylate-PEG-N-hydroxysuccinimide (AC-PEG-NHS). This layer is optimized for remodeling the senescent microenvironment in the cartilage region, thereby establishing a regenerative microenvironment that supports chondrogenesis. For the bone layer, silk fibroin methacryloyl (SilMA) is coated onto a three dimensional (3D)-printed 45S5 bioactive glass scaffold (BG scaffold). The "exercise hormone" N-lactoyl-phenylalanine (Lac-Phe) is loaded onto the SilMA, endowing it with diversified functions to regulate the osteogenic microenvironment. Systematic analysis in vitro reveals that PGelMA-CK2.1 shifts the microenvironment from a pro-inflammatory into an anti-inflammatory condition, and alleviates cellular senescence, thus modifying the cartilage microenvironment to improve the recruitment, proliferation and chondral differentiation of bone marrow mesenchymal stem cells (BMSCs). The scaffold bone layer enhances microvascular endothelial cell proliferation, migration, and angiogenic activities, which, couple with increased BMSC recruitment and regulatory mechanisms directing BMSC differentiation, favor a shift in the "osteogenesis-adipogenesis" balance toward enhanced osteogenesis. In vivo, it is found that this biphasic biomimetic scaffold favors simultaneous dual tissue regeneration. This approach facilitates the development of bioactive regenerative scaffolds and holds great potential for clinical application.