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Despite demonstrating promising outcomes in treating hematologic malignancies, the efficacy of chimeric antigen receptor-modified T (CAR-T) cell therapy remains limited when applied to solid tumors due to tumor immune microenvironment (TIME). Strategies to augment CAR-T cell efficacy against solid tumors have been investigated by ameliorating TIME to a certain extent. In this study, Cabozantinib was utilized in combination with CAR-T cells targeting carbonic anhydrase IX (CAIX) for the treatment of renal cancer. Our findings indicate that combination therapy with CAIX-CAR-T and Cabozantinib demonstrated synergistic efficacy against an orthotopic xenograft tumor model and a subcutaneous tumor model of renal cell carcinoma in mice. Mechanistically, it was observed that CAR-T cells combined with Cabozantinib led to an increase in the infiltration of tumor-infiltrating T cells, while reducing tumor-associated macrophages and M2 polarization. Additionally, Cabozantinib blocked the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis by decreasing the expression of PD-L1 in tumor cells and PD-1 in T cells. Furthermore, Cabozantinib promoted CAR-T cell effector function and reduced T cell exhaustion. This combination therapy represents a novel approach to enhancing CAR-T cell efficacy against solid tumors and holds significant promise for advancing CAR-T cell therapy in clinical settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cadmium (Cd) is a common heavy metal pollutant in the environment, and the widespread use of products containing Cd compounds in industry has led to excessive levels in the environment, which enter the animal body through the food chain, thus seriously affecting the reproductive development of animals. Related studies have reported that Cd severely affects spermatogonia development and spermatogenesis in animals. In contrast, the reproductive toxicity of Cd in males and its mechanism of action have not been clarified. Therefore, this paper reviewed the toxic effects of Cd on germ cells, spermatogonia somatic cells and hypothalamic-pituitary-gonadal axis (HPG axis) of male animals and its toxic action mechanisms of oxidative stress, apoptosis and autophagy from the perspectives of cytology, genetics and neuroendocrinology. The effects of Cd stress on epigenetic modification of reproductive development in male animals were also analyzed. We hope to provide a reference for the in-depth study of the toxicity of Cd on male animal reproduction., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

M1 polarization of macrophages works as a promoter in pathogenesis of acute lung injury / acute respiratory distress syndrome (ALI/ARDS) by the secretion of pro-inflammatory cytokines and recruiting other inflammatory cells. Lipopolysaccharide (LPS), a critical component of the wall of gram-negative bacteria, can induce M1 polarization and ALI. Recently, cluster of differentiation 36 (CD36) has been reported to be associated with inflammatory responses. However, it has not yet been clarified whether CD36 in macrophages is involved in LPS-induced ALI. Herein, we demonstrated that in macrophages, LPS-induced ALI was regulated by CD36. Loss of CD36 attenuated LPS-induced ALI by reducing M1 polarization. Mechanistically, CD36 promoted macrophage M1 polarization by regulating CD14 associated with TLR4 during LPS stimulation. The findings of this study, clarified the mechanism of LPS-induced ALI through CD36 in macrophages, which provides a potential target for the prevention and treatment of ALI., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Lenvatinib, a tyrosine kinase inhibitor, has been approved for the treatment of several cancers. However, its regulatory activity and related mechanisms on T cell antitumour immunity need to be further investigated., Methods: The antitumour activity of lenvatinib in immunocompetent and immunodeficient mice was compared to determine the role of T cell immunity. The antitumour activity of T cells was analysed by cytokine production and adoptive T cell therapy. The immunosuppressive effects of MDSCs on T cells were determined by detecting cytokine production in T cells after being cocultured with MDSCs. The adjuvant immunotherapy effect of lenvatinib was determined by combination therapy with CAR-T cells targeted carbonic anhydrase IX (CAIX) in a murine renal cancer model., Results: The antitumour activity of lenvatinib was greater in immunocompetent mice than in immunodeficient mice and was attenuated by CD8+T cell depletion. Lenvatinib increased proliferation, tumour infiltration and antitumour activity of T cells. Importantly, adoptive transfer of lenvatinib-treated T cells showed a long-term antitumour response in vivo. Mechanistically, lenvatinib upregulated T cell-related chemokines (CXCL10 and CCL8) in tumours and decreased the frequency and immunosuppressive activity of MDSCs. Furthermore, lenvatinib enhanced the efficacy of CAR-T cells in a murine renal cancer model., Conclusion: Our study revealed novel antitumour mechanisms of lenvatinib by enhancing T cell-mediated antitumour immunity. These findings are of great significance for guiding the clinical use of lenvatinib and provide a good candidate for future combination therapy with T-cell therapies or other immunotherapies., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Validation of a small molecular compound targeting the oncogenic pathways is the primary approach for the development of the anti-cancer drugs. In the present study, we employed the computational mimic drug targets prediction software to foresee the molecular targets of a series of spirooxindole-pyrrolizidine derivatives, which were synthesized by our laboratory viatargeted combinational chemistry. We found that CPHSP, a novel spirooxindole-pyrrolizidine derivative, can target the MDM2/p53 signaling that is essential for the tumorigenesis of hepatocellular carcinoma (HCC). To validate its anti-tumoral function, we firstly established the soluble receipt of CPHSP through 2-hydroxypropyl-β-cyclodextrin (HBC) loading and showed that oral administration of HBC-loaded CPHSP significantly inhibited the tumor growth and prolonged the survival time of tumor-bearing mice in the subcutaneously human hepatoma cells-xenografted nude mouse model of HCC. Immunohistochemistry staining showed that HBC-loaded CPHSP treatment suppressed the proliferation and induced apoptosis of tumor cells in this model. Our mechanistic studies showed that CPHSP treatment inhibited MDM2 protein expression and up-regulated p53 activity and activated MKK4/MKK7/JNK1/2/C-Jun signaling pathway, which resulted in cell cycle arrest and apoptosis of HepG2 cells in vitro. Moreover, we showed that JNK1/2 activation could also up-regulate p53 expression in CPHSP-treated HepG2 cells. Finally, we documented the antitumor activities of oral administration of the HBC-loaded CPHSP in the ML-1 bearing orthotopic mouse model. In summary, this study suggests that oral administration of HBC-loaded CPHSP is a safe and effective treatment for HCC, of which the clinical potency for patients with HCC warrants further studies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Development of an effective and safe anti-cancer drug is an urgent request for hepatocellular carcinoma (HCC). In this study, we synthesized a series of novel indole substituted dihydropyrido[2,3-d]pyrimidines through the multicomponent reactions to connect pyrido[2,3-d]pyrimidine and indole moities via an one-pot three-component reaction of 3-cyanoacetyl indoles 1, various aromatic aldehyde 2, and 2,6-diaminopyrimidin-4(3H)-one 3. Subsequently, we screened their cytotoxicity via CCK-8 assay in HepG2 cells, a human hepatoma cell line and chose compound 4p that showed the lowest dosage of IC50 to study the antitumor activities to HCC. Interestingly, 4p significantly induced the cell cycle arrest and apoptosis of HepG2 via targeting AKT and ERK1/2 signaling pathways in vitro. To improve the solubility of compound 4p, we hosted this compound into the substituted glucopyranose ring of (2-Hydroxypropyl)-β-cyclodextrin (HBC), a cosolvent approved by FDA with the help of ultrasonication and heating. Finally, we showed that oral administration of HBC-hosted 4p effectively inhibited tumor growth and prolonged the survival time of tumor-bearing mice in subcutaneously xenografted model. These results suggest that multicomponent reactions connecting pyrido[2,3-d]pyrimidine and indole moities is a productive and economical method for the synthesis of anticancer compound, and oral administration of HBC-hosted 4p is an effective and safe agents for treatment of HCC, whose clinical application potency warrant further studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Patients with bone cancer metastasis suffer from unbearable pain and bone fractures due to bone remodeling. This is caused by tumor cells that disturb the bone microenvironment. Here, we have investigated the role of tumor-secreted sugar-binding protein, i.e., galectin-3, on osteoblast differentiation and report that it downregulates the expression of osteoblast differentiation markers, e.g., RUNX2, SP7, ALPL, COL1A1, IBSP, and BGLAP, of treated human fetal osteoblast (hFOB) cells. Co-culturing of hFOB cells with human breast cancer BT-549 and prostate cancer LNCaP cells harboring galectin-3 has resulted in inhibition of osteoblast differentiation by the secreted galectin-3 into culture medium. The inhibitory effect of galectin-3 was found to be through its binding to Notch1 in a sugar-dependent manner that has led to accelerated Notch1 cleavage and activation of Notch signaling. Taken together, our findings show that soluble galectin-3 in the bone microenvironment niche regulates bone remodeling through Notch signaling, suggesting a novel bone metastasis therapeutic target.

Inactivation of the tumor suppressor p53 and activation of the oncogene Ras are the two most pivotal events in tumor development. However, potential intersection between p53 and Ras activity during an EMT process, which plays a crucial role during malignant tumor progression, remains elusive. Here, we report that increased expression of wild type p53 suppressed H-Ras(V12)-induced EMT phenotypes and restrained stem cell properties, through downregulation of MEK-ERK signaling pathways. In vivo experiments showed that p53 was able to inhibit H-Ras(V12)-induced tumor growth of human mammary epithelial cells. This study elucidates a novel correlation between the tumor suppressor gene p53 and the oncogene Ras in regulating EMT program, and expands the knowledge about the function of p53 in EMT process., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)