Bara&#x;ah Khaleel  Eitan Lunenfeld  Joseph Kapelushnik  Mahmoud Huleihel 《International journal of molecular sciences》2022,23(7)

Acute myeloid leukemia (AML) accounts for around 20% of diagnosed childhood leukemia. Cytarabine (CYT) is involved in the AML treatment regimen. AML and CYT showed impairment in spermatogenesis in human and rodents in adulthood. We successfully developed an AML disease model in sexually immature mice. Monocytes and granulocytes were examined in all groups: untreated control, AML alone, CYT alone and AML+CYT (in combination). There was a significant increase in the counts of monocytes and granulocytes in the AML-treated immature mice (AML) compared to the control, and AML cells were demonstrated in the blood vessels of the testes. AML alone and CYT alone impaired the development of spermatogenesis at the adult age of the AML-treated immature mice. The damage was clear in the structure/histology of their seminiferous tubules, and an increase in the apoptotic cells of the seminiferous tubules was demonstrated. Our results demonstrated a significant decrease in the meiotic/post-meiotic cells compared to the control. However, CYT alone (but not AML) significantly increased the count of spermatogonial cells (premeiotic cells) that positively stained with SALL4 and PLZF per tubule compared to the control. Furthermore, AML significantly increased the count of proliferating spermatogonial cells that positively stained with PCNA in the seminiferous tubules compared to the control, whereas CYT significantly decreased the count compared to the control. Our result showed that AML and CYT affected the microenvironment/niche of the germ cells. AML significantly decreased the levels growth factors, such as SCF, GDNF and MCSF) compared to control, whereas CYT significantly increased the levels of MCSF and GDNF compared to control. In addition, AML significantly increased the RNA expression levels of testicular IL-6 (a proinflammatory cytokine), whereas CYT significantly decreased testicular IL-6 levels compared to the control group. Furthermore, AML alone and CYT alone significantly decreased RNA expression levels of testicular IL-10 (anti-inflammatory cytokine) compared to the control group. Our results demonstrate that pediatric AML disease with or without CYT treatment impairs spermatogenesis at adult age (the impairment was more pronounced in AML+CYT) compared to control. Thus, we suggest that special care should be considered for children with AML who are treated with a CYT regimen regarding their future fertility at adult age.  相似文献   

    

Oluwakemi Ebenezer  Michael Shapi  Jack A. Tuszynski 《International journal of molecular sciences》2022,23(7)

Microtubules are cylindrical protein polymers formed from αβ-tubulin heterodimers in the cytoplasm of eukaryotic cells. Microtubule disturbance may cause cell cycle arrest in the G2/M phase, and anomalous mitotic spindles will form. Microtubules are an important target for cancer drug action because of their critical role in mitosis. Several microtubule-targeting agents with vast therapeutic advantages have been developed, but they often lead to multidrug resistance and adverse side effects. Thus, single-target therapy has drawbacks in the effective control of tubulin polymerization. Molecular hybridization, based on the amalgamation of two or more pharmacophores of bioactive conjugates to engender a single molecular structure with enhanced pharmacokinetics and biological activity, compared to their parent molecules, has recently become a promising approach in drug development. The practical application of combined active scaffolds targeting tubulin polymerization inhibitors has been corroborated in the past few years. Meanwhile, different designs and syntheses of novel anti-tubulin hybrids have been broadly studied, illustrated, and detailed in the literature. This review describes various molecular hybrids with their reported structural–activity relationships (SARs) where it is possible in an effort to generate efficacious tubulin polymerization inhibitors. The aim is to create a platform on which new active scaffolds can be modeled for improved tubulin polymerization inhibitory potency and hence, the development of new therapeutic agents against cancer.  相似文献   

    

Danai G. Topouza  Jihoon Choi  Sean Nesdoly  Anastasiya Tarnouskaya  Christopher J. B. Nicol  Qing Ling Duan 《International journal of molecular sciences》2022,23(9)

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Zhouqi Meng  Fang Wei  Ronghua Wang  Mengge Xia  Zhigang Chen  Huiping Wang  Meifang Zhu 《Advanced materials (Deerfield Beach, Fla.)》2016,28(2):245-253

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Wenxuan Xu  Dongdong Li  Chaoran Chen  Junxia Wang  Xinhua Wei  Xianzhu Yang 《Advanced functional materials》2023,33(40):2302231

Metastatic triple-negative breast cancer (TNBC) has a poor prognosis and high mortality with no effective treatment options, and immunotherapy is highly anticipated as a potential treatment but is limited by the lack of tumor-infiltrating T lymphocytes in TNBC. Herein, red blood cell (RBC) membrane-camouflaged polyphosphoester (PPE) nanoparticles (RBC@PPE_MTO/PFA) are prepared as the nanocarriers of mitoxantrone (MTO) and perfluoroalkane (PFA) for synergized immunotherapy. The encapsulated MTO can generate heat and reactive oxygen species (ROS) to achieve photothermal and photodynamic therapy; moreover, ROS further triggers the self-accelerating release of MTO from the ROS-sensitive PPE core to enable chemotherapy. The RBC@PPE_MTO/PFA-mediated sequential photothermal/photodynamic/chemotherapy efficiently promotes the infiltration of CD8⁺ T cells into TNBC tumor tissue and synergizes the therapeutic activity of an immune checkpoint blockade antibody for metastatic TNBC treatment in distant and lung metastasis models. This biomimetic nanomedicine of MTO provides a convenient and available strategy to sensitize TNBC to immune checkpoint blockade antibody.  相似文献   

    

Zixuan Li  Qing Pei  Min Zhao  Zhigang Xie  Min Zheng 《Advanced functional materials》2024,34(30):2312500

The combination of chemotherapy and immunotherapy holds great potential in clinical treatment of advanced cancers. Whereas, the therapeutic outcome of chemotherapeutic and immune regulator is suboptimal due to their poor tumor availability and severe off-target toxicity. Herein, self-carrier nanoparticles (PSMT NPs) integrating a paclitaxel (PTX) prodrug and indoleamine 2,3-dioxygenase 1 (IDO) inhibitor (1-methyl-tryptophan, 1MT) for tumor-specific chemo-immunotherapy is constructed. After internalization by cancer cells, PSMT NPs can respond to endogenous redox stimulus, and release PTX and 1MT. The released PTX can not only promote cell apoptosis via the intervention of cell mitosis but also initiate immunogenic cell death to facilitate the recruitment and activation of tumor-infiltrating cytotoxic T lymphocytes. The concomitant 1MT can inhibit the IDO activity to exhaust regulatory T cells, thereby synergistically activating cytotoxic T lymphocytes. PSMT NPs exhibit potentiated antitumor output toward triple-negative breast cancer and negligible systemic toxicity. This facile and versatile nanoplatform provides a promising strategy to cooperatively activate antitumor immunity for potentiated chemo-immunotherapy.  相似文献   

    

Chen-Cheng Xue  Meng-Huan Li  Linawati Sutrisno  Bei-Bei Yan  Yang Zhao  Yan Hu  Kai-Yong Cai  Yanli Zhao  Shu-Hong Yu  Zhong Luo 《Advanced functional materials》2021,31(20):2008732

New biomaterials with antitumor and tissue repair function have become increasingly important for the postoperative care of melanoma surgery, which could prolong the tumor-free survival of patients while simultaneously facilitating the reconstruction of the trauma tissue. For this purpose, a bioresorbable composite scaffold is designed which is fabricated by depositing therapeutic amorphous calcium carbonate (ACC)-based nanoformulations in gelatin/polycaprolactone (GP) nanofibers via electrospinning. The ACC nanoformulations are integrated with Fe²⁺-preactivated bleomycin to deliver biocatalytically enhanced therapeutic effect while the hydrolysable ACC contents can act as proton scavengers to ameliorate the tumor tissue acidity in situ, leading to sustained inhibition on tumor recurrence and metastasis. The acid-triggered ACC decomposition also releases Ca²⁺ to activate the downstream Wnt/β-catenin signaling pathways, which can cooperate with the healing effect of the GP substrate and accelerate wound regeneration. The nanoengineered scaffold can be useful as a supplementary treatment for the postoperative management of melanoma.  相似文献   

    

Yi Liu  Uday K. Sukumar  Masamitsu Kanada  Anandi Krishnan  Tarik F. Massoud  Ramasamy Paulmurugan 《Advanced functional materials》2021,31(41):2103600

Camouflaged cell-membrane-based nanoparticles have gained increasing attention owing to their improved biocompatibility and immunomodulatory properties. Using nanoparticles prepared from the membranes of specific cell types or fusions derived from different cells membranes, their functional performance could be improved in several aspects. Here, cell membranes extracted from breast cancer cells and platelets are used to fabricate a hybrid-membrane vesicle (cancer cell-platelet-fusion-membrane vesicle, CPMV) loaded with therapeutic microRNAs (miRNAs) for the treatment of triple-negative breast cancer (TNBC). A clinically scalable microfluidic platform is presented for fusion of cell membranes. The reconstitution process during synthesis allows for efficient loading of miRNAs into CPMVs. Conditions for preparation of miRNA-loaded CPMVs are systematically optimized and their property of homing to source cells is demonstrated using in vitro experiments and therapeutic evaluation in vivo. In vitro, the CPMVs exhibit significant recognition of their source cells and avoided engulfment by macrophages. After systemic delivery in mice, CPMVs show a prolonged circulation time and site-specific accumulation at implanted TNBC-xenografts. The delivered antimiRNAs are sensitized TNBCs to doxorubicin, resulting in an improved therapeutic response and survival rate. This strategy has considerable potential for clinical translation to improve personalized therapy for breast cancer and other malignancies.  相似文献   

    

Dongdong Wang  Xiangxiang Zhu  Xiaocui Tang  Hongye Li  Xie Yizhen  Diling Chen 《Journal of food science》2020,85(6):1872-1890

Cancer represents a major disease burden worldwide. Despite continuous advances obtained in medical therapies recently, resistance to standard drugs and adverse effects still represent important causes of therapeutic failure. There is growing evidence that the gut microbiota can affect the response to chemo- and immunotherapeutic drugs by modulating efficacy and/or toxicity, and diet is the most important factor affecting the gut microbiota. In this study, we assessed the auxiliary antitumor effects of immunomodulatory fungal proteins from Hericium erinaceus (HEP) administered with the chemotherapy drug 5-Fluorouracil (5-Fu), and we attempted to identify new potential prebiotic bacteria for auxiliary antitumor treatment. There were 1,455 proteins identified from H. erinaceus. In a xenografted mouse model of cancer, HEP with 5-Fu significantly suppressed tumor growth, inhibited inflammatory markers such as interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-6, tumor necrosis factor (TNF)-α, and lipopolysaccharide (LPS), and regulated the expression of Akt, CCDN1, CKD4, FOXM1, MMP7, MYC, PPAR-α, and PPAR-γ. 16S rRNA sequencing showed that HEP ameliorated the dysbacteriosis induced by 5-Fu, as it inhibited certain aerobic and microaerobic bacteria including Parabacteroides, Flavobacteriaceae, Christensenellaceae, Anoxybacillus, Aggregatibacter, Comamonadaceae, Planococcaceae, Desulfovibrionaceae, Sporosarcina, Staphylococcus, Aerococcaceae, and Bilophila in the xenografted mice, and increase some probiotic bacteria such as Bifidobacterium, Gemellales, Blautia, Sutterella, Anaerostipes, Roseburia, Lachnobacterium, Lactobacillus, and Desulfovibrio. This demonstrates that HEP could promote the antitumor efficacy of 5-Fu by improving the microbiota composition, the immune inflammatory response, and homeostasis.  相似文献   

    

Carmelo Gurnari  Simona Pagliuca  Valeria Visconte 《International journal of molecular sciences》2020,21(22)

Acute myeloid leukemia (AML) is a clonal hematopoietic disorder characterized by abnormal proliferation, lack of cellular differentiation, and infiltration of bone marrow, peripheral blood, or other organs. Induction failure and in general resistance to chemotherapeutic agents represent a hindrance for improving survival outcomes in AML. Here, we review the latest insights in AML biology concerning refractoriness to therapies with a specific focus on cytarabine and daunorubicin which still represent milestones agents for inducing therapeutic response and disease eradication. However, failure to achieve complete remission in AML is still high especially in elderly patients (40–60% in patients >65 years old). Several lines of basic and clinical research have been employed to improve the achievement of complete remission. These lines of research include molecular targeted therapy and more recently immunotherapy. In terms of molecular targeted therapies, specific attention is given to DNMT3A and TP53 mutant AML by reviewing the mechanisms underlying epigenetic therapies’ (e.g., hypomethylating agents) resistance and providing critical points and hints for possible future therapies overcoming AML refractoriness.  相似文献