Subcutaneous Transplantation Research Articles

Integrin β6/Annexin A2 axis triggers autophagy to orchestrate hepatocellular carcinoma radioresistance.

Radiotherapy (RT) is one of the main therapies for hepatocellular carcinoma (HCC), but its effectiveness has been constrained due to the resistance effect of radiation. Thus, the factors involved in radioresistance are evaluated and the underlying molecular mechanisms are also done. In this present study, we identified Integrin β6 (ITGB6) as a potential radioresistant gene through an integrative analysis of transcriptomic profiles, proteome datasets and survival using HCC cases treated with IR. We show that ITGB6 functionally contributed to radioresistance by activating autophagy through a series of in vitro and in vivo methods, such as clonogenic assays, autophagy flux (LC3B-GFP-mCherry reporter) analysis and a subcutaneous transplantation model. Mechanically, ITGB6 binds to Annexin A2 (ANXA2) and enhanced its stability by competitively antagonizing proteasome mediated ANXA2 degradation, thereby promoting autophagy and radioresistance. Notably, HCC radioresistance was significantly improved by either blocking ITGB6 or autophagy, but the combination was more effective. Importantly, ITGB6/ANXA2 axis triggered autophagic program endowed HCC cells with radioresistant activity in a radiated patient-derived xenograft (PDX) model and hydrodynamic injection in liver-specific Itgb6-knockout mice, further supported by clinical evidence. Together, our data revealed that ITGB6 is a radioresistant gene stabilizing the autophagy regulatory protein ANXA2, providing insights into the biological and potentially clinical significance of ITGB6/ANXA2 axis in radiotherapy planning of HCC.

Low-intensity pulsed ultrasound combined with microbubble mediated JNK/c-Jun pathway to reverse multidrug resistance in triple-negative breast cancer

To investigate the effects of low-intensity pulsed ultrasound combined with microbubble (LIPUS-MB) mediated JNK/c-Jun pathway reversal on multidrug resistance in triple-negative breast cancer and the underlying mechanisms. An orthogonal experiment was designed to screen for the optimal parameters of LIPUS-MB in MDA-MB-231/DOX cells. The CCK-8 assay was used to determine the drug resistance of the cells and to measure their proliferation activity and resistance reversal efficiency at the optimal parameters. Hoechst 33,342 staining and Annexin V-FITC/PI staining were employed to detect cell morphological changes and apoptosis, respectively. The MDA-MB-231/DOX models of transplanted tumor were established in BALB/c. The impact of LIPUS-MB on allograft tumor growth was observed in vivo. Immunohistochemistry was employed to investigate the expression of P-gp, ABCG2, and Ki-67 in tumor tissues, while western blot was utilized to assess the protein expression of P-gp, ABCG2, JNK, p-JNK, c-Jun, p-c-Jun, Bcl-2 and Bax in both MDA-MB-231/DOX cells and allograft tumor tissues. The optimal LIPUS-MB parameters for MDA-MB-231/DOX cells are the microbubble concentration of 20%, ultrasound intensity of 1.0 W/cm2, and irradiation time of 60 s. The drug resistance index of MDA-MB-231/DOX cells is 19.17. Following the optimal parameter application, the IC50 value of the cells decreases by 5.71-fold, with a reversal efficiency of 87.03%, and a simultaneous decrease in cell proliferation activity. Compared with other groups, the DOX + LIPUS-MB group displayed the highest incidence of apoptotic nuclear morphology, and the greatest quantity of cellular apoptosis and the most pronounced decrease in the expression levels of P-gp, ABCG2, p-JNK, p-c-Jun, and Bcl-2 proteins within the cells. Conversely, the expression levels of Bax proteins reach the highest levels (all P < 0.05). Furthermore, in vivo subcutaneous tumor transplantation experiments in nude mice revealed that the DOX + LIPUS-MB group exhibited smaller tumor growth rate, volume and the expression of P-gp, ABCG2, and Ki-67 compared to the DOX + LIPUS group, indicating the most pronounced inhibitory effect on tumor growth and it significantly inhibited tumor proliferation, promoted its apoptosis. In conclusion, following parameter optimization, LIPUS-MB was found to reduce the drug resistance of MDA-MB-231/DOX cells. The underlying mechanism may involve the downregulation of P-gp and ABCG2 proteins expression through the modulation of the JNK/c-Jun pathway by LIPUS-MB, thereby inhibiting cell proliferation activity and promoting apoptosis, and enhancing the in vivo anti-tumor effect of DOX, thus reversing multidrug resistance in triple-negative breast cancer.

Establishment of Periodontal Ligament Stem Cell-like Cells Derived from Feeder-Free Cultured Induced Pluripotent Stem Cells.

The periodontal ligament (PDL) is a fibrous connective tissue that connects the cementum of the root to the alveolar bone. PDL stem cells (PDLSCs) contained in the PDL can differentiate into cementoblasts, osteoblasts, and PDL fibroblasts, with essential roles in periodontal tissue regeneration. Therefore, PDLSCs are expected to be useful in periodontal tissue regeneration therapy. In a previous study, we differentiated induced pluripotent stem cells (iPSCs) into PDLSC-like cells (iPDLSCs), which expressed PDL-related markers and mesenchymal stem cell (MSC) markers; they also exhibited high proliferation and multipotency. However, the iPSCs used in this differentiation method were cultured on mouse embryonic fibroblasts; thus, they constituted on-feeder iPSCs (OF-iPSCs). Considering the risk of contamination with feeder cell-derived components, iPDLSCs differentiated from OF-iPSCs (ie, OF-iPDLSCs) are unsuitable for clinical applications. In this study, we aimed to obtain PDLSC-like cells from feeder-free iPSCs (FF-iPSCs) using OF-iPDLSC differentiation method. First, we differentiated FF-iPSCs into neural crest cell-like cells (FF-iNCCs) and confirmed that FF-iNCCs expressed NCC markers (eg, Nestin and p75NTR). Then, we cultured FF-iNCCs on human primary PDL cell-derived extracellular matrix for 2 weeks; the resulting cells were named FF-iPDLSCs. FF-iPDLSCs exhibited higher expression of PDL-related and MSC markers compared with OF-iPDLSCs. FF-iPDLSCs also demonstrated proliferation and multipotency in vitro. Finally, we analyzed the ability of FF-iPDLSCs to form periodontal tissue invivo upon subcutaneous transplantation with β-tricalcium phosphate scaffolds into dorsal tissues of immunodeficient mice. Eight weeks after transplantation, FF-iPDLSCs had formed osteocalcin-positive bone/cementum-like tissues and collagen 1-positive PDL-like fibers. These results suggested that we successfully obtained PDLSC-like cells from FF-iPSCs. Our findings will contribute to the development of novel periodontal regeneration therapies.

A computational analysis of the oncogenic and anti-tumor immunity role of P4HA3 in human cancers

Prolyl-4-hydroxylase subunit alpha3 (P4HA3) is a triple helical procollagen synthesis protein. The role of P4HA3 in cancer development is not well known and lacks comprehensive analyses among human cancers. This study aimed to investigate the relationship between P4HA3 expression and anti-tumor immunity and its prognostic value in pan-cancer. P4HA3 expression was analyzed from TIMER2.0, GTEx, GEPIA2.0 and TCGA databases. Genetic and DNA methylation alterations, survival analysis and proteins co-expression analysis of P4HA3 in cBio Cancer Genomics Portal, TCGA, GSCA and TIMER2.0. The correlation between P4HA3 expression and immune infiltration was analyzed by TIDE, XCELL, MCPCOUNTER, and EPIC. We performed EdU and transwell experiments to evaluate the influence of P4HA3 on the proliferation, migration and invasion abilities of different tumors. Patients derived xenograft (PDX) and subcutaneous transplantation models were utilized to explore the correlation between P4HA3 and immunotherapy response in triple-negative breast cancer (TNBC). Among 33 types of cancers, P4HA3 had generally different expression between different tumors, further analysis showed that the expression of P4HA3 was correlated with the cells infiltration of the tumor microenvironment (TME). The expression of P4HA3 was positively with the cell proliferation markers and epithelial-mesenchymal transition (EMT) markers. Moreover, P4HA3 deficiency inhibited the proliferation, migration and invasion abilities of tumor cells, and promoted anti-tumor immunotherapy of PD-1/PD-L1 inhibitor. This pan-cancer analysis of P4HA3 provides a comprehensive understanding of its oncogenic and prognosis role in different cancers, P4HA3 abnormal expression could be a useful biomarker for predicting the effectiveness of immunotherapy in cancer patients.

In Situ Transformable Fibrillar Clusters Disrupt Intracellular Copper Metabolic Homeostasis by Comprehensive Blockage of Cuprous Ions Efflux.

Dysregulation of copper metabolism is intricately associated with the occurrence and therapeutic management of colorectal cancer. Previous studies have attempted to induce cuproptosis by delivering lethal doses of copper ions into tumor cells, often with systemic safety risks. In vivo, transformable peptide is modular and designed for various tumor-related proteins, which can affect protein function and distribution. Here, a fibrillar transformation peptidic (FTP) nanoparticle is synthesized, which can bind ATP7B membrane proteins (cuprous ions transporter) and transform into nanofibrils/ATP7B clusters, inducing "copper-free cuproptosis" in vivo. Without adding exogenous copper ions, the spherical FTP nanoparticles bound the high distribution regions of ATP7B membrane proteins, transforming into fibrillar networks in situ with prolonged retention. The cage-like fibrillar network would further capture unbound or newly generated free ATP7B membrane proteins, thereby significantly and consistently preventing cuprous ions efflux. The FTP nanoparticles would not undergo in situ fibrillar transformation on the low expression region of ATP7B membrane proteins but enter the cell for safe degradation, which exhibited high specificity and safety in vivo. By disrupting intracellular copper homeostasis, the transformable fibrillar clusters displayed a long-term anti-tumor effect on subcutaneous transplantation and liver metastatic CRC models.

A 3D-Printed Microdevice Encapsulates Vascularized Islets Composed of iPSC-derived β-like Cells and Microvascular Fragments for Type 1 Diabetes Treatment

Tranplantation of insulin-secreting cells provides a promising method for re-establishing the autonomous blood glucose control ability of type 1 diabetes (T1D) patients, but the low survival of the tranlplanted cells hinder the therapeutic efficacy. In this study, we 3D-printed an encapsulation system contraining β-like cells and microvascular fragments (MVF), to create a retrivable microdevice with vascularized islets in vivo for T1D therapy. The functional β-like cells were differentiated from the urine epithelial cell-derived induced pluripotent stem cells (UiPSCs). Single-cell RNA sequencing provided an integrative study and macroscopic developmental analyses of the entire process of differentiation, which revealed the developmental trajectory of differentiation in vitro follows the developmental pattern of embryonic pancreas in vivo. The MVF were isolated from the epididymal fat pad. The microdevice with a groove structure were rapidly fabricated by the digital light processing (DLP)-3D printing technology. The β-like cells and MVF were uniformly distributed in the device. After subcutaneous transplantation into C57BL/6 mice, the microdevice have less collagen accumulation and low immune cell infiltration. Moerover, the microdevice encapsulated vascularized islets reduced hyperglycemica in 33% of the treated mice for up to 100 days without immunosuppressants, and the humanized C-peptide was also detected in the serum of the mice. In summary, we described the microdevice-protecd vasculared islets for long-term treatment of T1D, with high safety and potential clinical transformative value, and may therefore provide a translatable solution to advance the research progress of β cell replacement therapy for T1D.

Cyclanoline Reverses Cisplatin Resistance in Bladder Cancer Cells by Inhibiting the JAK2/STAT3 Pathway.

Cisplatin is a key therapeutic agent for bladder cancer, yet the emergence of cisplatin resistance presents a significant clinical challenge. This study aims to investigate the potential and mechanisms of cyclanoline (Cyc) in overcoming cisplatin resistance. Cisplatin-resistant T24 and BIU-87 cell models (T24/DR and BIU-87/DR) were established by increasing gradual concentration. Western Blot (WB) assessed the phosphorylation of STAT3, JAK2, and JAK3. T24/DR and BIU-87/DR cell lines were treated with selective STAT3 phosphorylation modulators, and cell viability was evaluated by CCK-8. Cells were subjected to cisplatin, Cyc, or their combination. Immunofluorescence (IHC) examined p-STAT3 expression. Protein and mRNA levels of apoptosis-related and cell cycle-related factors were measured. Changes in proliferation, invasion, migration, apoptosis, and cell cycle were monitored. In vivo, subcutaneous tumor transplantation models in nude mice were established, assessing tumor volume and weight. Changes in bladder cancer tissues were observed through HE staining, and the p-STAT3 was assessed via WB and IHC. Cisplatin-resistant cell lines were successfully established, demonstrating increased phosphorylation of STAT3, JAK2, and JAK3. Cisplatin or Cyc treatment decreased p-STAT3, inhibited invasion and migration, and induced apoptosis and cell cycle arrest in the G0/G1 phase in vitro. In vivo, tumor growth was significantly suppressed, with extensive tumor cell death. IHC and WB consistently showed a substantial downregulation of STAT3 phosphorylation. These changes were more pronounced when cisplatin and Cyc were administered in combination. Cyc reverses cisplatin resistance via JAK/STAT3 inhibition in bladder cancer, offering a potential clinical strategy to enhance cisplatin efficacy in treating bladder cancer.

Isocitrate dehydrogenase 2 mutation promotes cytarabine resistance in acute myeloid leukemia by Warburg effect.

Mutation of isocitrate dehydrogenase 2 (IDH2) is a key factor in promoting cytarabine (Ara-C) resistance in acute myeloid leukemia (AML), however the underly mechanism remains unclear. Acute myeloid leukemia cells, were cultured with either IDH2 knockdown (KD-IDH2) or overexpression (OE-IDH2) to elucidate the role of IDH2 in these leukemic cell lines. Additionally, mutant cell lines were engineered to replicate clinically relevant IDH2 mutations. To investigate cellular responses, the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) was administered to the cells. Cell proliferation was quantified using a Cell Counting Kit-8 (CCK-8), while apoptosis was evaluated through propidium iodide staining followed by flow cytometry. Glycolytic metabolism levels were measured using a specific reagent kit, and Western blotting was employed to determine the expression levels of glycolysis-related proteins. Transcriptome sequencing was conducted to elucidate the mechanisms by which IDH2 mutations influence glycolysis. Furthermore, both in vitro cell experiments and in vivo subcutaneous transplantation tumor models in nude mice were utilized to validate these mechanisms. OE-IDH2 in AML cells, enhances resistance to the Ara-C, promotes cell proliferation and glycolysis, and inhibits apoptosis. KD-IDH2 exhibits opposite effects. Both IDH2 mutations and OE-IDH2 produce similar effects on these cellular processes. The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells. Transcriptome sequencing results indicate an enrichment of the PI3K/Akt signaling pathway in IDH2-mutant AML cells. BEZ235 significantly inhibits the expression of phosphorylated PI3K (p-PI3K), phosphorylated Akt (p-Akt), mTOR, glycolytic metabolism, and Ara-C resistance both in vitro and in vivo. Overexpression and mutation of IDH2 coordinate with the Warburg effect through the PI3K/Akt/mTOR pathway to promote Ara-C resistance in AML.

Microspheres of stem cells from human exfoliated deciduous teeth exhibit superior pulp regeneration capacity

ObjectivesEngineering spheroids to create three-dimensional (3D) cell cultures has gained increasing attention in recent years due to their potential advantages over traditional two-dimensional (2D) tissue culture methods. Stem cells derived from human exfoliated deciduous teeth (SHEDs) demonstrate significant potential for pulpal regeneration applications. Nevertheless, the feasibility of microsphere formation of SHEDs and its impact on pulpal regeneration remain unclear. MethodsIn this study, SHEDs were isolated, identified, and cultured in ultra-low attachment six-well plates to produce SHED microspheres. The biological properties of SHED microspheres were compared to those of traditional 2D culture using live-dead staining, Alizarin red staining, Oil-red O staining, scratch experiments, Immunofluorescence, Transmission electron microscopy scan, Western blotting, RNA sequencing, and a nude mice subcutaneous transplantation model. ResultsWe found SHED cells can form microspheres with a dense internal structure. SHED microspheres exhibited notable advantages over SHED cells in terms of biological properties, maintaining cell activity and enhancing cell differentiation, migration, and stemness in vitro. RNA-seq revealed that the SHED microspheres potentially influenced cell development, regulation of neurogenesis, skeletal system development, tissue morphogenesis singling pathway. In vivo, SHED microspheres promoted the generation of pulp tissue in dental pulp compared to traditional 2D culture. ConclusionsMicrosphereization of SHED through 3D cell culture enhances its pulp regeneration capacity, presenting a novel strategy for dental pulp regeneration and the clinical treatment of dental pulp diseases.

Baicalein inhibits cell proliferation and induces apoptosis in brain glioma cells by downregulating the LGR4-EGFR pathway.

Patients diagnosed with brain glioma have a poor prognosis and limited therapeutic options. LGR4 is overexpressed in brain glioma and involved in the tumorigenesis of many tumors. Baicalein (BAI) is a kind of flavonoid that has exhibited anti-tumor effects in various tumors. Nevertheless, the functions and associations of BAI and LGR4 in brain glioma remain unclear. In this study, Gene Expression Profiling Interactive Analysis and Human Protein Atlas databases were used to perform expression and survival analysis of LGR4 in brain glioma patients. Subsequently, the significance of LGR4-EGFR in brain glioma cells (HS683 and KNS89) and brain glioma animal models was explored by RNA interference and subcutaneous transplantation. Additionally, brain glioma cells were treated with BAI to explore the roles and mechanisms of BAI in brain glioma. The results showed that LGR4 was highly expressed in brain glioma and was related to a poor prognosis. LGR4 knockdown repressed the proliferation and EGFR phosphorylation but induced apoptosis in brain glioma cells. However, these effects were reversed by EGFR overexpression and CBL knockdown. In contrast, both in vitro and in vivo experiments revealed that LGR4 overexpression facilitated brain glioma cell malignant behavior and promoted tumor development, but these effects were rescued by BAI and an EGFR inhibitor. Furthermore, si-LGR4 accelerated EGFR protein degradation, while oe-LGR4 exhibited the opposite effect. Without affecting normal cellular viability, BAI inhibited malignant behavior, interacted with LGR4, and blocked the LGR4-EGFR pathway for brain glioma cells. In conclusion, our data suggested that BAI inhibited brain glioma cell proliferation and induced apoptosis by downregulating the LGR4-EGFR pathway, which provides a novel strategy and potential therapeutic targets to treat brain glioma.

Emodin regulated lactate metabolism by inhibiting MCT1 to delay non-small cell lung cancer progression.

Lung cancer is one of the most common malignant tumors in the world, with high incidence rate and mortality. Monocarboxylate transporter (MCT) 1 has been found to be widely expressed in various tumors and plays a crucial role in regulating energy metabolism. Emodin, as an important traditional Chinese medicine in China, has been reported to inhibit the progression of lung cancer. However, its potential mechanism has not been fully elucidated. The effects of emodin and MCT1 inhibitor AZD3965 on the proliferation, migration, and invasion of lung cancer cells were detected using cell counting kit-8 (CCK-8) assay, wound-healing assay, and transwell small chamber assay. The content of glucose, lactate, and pyruvate in the cell culture medium was detected using a glucose, lactate, and pyruvate detection kit, and also detected protein expression using western blotting. In addition, to investigate the effects of emodin and AZD3965 on lung cancer in vivo, we constructed nude mice subcutaneous transplant tumor model by subcutaneous injection of lung cancer cells. The results showed that emodin and AZD3965 could inhibit the proliferation, migration, and invasion of lung cancer cells. At the same time, they could inhibit the expression of MCT1 in lung cancer cells and promote the release of lactate, but did not affect the content of glucose and pyruvate. In vivo experiments had shown that emodin and AZD3965 could effectively inhibit the growth of lung cancer and inhibit the expression of MCT1. All in all, our data suggested that emodin inhibited the proliferation, migration, and invasion of lung cancer cells, possibly by inhibiting MCT1, providing important theoretical basis for elucidating the mechanism of emodin in treating lung cancer.

Quercetin regulates sensitivity to X-ray radiation of hepatocellular carcinoma through miR-216a-3p.

Hepatocellular carcinoma (HCC) is a highly aggressive liver cancer with limited therapeutic options, and enhancing radiosensitivity remains a key challenge in improving treatment outcomes. Quercetin (Que) can inhibit the progression of hepatocellular carcinoma (HCC); however, its effect on HCC radiosensitivity remains unclear. This research investigates the role of Que in regulating HCC growth and radiosensitivity, aiming to provide a scientific foundation for enhancing the clinical efficacy of radiation therapy in HCC. The CCK-8 assay was used to determine the optimal treatment conditions for Que and X-rays. Changes in cell growth, cycle arrest, invasion, migration, the relative proportion of JC-1 red and green fluorescence (mitochondrial membrane potential), and the levels of ROS, MDA, SOD, and GSH-Px (oxidative stress) were assessed using flow cytometry, Transwell assays, JC-1 staining, Western blot, and ELISA, respectively, under Que, X-ray, and co-treatment conditions. The effect of miR-216a-3p knockdown on the action of Que was also explored, and the potential pathways by which Que regulates HCC growth and radiosensitivity were investigated in conjunction with in vivo subcutaneous transplantation tumor experiments. The in vitro treatment parameters for Que and X-rays were 100 µM and 4 Gy. Que combined with X-ray therapy enhanced HCC cell radiosensitivity, reduced proliferation, invasion, and migration, and promoted oxidative stress and apoptosis. Que was found to upregulate miR-216a-3p in HCC cells. Rescue experiments with miR-216a-3p knockdowns demonstrated that Que regulates HCC cell radiosensitivity via miR-216a-3p. In vivo research further showed that Que increased tumor sensitivity to X-rays by upregulating miR-216a-3p, thereby inhibiting HCC growth. In conclusion, Que has been shown to enhance HCC radiosensitization by upregulating miR-216a-3p and inhibiting HCC progression. Que may be a promising agent for increasing the radiosensitivity of HCC.

Novel astatine (211At)-labelled prostate-specific membrane antigen ligand with a neopentyl-glycol structure: evaluation of stability, efficacy, and safety using a prostate cancer xenograft model.

Prostate-specific membrane antigen (PSMA)-targeted alpha therapy is considered a promising alternative treatment for metastatic castration-resistant prostate cancer (mCRPC). Though astatine-211 (211At) is potentially useful alpha-emitter producible by cyclotrons, its clinical application has been limited by instability and a tendency to deastatination in vivo. To overcome these challenges, we developed [211At]At-NpG-PSMA, a novel PSMA ligand with a neopentyl-glycol structure that enhances in vivo stability against deastatination. This study aimed to evaluate the stability, anti-tumour effect, and safety of [211At]At-NpG-PSMA in mice. Xenograft models were prepared by subcutaneous transplantation of PSMA-positive PC-3 PIP cells into BALB/c nu/nu mice. [211At]At-NpG-PSMA was administered to assess biodistribution, and the anti-tumour effect was evaluated at doses of 0.32, 1.00 and 1.93 MBq in comparison with saline. Histopathological examinations were performed to evaluate damage to normal organs. [211At]At-NpG-PSMA demonstrated high tumour uptake (42.0 ± 13.1%ID/g at 3h) with minimal uptake in non-target tissues, including thyroid, stomach and salivary grands (0.28 ± 0.20%ID, 0.71 ± 0.12%ID/g and 0.88 ± 0.10%ID/g at 3h, respectively). A dose-dependent anti-tumour effect was observed, with tumour volumes increasing by 796.0 ± 437.6% in the control versus 161.0 ± 213.4%, -76.4 ± 19.2% and - 59.5 ± 41.6% in the 0.32, 1.00 and 1.93 MBq groups, respectively, by day 15. Mild renal tubule regeneration was noted in the 1.00 MBq group. [211At]At-NpG-PSMA demonstrated significant stability in vivo and anti-tumour effects with minimal side effects, indicating its potential as a new therapeutic drug for PSMA-targeted alpha therapy in mCRPC.

Comparative In Vivo Biocompatibility of Cellulose-Derived and Synthetic Meshes in Subcutaneous Transplantation Models.

Despite the increasing interest in cellulose-derived materials in biomedical research, there remains a significant gap in comprehensive in vivo analyses of cellulosic materials obtained from various sources and processing methods. To explore durable alternatives to synthetic medical meshes, we evaluated the in vivo biocompatibility of bacterial nanocellulose, regenerated cellulose, and cellulose nanofibrils in a subcutaneous transplantation model, alongside incumbent polypropylene and polydioxanone. Notably, this study demonstrates the in vivo biocompatibility of regenerated cellulose obtained through alkali dissolution and subsequent regeneration. All cellulose-derived implants triggered the expected foreign body response in the host tissue, characterized predominantly by macrophages and foreign body giant cells. Porous materials promoted cell ingrowth and biointegration. Our results highlight the potential of bacterial nanocellulose and regenerated cellulose as safe alternatives to commercial polypropylene meshes. However, the in vivo fragmentation observed for cellulose nanofibril meshes suggests the need for measures to optimize their processing and preparation.

Inhibition of hERG by ESEE suppresses the progression of colorectal cancer

Colorectal cancer (CRC) is one of the most common malignant cancers. Emodin is a lipophilic anthraquinone commonly found in medicinal herbs and known for its antitumor properties. However, its clinical utility has been hampered by low druggability. We designed and synthesized a new compound named Emodin succinimidyl ethyl ester (ESEE), which improves the bioavailability and preserves the original pharmacological effects of Emodin. In vitro, we have confirmed that ESEE induces apoptosis in colon cancer cells, suppresses cell proliferation, migration, and invasion, and inhibits the growth of subcutaneous transplantation tumors associated with colon cancer. And, in vivo, ESEE robustly inhibited tumor growth. Human Ether-a-go-go Related Gene (hERG) is aberrantly expressed in various cancer cells, where they play an important role in cancer progression. Focal adhesion kinase (FAK) is a tyrosine kinase overexpressed in cancer cells and plays an important role in the progression of tumors to a malignant phenotype. Mechanistically, the anti-CRC properties of ESEE are exerted through direct binding with hERG, which impedes the FAK/PI3K/AKT signaling axis-dependent apoptotic cascade.

Hydrogel based on M1 macrophage lysate and alginate loading with oxaliplatin for effective immunomodulation to inhibit melanoma progression, recurrence and metastasis

Despite the monumental success of immunotherapy in treating melanoma clinically, it still confronts significant challenges, chiefly that singular immunomodulatory tactics are insufficient to suppress the recurrence and metastasis of melanoma. Herein, these challenges are addressed by a hydrogel based on M1 macrophage lysate and alginate (M1LMHA) loaded with oxaliplatin (OXA), named M1LMHA@OXA.The results obtained from scanning electron microscopy and confocal microscopy indicate that the structure and morphology of M1LMHA@OXA remain unchanged. Flow cytometry results reveal that M1LMHA@OXA significantly promotes the maturation of dendritic cells (DCs) and enhances the proliferation of T lymphocytes. In a subcutaneous melanoma transplant model, M1LMHA@OXA effectively suppressed tumor growth in comparison to OXA alone and M1LMHA alone. Flow cytometry demonstrated that M1LMHA@OXA markedly increased the number of mature DCs and CD8+ T cells at the tumor site, while significantly reducing the quantity of M2-like tumor-associated macrophages (TAM) and enhancing the presence of M1 macrophages. Enzyme-linked immunosorbent assay (ELISA) results indicated that following treatment with M1LMHA@OXA, the levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in the bloodstream of mice were significantly elevated, whereas interleukin-10 (IL-10) exhibited no significant difference. This outcome further corroborates the ability of M1LMHA@OXA to substantially bolster the immune capability of mice. Similar results have also been observed in a melanoma subcutaneous transplantation recurrence model, and optical imaging of the lungs of mice revealed that M1LMHA@OXA inhibited tumor metastasis to the lungs. Notably, M1LMHA@OXA exhibits an exceptional therapeutic effect on the growth, post-surgical recurrence, and metastasis of the B16F10 melanoma. Therefore, this study provides a straightforward strategy that leverages the cooperative regulation of multiple immune cells to thwart the proliferation, recurrence, and spread of melanoma.

MG53 suppresses tumor growth via transcriptional inhibition of KIF11 in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) poses a formidable challenge in oncology due to its limited treatment options and poor long-term survival rates. Our previous work identified MG53, a member of the tripartite motif family protein (TRIM72), as a key player in tissue repair with potential applications in regenerative medicine. Despite the focus on MG53’s cytosolic functions, its nuclear role in suppressing pancreatic cancer remains unknown. Through orthotopic and subcutaneous transplantation studies in mice, we observed enhanced tumor growth in MG53-deficient mice compared to wild-type counterparts. The overexpression of KIF11, a motor protein crucial for cell mitosis regulation, has been linked to the aggressive proliferation of pancreatic cancer cells. Confocal imaging confirmed MG53′s presence in the nucleus of human pancreatic cancer cells, while functional assays demonstrated its impact on KIF11 expression and subsequent cell proliferation. Mechanistically, we revealed MG53′s transcriptional control over KIF11, leading to cell cycle arrest. Our findings position MG53 as a promising tumor suppressor in PDAC, offering a novel avenue for therapeutic intervention by regulating KIF11 expression.

443.4: Regulatory T cells enhance the engraftment of subcutaneous islet transplantation.

443.4: Regulatory T cells enhance the engraftment of subcutaneous islet transplantation.

V-311.4: The impact of improving hypoxic conditions on graft viability in subcutaneous islet transplantation.

V-311.4: The impact of improving hypoxic conditions on graft viability in subcutaneous islet transplantation.

Ginsenoside Rh1 regulates the immune microenvironment of hepatocellular carcinoma via the glucocorticoid receptor

ObjectiveGinsenoside Rh1 (G-Rh1) has been confirmed to inhibit the growth of breast cancer and colon cancer, but its therapeutic effect on hepatocellular carcinoma (HCC) is unclear. This study investigates the therapeutic effect of G-Rh1 on HCC as well as the underlying mechanism. MethodsBioinformatics methods were used to analyze glucocorticoid receptor (GR) expression and the tumor microenvironment in HCC tissues from HCC patients. The effect of G-Rh1 on HCC cells was investigated in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. The therapeutic effect of G-Rh1 was investigated in vivo using subcutaneous transplantation models in C57BL/6J and nude mice. Additionally, the proportion of infiltrating immune cells in tumors was analyzed using flow cytometry, the GR and major histocompatibility complex class I (MHC-I) expression of HCC cells after G-Rh1 treatment was analyzed using Western blotting, and G-Rh1-treated Hepa1-6 cells were cocultured with bone marrow-derived dendritic cells and B3Z T cells to further analyze the ability of G-Rh1 to induce dendritic cell (DC) maturation and CD8+ T cell activation. ResultsGR expression was upregulated in HCC tissues, and high GR expression was associated with a worsened immune microenvironment. In vitro studies showed that G-Rh1 had no significant effect on the proliferation of HCC cells, while in vivo studies showed that G-Rh1 exerted antitumor effects in C57BL/6J mice but not in nude mice. Further research revealed that G-Rh1 ameliorated the immunosuppressive tumor microenvironment, thereby enhancing the antitumor effects of lenvatinib by increasing the infiltration of CD8+ T cells, mature DCs, and MHC-I-positive cells. MHC-I was upregulated by G-Rh1 via GR suppression. Moreover, overexpression of GR abolished the G-Rh1-mediated promotion of MHC-I expression in Huh7 cells, as well as the maturation of DCs and the activation of CD8+ T cells. ConclusionG-Rh1 can regulate the immune microenvironment of HCC by targeting GR, thus increasing the antitumor effect of lenvatinib.