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Cancer immunotherapy remains a significant challenge due to insufficient proliferation of immune cells and the sturdy immunosuppressive tumor microenvironment. Herein, we proposed the hypothesis of cuproptosis-lactate regulation to provoke cuproptosis and enhance anti-tumor immunity. For this purpose, copper-human serum albumin nanocomplex loaded gold nanocages with bacterial membrane coating (BAu-CuNCs) were developed. The targeted delivery and disassembly of BAu-CuNCs in tumor cells initiated a cascade of reactions. Under near infrared (NIR) laser irradiation, the release of copper-human serum albumin (Cu-HSA) was enhanced that reacted with intratumoral glutathione (GSH) via a disulfide exchange reaction to liberate Cu2+ ions and exert cuproptosis. Subsequently, the cuproptosis effect triggered immunogenic cell death (ICD) in tumor by the release of damage associated molecular patterns (DAMPs) to realize anti-tumor immunity via robust production of cytotoxic T cells (CD8+) and helper T cells (CD4+). Meanwhile, under NIR irradiation, gold nanocages (AuNCs) promoted excessive reactive oxygen species (ROS) generation that played a primary role in inhibiting glycolysis, reducing the lactate and ATP level. The combine action of lower lactate level, ATP reduction and GSH depletion further sensitized the tumor cells to cuproptosis. Also, the lower lactate production led to the significant blockage of immunosuppressive T regulatory cells (Tregs) and boosted the anti-tumor immunity. Additionally, the effective inhibition of breast cancer metastasis to the lungs enhanced the anti-tumor therapeutic impact of BAu-CuNCs + NIR treatment. Hence, BAu-CuNCs + NIR concurrently induced cuproptosis, ICD and hindered lactate production, leading to the inhibition of tumor growth, remodeling of the immunosuppressive tumor microenvironment and suppression of lung metastasis. Therefore, leveraging cuproptosis-lactate regulation, this approach presents a novel strategy for enhanced tumor immunotherapy.

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KEY MESSAGE: R2R3 MYB transcription factor GhMYB18 is involved in the defense response to cotton aphid by participating in the synthesis of salicylic acid and flavonoids. R2R3 MYB transcription factors (TFs) play crucial roles in plant growth and development as well as response to abiotic and biotic stresses. However, the mechanism of R2R3 MYB TFs in cotton response to aphid infestation remains largely unknown. Here, an R2R3 MYB transcription factor GhMYB18 was identified as a gene up-regulated from upland cotton (Gossypium hirsutum L.) under cotton aphid (Aphis gossypii Glover) infestation. GhMYB18, which has transcription activity, was localized mainly to nucleus and cell membranes. Transient overexpression of GhMYB18 in cotton activates salicylic acid (SA) and phenylpropane signaling pathways and promoted the synthesis of salicylic acid and flavonoids, which leads to enhancing the tolerance to cotton aphid feeding. In contrast, silencing of GhMYB18 increased the susceptibility of G. hirsutum to aphid. Additionally, GhMYB18 significantly promoted the activities of defense-related enzymes including catalase (CAT), peroxidase (POD), polyphenol oxidase (PPO) and phenylalanine ammonia-lyase (PAL). These results collectively suggest that GhMYB18 is involved in cotton defense response to cotton aphid attacks through regulating the synthesis of salicylic acid and flavonoids.

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As plant-specific molecular switches, Rho-like GTPases (Rops) are vital for plant survival in response to biotic and abiotic stresses. However, their roles in plant defense response to phytophagous insect's damage are largely unknown. In this study, the expression levels of nine maize RAC family genes were analyzed after fall armyworm (FAW) larvae infestation. Among the analyzed genes, ZmRop1 was specifically and highly expressed, and its role in maize response to FAW larvae damage was studied. The results showed that upon FAW larvae infestation, salicylic acid and methyl jasmonate treatment ZmRop1 gene transcripts were all down-regulated. However, upon mechanical injury, the expression level of ZmRop1 was up-regulated. Overexpression of ZmRop1 gene in maize plants could improve maize plant resistance to FAW larvae damage. Conversely, silencing of ZmRop1 increased maize plant susceptibility to FAW larvae damage. The analysis of the potential anti-herbivore metabolites, showed that ZmRop1 promoted the enzyme activities of catalase, peroxidase and the expression levels of ZmCAT, ZmPOD, ZmRBOHA and ZmRBOHB, thereby enhancing the reactive oxygen species (ROS) production, including the content of O2- and H2O2. In addition, overexpression or silencing of ZmRop1 could have influence on the content of the total soluble phenol through mediating the activity of polyphenol oxidase. In summary, the results illuminated our understanding of how ZmRop1 participate in maize defense response to FAW larvae damage as a positive regulator through mediating ROS production and can be used as a reference for the green prevention and control of FAW larvae.

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Callose synthase plays an essential role in plant growth and development and in response to all sorts of stresses through regulating callose formation. However, few research about the function and mechanism of the insect resistance of callose synthase genes have been reported in cotton. In this study, a cotton callose synthase gene GhCalS5 was cloned, and its function and mechanism of resistance to cotton aphids were analyzed. The expression of GhCalS5 was significantly upregulated in both, leaves and stems of cotton plants at 48 h after cotton aphid infestation and in the leaves of cotton plants at 24 h after salicylic acid treatment. The overexpression of GhCalS5 enhanced cotton resistance to cotton aphids. Expectedly silencing of GhCalS5 reduced cotton resistance to cotton aphids. Overexpression of GhCalS5 enhanced callose formation in cotton leaves. Our results suggest that GhCalS5 is involved in cotton resistance against cotton aphids by influencing callose formation.

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The aggressive progression of breast cancer is impacted significantly by the tumor microenvironment (TME). The current chemotherapy normally causes cytotoxicity to tumor cells, while does not effectively modulate the TME. Thus, the chemotherapy effect of breast cancer is usually dissatisfactory. In this study, a kind of hierarchically releasing bio-responsive nanoparticles (R(D)/H(S) NPs), constructed by ß-cyclodextrin-grafted heparin and pH-sensitive pseudorotaxane, were investigated to enhance the breast cancer chemotherapeutic efficacy through TME modulation. Doxorubicin (DOX) and transforming growth factor-ß (TGF-ß) receptor inhibitor (SB431542) loaded onto R(D)/H(S) NPs were released rapidly for the respective response to low pH in endosomes/lysosomes and heparanase (HPSE) in TME. Our results showed that R(D)/H(S) NPs effectively inhibited the formation of tumor-associated fibroblasts (TAFs) and reduced TGF-ß and collagen I secretion. Besides, the immunosuppressive microenvironment was effectively reversed into immunogenic, characterized by increased CD8+ and CD4+ T cell infiltration, which distinctly inhibited breast cancer metastasis. Therefore, R(D)/H(S) NPs remodeled the TME by downregulating TAFs, TGF-ß, and collagen I; activating the immune microenvironment; and then amplifying the chemotherapeutic efficacy of DOX.

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The desmoplastic tumor microenvironment (DTME), including overexpressed stromal cells and extracellular matrix, formed the first barrier for the accumulation and penetration of nanoparticles in tumors, which compromised the therapeutic efficacy and prognosis. In some metastatic cells, overactivity of the tricarboxylic cycle could overload the electron transport chain resulting in increased mtROS production, which triggered the mitochondria-driven tumor migration and metastasis. Hence, we developed HPBC@TRP/NPs for down-regulating the mtROS-PYK2 pathway and remodeling the DTME to inhibit tumor growth and metastasis for the first time. TPP-RSV prodrugs were synthesized and targeted at mitochondria, resulting in the scavenging of mtROS, lower PYK2 expression, and activation of the mitochondria-driven apoptotic pathway. Pirfenidone fully remodeled the DTME through inhibiting the expression of CAFs, hyaluronan and collagen I, thereby reducing IFP, eliminating the immunosuppressive microenvironment by decreasing the expression of TGF-ß, and increasing the infiltration of cytotoxic T lymphocytes. The combination therapy of different mechanisms via targeting the mtROS-PYK2 pathway and CAFs might provide deeper insights into the inhibition of malignant breast cancer growth and metastasis.

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The normal chemotherapy only induces the intracellular apoptosis pathway to promote primary tumor cells death, while not inhibit tumor metastasis. Herein, we proposed a kind of heparanase (HPSE)-driven sequential released nanoparticles, which modified with ß-cyclodextrin (ß-CD) grafted heparin (NLC/H(D + F + S) NPs) co-loading with doxorubicin (DOX), ferrocene (Fc), and TGF-ß receptor inhibitor (SB431542). NLC/H(D + F + S) NPs successfully inhibited breast cancer metastasis by intracellular and extracellular hybrid mechanism. DOX and Fc loaded in NLC/H(D + F + S) NPs effectively enhanced intracellular ROS level to activate ferroptosis pathway, the enhanced ROS also induced the apoptosis pathway and decreased MMP-9 expression to synergize with ferroptosis for tumor therapy. In extracellular site, SB431542 was sequentially released by HPSE-driven, which blocked tumor metastasis by modulating tumor microenvironment, decreasing TAFs activation, and reducing the secretion of TGF-ß. In addition, anti-tumor immune response induced by ferroptosis further strengthened the effect of tumor therapy. Finally, under the help of intracellular and extracellular mechanisms launched by NLC/H(D + F + S) NPs, the satisfactory anti-tumor metastasis effect was obtained in the in vivo anti-tumor assays. Therefore, NLC/H(D + F + S) NPs was a novel dosage regimen for breast cancer therapy through intracellular and extracellular mechanisms, in which ferroptosis induced by ROS played an important role.

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