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Background: Breast cancer (BC) is one of the most frequently observed malignancies globally, yet drug development for BC has been encountering escalating challenges. Commiphora myrrha is derived from the dried resin of C. myrrha (T. Nees) Engl., and is widely adopted in China for treating BC. However, the anti-BC effect and underlying mechanism of C. myrrha remain largely unclear. Methods: MTT assay, EdU assay, and colony formation were used to determine the effect of C. myrrha n-hexane extract (CMHE) on the proliferation of human BC cells. Cell cycle distribution and apoptosis were assessed via flow cytometry analysis. Moreover, metastatic potential was evaluated using wound-scratch assay and matrigel invasion assay. The 4T1 breast cancer-bearing mouse model was established to evaluate the anti-BC efficacy of CMHE in vivo. RNA-sequencing analysis, quantitative real-time PCR, immunoblotting, immunohistochemical analysis, RNA interference assay, and database analysis were conducted to uncover the underlying mechanism of the anti-BC effect of CMHE. Results: We demonstrated the significant inhibition in the proliferative capability of BC cell lines MDA-MB-231 and MCF-7 by CMHE. Moreover, CMHE-induced G0/G1 phase arrest and apoptosis of the above two BC cell lines were also observed. CMHE dramatically repressed the metastatic potential of these two cells in vitro. Additionally, the administration of CMHE remarkably suppressed tumor growth in 4T1 tumor-bearing mice. No obvious toxic or side effects of CMHE administration in mice were noted. Furthermore, immunohistochemical (IHC) analysis demonstrated that CMHE treatment inhibited the proliferative and metastatic abilities of cancer cells, while also promoting apoptosis in the tumor tissues of mice. Based on RNA sequencing analysis, quantitative real-time PCR, immunoblotting, and IHC assay, the administration of CMHE downregulated Cyclin D1/CDK4-Rb signaling pathway in BC. Furthermore, RNA interference assay and database analysis showed that downregulated Cyclin D1/CDK4 signaling cascade participated in the anti-BC activity of CMHE. Conclusion: CMHE treatment resulted in the suppression of BC cell growth through the stimulation of cell cycle arrest at the G0/G1 phase and the induction of apoptotic cell death via the inhibition of the Cyclin D1/CDK4-Rb pathway, thereby enhancing the anti-BC effect of CMHE. CMHE has potential anti-BC effects, particularly in those harboring aberrant activation of Cyclin D1/CDK4-Rb signaling.
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The emergence of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b viruses and their transmission to dairy cattle and animals, including humans, poses a major global public health threat. Therefore, the development of effective vaccines and therapeutics against H5N1 clade 2.3.4.4b virus is considered a public health priority. In the United States, three H5N1 vaccines derived from earlier strains of HPAI H5N1 (A/Vietnam, clade 1, and A/Indonesia, clade 2.1) virus, with (MF59 or AS03) or without adjuvants, are licensed and stockpiled for pre-pandemic preparedness, but whether they can elicit neutralizing antibodies against circulating H5N1 clade 2.3.4.4b viruses is unknown. In this study, we evaluated the binding, hemagglutination inhibition and neutralizing antibody response generated after vaccination of adults with the three licensed vaccines. Individuals vaccinated with the two adjuvanted licensed H5N1 vaccines generated cross-reactive binding and cross-neutralizing antibodies against the HPAI clade 2.3.4.4b A/Astrakhan/3212/2020 virus. Seroconversion rates of 60-95% against H5 clade 2.3.4.4b were observed after two doses of AS03-adjuvanted-A/Indonesia or three doses of MF59-adjuvanted-A/Vietnam vaccine. These findings suggest that the stockpiled US-licensed adjuvanted H5N1 vaccines generate cross-neutralizing antibodies against circulating HPAI H5N1 clade 2.3.4.4b in humans and may be useful as bridging vaccines until updated H5N1 vaccines become available.
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Breast cancer (BC) remains a significant health concern for women globally, prompting the relentless pursuit of novel therapeutic modalities. As a traditional Chinese medicine, Boswellia carterii has been extensively used to treat various cancers, such as BC. However, the anti-BC effect and underlying mechanism of Boswellia carterii remain largely unclear. The aim of this study is to explore the therapeutic effect of Boswellia carterii n-hexane extract (BCHE) against BC as well as its underlying mechanism. The present study showed that BCHE significantly suppressed the viability of human BC cells. Moreover, BCHE exhibited potent anti-BC activity in vivo with no significant toxic effects. Additionally, BCHE induced ferroptosis via increased Transferrin expression and the intracellular accumulation of Fe2+, as well as decreased glutathione peroxidase 4 (GPX4) expression and the upregulation of reactive oxygen species (ROS)-induced lipid peroxidation in BC cells. In vivo experimental results also demonstrated that BCHE effectively induced ferroptosis through GPX4 downregulation and Transferrin upregulation in tumor-bearing mice. Overall, BCHE inhibited the growth of BC cells by inducing ferroptosis mediated by modulating the iron accumulation pathway and the lipid peroxidation pathway. Therefore, BCHE could serve as a potential ferroptosis-targeting drug for treating BC.
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Boswellia , Neoplasias da Mama , Ferroptose , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Extratos Vegetais , Transferrina , Ferroptose/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Animais , Transferrina/metabolismo , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Linhagem Celular Tumoral , Boswellia/química , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proliferação de Células/efeitos dos fármacos , Hexanos/química , Regulação para Baixo/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos Nus , Camundongos Endogâmicos BALB CRESUMO
Sclerotinia stem rot (SSR), caused by the necrotrophic fungus Sclerotinia sclerotiorum, is one of the most devastating diseases for several major oil-producing crops. Despite its impact, the genetic basis of SSR resistance in plants remains poorly understood. Here, through a genome-wide association study, we identify a key gene, BnaA07. MKK9, that encodes a mitogen-activated protein kinase kinase that confers SSR resistance in oilseed rape. Our functional analyses reveal that BnaA07.MKK9 interacts with BnaC03.MPK3 and BnaC03.MPK6 and phosphorylates them at the TEY activation motif, triggering a signaling cascade that initiates biosynthesis of ethylene, camalexin, and indole glucosinolates, and promotes accumulation of H2O2 and the hypersensitive response, ultimately conferring resistance. Furthermore, variations in the coding sequence of BnaA07.MKK9 alter its kinase activity and improve SSR resistance by ~30% in cultivars carrying the advantageous haplotype. These findings enhance our understanding of SSR resistance and may help engineer novel diversity for future breeding of oilseed rape.
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Ascomicetos , Brassica napus , Resistência à Doença , Estudo de Associação Genômica Ampla , Doenças das Plantas , Proteínas de Plantas , Ascomicetos/genética , Ascomicetos/patogenicidade , Doenças das Plantas/microbiologia , Doenças das Plantas/imunologia , Doenças das Plantas/genética , Resistência à Doença/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Brassica napus/microbiologia , Brassica napus/genética , Brassica napus/imunologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Regulação da Expressão Gênica de Plantas , Fosforilação , Variação GenéticaRESUMO
Lipid droplets (LDs) are cellular organelles derived from the endoplasmic reticulum (ER), serving as lipid storage sites crucial for maintaining cellular lipid homeostasis. Recent attention has been drawn to their roles in viral replication and their interactions with viruses. However, the precise biological functions of LDs in viral replication and pathogenesis remain incompletely understood. To elucidate the interaction between LDs and viruses, it is imperative to comprehend the biogenesis of LDs and their dynamic interactions with other organelles. In this review, we explore the intricate pathways involved in LD biogenies within the cytoplasm, encompassing the uptake of fatty acid from nutrients facilitated by CD36-mediated membranous protein (FABP/FATP)-FA complexes, and FA synthesis via glycolysis in the cytoplasm and the TCL cycle in mitochondria. While LD biogenesis primarily occurs in the ER, matured LDs are intricately linked to multiple organelles. Viral infections can lead to diverse consequences in terms of LD status within cells post-infection, potentially involving the breakdown of LDs through the activation of lipophagy. However, the exact mechanisms underlying LD destruction or accumulation by viruses remain elusive. The significance of LDs in viral replication renders them effective targets for developing broad-spectrum antivirals. Moreover, considering that reducing neutral lipids in LDs is a strategy for anti-obesity treatment, LD depletion may not pose harm to cells. This presents LDs as promising antiviral targets for developing therapeutics that are minimally or non-toxic to the host.
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The gut microbiota, known as the "forgotten organ" and "human second genome," comprises a complex microecosystem. It significantly influences the development of various tumors, including colorectal, liver, stomach, breast, and lung cancers, through both direct and indirect mechanisms. These mechanisms include the "gut-liver" axis, the "lung-intestine" axis, and interactions with the immune system. The intestinal flora exhibits dual roles in cancer, both promoting and suppressing its progression. Traditional Chinese medicine (TCM) can alter cancer progression by regulating the intestinal flora. It modifies the intestinal flora's composition and structure, along with the levels of endogenous metabolites, thus affecting the intestinal barrier, immune system, and overall body metabolism. These actions contribute to TCM's significant antitumor effects. Moreover, the gut microbiota metabolizes TCM components, enhancing their antitumor properties. Therefore, exploring the interaction between TCM and the intestinal flora offers a novel perspective in understanding TCM's antitumor mechanisms. This paper succinctly reviews the association between gut flora and the development of tumors, including colorectal, liver, gastric, breast, and lung cancers. It further examines current research on the interaction between TCM and intestinal flora, with a focus on its antitumor efficacy. It identifies limitations in existing studies and suggests recommendations, providing insights into antitumor drug research and exploring TCM's antitumor effectiveness. Additionally, this paper aims to guide future research on TCM and the gut microbiota in antitumor studies.
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Microbioma Gastrointestinal , Medicina Tradicional Chinesa , Neoplasias , Humanos , Neoplasias/microbiologia , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Animais , Medicamentos de Ervas Chinesas/uso terapêuticoRESUMO
The global impact of emerging viral infections emphasizes the urgent need for effective broad-spectrum antivirals. The cellular organelle, lipid droplet (LD), is utilized by many types of viruses for replication, but its reduction does not affect cell survival. Therefore, LD is a potential target for developing broad-spectrum antivirals. In this study, we found that 2-bromopalmitate (2 BP), a previously defined palmitoylation inhibitor, depletes LD across all studied cell lines and exerts remarkable antiviral effects on different coronaviruses. We comprehensively utilized 2 BP, alongside other palmitoylation inhibitors such as cerulenin and 2-fluoro palmitic acid (2-FPA), as well as the enhancer palmostatin B and evaluated their impact on LD and the replication of human coronaviruses (hCoV-229E, hCoV-Oc43) and murine hepatitis virus (MHV-A59) at non-cytotoxic concentrations. While cerulenin and 2-FPA exhibited moderate inhibition of viral replication, 2 BP exhibited a much stronger suppressive effect on MHV-A59 replication, although they share similar inhibitory effects on palmitoylation. As expected, palmostatin B significantly enhanced viral replication, it failed to rescue the inhibitory effects of 2 BP, whereas it effectively counteracted the effects of cerulenin and 2-FPA. This suggests that the mechanism that 2 BP used to inhibit viral replication is beyond palmitoylation inhibition. Further investigations unveil that 2 BP uniquely depletes LDs, a phenomenon not exhibited by 2-FPA and cerulenin. Importantly, the depletion of LDs was closely associated with the inhibition of viral replication because the addition of oleic acid to 2 BP significantly rescued LD depletion and its inhibitory effects on MHV-A59. Our findings indicate that the inhibitory effects of 2 BP on viral replication primarily stem from LD disruption rather than palmitoylation inhibition. Intriguingly, fatty acid (FA) assays demonstrated that 2 BP reduces the FA level in mitochondria while concurrently increasing FA levels in the cytoplasm. These results highlight the crucial role of LDs in viral replication and uncover a novel biological activity of 2 BP. These insights contribute to the development of broad-spectrum antiviral strategies. IMPORTANCE: In our study, we conducted a comparative investigation into the antiviral effects of palmitoylation inhibitors including 2-bromopalmitate (2-BP), 2-fluoro palmitic acid (2-FPA), and cerulenin. Surprisingly, we discovered that 2-BP has superior inhibitory effects on viral replication compared to 2-FPA and cerulenin. However, their inhibitory effects on palmitoylation were the same. Intrigued by this finding, we delved deeper into the underlying mechanism of 2-BP's potent antiviral activity, and we unveiled a novel biological activity of 2-BP: depletion of lipid droplets (LDs). Importantly, we also highlighted the crucial role of LDs in viral replication. Our insights shed new light on the antiviral mechanism of LD depletion paving the way for the development of broad-spectrum antiviral strategies by targeting LDs.
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Antivirais , Coronavirus , Vírus da Hepatite Murina , Palmitatos , Animais , Humanos , Camundongos , Antivirais/farmacologia , Antivirais/metabolismo , Cerulenina/metabolismo , Cerulenina/farmacologia , Coronavirus/efeitos dos fármacos , Coronavirus/fisiologia , Gotículas Lipídicas/efeitos dos fármacos , Palmitatos/farmacologia , Ácido Palmítico/farmacologia , Ácido Palmítico/metabolismo , Propiolactona/análogos & derivados , Replicação Viral/efeitos dos fármacos , Vírus da Hepatite Murina/efeitos dos fármacos , Vírus da Hepatite Murina/fisiologiaRESUMO
BACKGROUND: Usenamine A, a novel natural compound initially isolated from the lichen Usnea longissima, has exhibited promising efficacy against hepatoma in prior investigation. Nevertheless, the underlying mechanisms responsible for its antihepatoma effects remain unclear. Furthermore, the role of the AKT/mechanistic target of the rapamycin (mTOR)/signal transducer and activator of transcription 3 (STAT3)/inhibitor of differentiation/DNA binding 1 (ID1) signaling axis in hepatocellular carcinoma (HCC), and the potential anti-HCC effects of drugs targeting this pathway are not well understood. METHODS: CCK-8 assay was used to investigate the effects of usenamine A on the proliferation of human HCC cells. Moreover, the effects of usenamine A on the invasion ability of human HCC cells were evaluated by transwell assay. In addition, expression profiling analysis, quantitative real-time PCR, immunoblotting, immunohistochemistry (IHC) analysis, RNAi, immunoprecipitation, and chromatin immunoprecipitation (ChIP) assay were used to explore the effects of usenamine A on the newly identified AKT/mTOR/STAT3/ID1 signaling axis in human HCC cells. RESULTS: Usenamine A inhibited the proliferation and invasion of human HCC cell lines (HepG2 and SK-HEP-1). Through the analysis of gene expression profiling, we identified that usenamine A suppressed the expression of ID1 in human HCC cells. Furthermore, immunoprecipitation experiments revealed that usenamine A facilitated the degradation of the ID1 protein via the ubiquitin-proteasome pathway. Moreover, usenamine A inhibited the activity of STAT3 in human HCC cells. ChIP analysis demonstrated that STAT3 positively regulated ID1 expression at the transcriptional level in human HCC cells. The STAT3/ID1 axis played a role in mediating the anti-proliferative and anti-invasive impacts of usenamine A on human HCC cells. Additionally, usenamine A suppressed the STAT3/ID1 axis through AKT/mTOR signaling in human HCC cells. CONCLUSION: Usenamine A displayed robust anti-HCC potential, partly attributed to its capacity to downregulate the AKT/mTOR/STAT3/ID1 signaling pathway and promote ubiquitin-proteasome-mediated ID1 degradation. Usenamine A has the potential to be developed as a therapeutic agent for HCC cases characterized by abnormal AKT/mTOR/STAT3/ID1 signaling, and targeting the AKT/mTOR/STAT3 signaling pathway may be a viable option for treating patients with HCC exhibiting elevated ID1 expression.
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IMPORTANCE: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has tragically claimed millions of lives through coronavirus disease 2019 (COVID-19), and there remains a critical gap in our understanding of the precise molecular mechanisms responsible for the associated fatality. One key viral factor of interest is the SARS-CoV-2 ORF3a protein, which has been identified as a potent inducer of host cellular proinflammatory responses capable of triggering the catastrophic cytokine storm, a primary contributor to COVID-19-related deaths. Moreover, ORF3a, much like the spike protein, exhibits a propensity for frequent mutations, with certain variants linked to the severity of COVID-19. Our previous research unveiled two distinct types of ORF3a mutant proteins, categorized by their subcellular localizations, setting the stage for a comparative investigation into the functional and mechanistic disparities between these two types of ORF3a variants. Given the clinical significance and functional implications of the natural ORF3a mutations, the findings of this study promise to provide invaluable insights into the potential roles undertaken by these mutant ORF3a proteins in the pathogenesis of COVID-19.
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COVID-19 , Retículo Endoplasmático , SARS-CoV-2 , Proteínas Viroporinas , Humanos , COVID-19/virologia , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/virologia , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/virologia , Degradação Associada com o Retículo Endoplasmático , Proteínas Mutantes , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Proteínas Viroporinas/genética , Proteínas Viroporinas/metabolismoRESUMO
Objective: Dengue viruses (DENV) and Zika viruses (ZIKV) are transmitted from human to human or from non-human primates to humans by mosquito biting, so the viral interaction with mosquito cells is one key step within the viral life cycle. Therefore, our objective is to know how DENV or ZIKV interacts with mosquito cells. Methods: Immunofluorescence assay and a direct visualization system are combined to monitor the syncytial or congregative effects of DENVs and ZIKVs on C6/36 cells. we studied the cytopathic effects of DENVs and ZIKVs on the mosquito cells, C6/36 which are widely used in the laboratory for the infections of DENV and ZIKV. Results: Our results show that all strains of DENV-1 and DENV-2, most DENV-4 and some DENV-3 strains caused syncytial effects on C6/36 cells, while some DENV-3 and DENV-4 strains, and all the tested ZIKV strains caused cell congregation after infection but no cell fusion. In addition, we detected a range of pH environments from 6.0 to 8.0 that support the virus-caused cell fusion and figured out that the optimal pH condition is 7.5 at which the viral production is also the best. Furthermore, viral replication may be required for DENV's syncytial effects on C6/36 cells because the UV-inactivated virus failed to cause cell fusion. Conclusion: Syncytial and congregative effects of DENV and ZIKV on the Aedes albopictus cells differ among the viral strains. Syncytial effects of DENV on C6/36 are important for viral replication.
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IMPORTANCE: Coronaviruses are important pathogens of humans and animals, and vaccine developments against them are imperative. Due to the ability to induce broad and prolonged protective immunity and the convenient administration routes, live attenuated vaccines (LAVs) are promising arms for controlling the deadly coronavirus infections. However, potential recombination events between vaccine and field strains raise a safety concern for LAVs. The porcine epidemic diarrhea virus (PEDV) remodeled TRS (RMT) mutant generated in this study replicated efficiently in both cell culture and in pigs and retained protective immunogenicity against PEDV challenge in pigs. Furthermore, the RMT PEDV was resistant to recombination and genetically stable. Therefore, RMT PEDV can be further optimized as a backbone for the development of safe LAVs.
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Infecções por Coronavirus , Vírus da Diarreia Epidêmica Suína , Recombinação Genética , Doenças dos Suínos , Suínos , Vacinas Atenuadas , Vacinas Virais , Animais , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/veterinária , Vírus da Diarreia Epidêmica Suína/genética , Vírus da Diarreia Epidêmica Suína/crescimento & desenvolvimento , Vírus da Diarreia Epidêmica Suína/imunologia , Suínos/imunologia , Suínos/virologia , Doenças dos Suínos/imunologia , Doenças dos Suínos/prevenção & controle , Doenças dos Suínos/virologia , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Vacinas Virais/genética , Vacinas Virais/imunologia , Replicação Viral , Células Cultivadas , MutaçãoRESUMO
Ferroptosis is a non-apoptotic form of regulated cell death characterized by iron-dependent lipid peroxidation. It can be triggered by various mechanisms, including the glutathione peroxidase 4 (GPX4)-glutathione (GSH) axis, iron metabolism, lipid metabolism, the GTP cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) pathway, and the ferroptosis suppressor protein 1 (FSP1)-coenzyme Q10 axis. The redox balance is disrupted when ferroptosis occurs in cells, which is fatal to cancer cells. Additionally, some tumor-associated genes are involved in ferroptosis. Hence, targeting ferroptosis might be an effective strategy for treating cancer. Several small-molecule compounds exhibit anti-tumor effects through ferroptosis, including sorafenib and altretamine, which induce ferroptosis by inhibiting System-Xc and GPX4 respectively, but many problems, such as poor druggability, still exist. Some studies have shown that many traditional Chinese medicine (TCM) induce ferroptosis by inhibiting GPX4, solute carrier family 7 member 11 (SLC7A11), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2), or by increasing the expression of Acyl-CoA synthetase long-chain family member 4 (ACSL4), transferrin (TF), and transferrin receptor 1 (TFR1). These changes can lead to the lysosomal degradation of ferritin, accumulation of iron, lipid peroxidation and the production of reactive oxygen species (ROS), which in turn can promote anti-tumor activities or synergistic effects with chemotherapeutic drugs. In this study, we elucidated the underlying mechanisms of ferroptosis, and the anti-tumor pharmacology of TCM targeting ferroptosis including prescriptions, Chinese herbs, extracts, and natural compounds. Our findings might act as valuable reference for research on anti-tumor drugs targeting ferroptosis, especially those drugs developed from TCM.
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The tumor microenvironment (TME) plays an important role in the development of tumors. Immunoregulatory cells and cytokines facilitate cancer cells to avoid immune surveillance. Overexpression of immune checkpoint molecules such as CTLA-4 and PD-1/PD-L1 inhibits immune function and enables cancer cells to avoid clearance by the immune system. Thus, minimizing tumor immunosuppression could be an important strategy for cancer therapy. Currently, many immune checkpoint-targeted drugs, such as PD-1/PD-L1 inhibitors, have been approved for marketing and have shown unique advantages in the clinical treatment of cancers. The concept of "strengthening resistance to eliminate pathogenic factors" in traditional Chinese medicine (TCM) is consistent with the immunotherapy of cancer. According to previous studies, the role of TCM in tumor immunotherapy is mainly associated with the positive regulation of natural killer cells, CD8/CD4 T cells, dendritic cells, M2 macrophages, interleukin-2, tumor necrosis factor-[Formula: see text], and IFN-[Formula: see text], as well as with the negative regulation of Tregs, myeloid-derived suppressor cells, cancer-associated fibroblasts, PD-1/PD-L1, transforming growth factor-[Formula: see text], and tumor necrosis factor-[Formula: see text]. This paper summarizes the current research on the effect of TCM targeting the TME, and further introduces the research progress on studying the effects of TCM on immune checkpoints. Modern pharmacological studies have demonstrated that TCM can directly or indirectly affect the TME by inhibiting the overexpression of immune checkpoint molecules and enhancing the efficacy of tumor immunotherapy. TCM with immunomodulatory stimulation could be the key factor to achieve benefits from immunotherapy for patients with non-inflammatory, or "cold", tumors.
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Antígeno B7-H1 , Neoplasias , Humanos , Antígeno B7-H1/farmacologia , Medicina Tradicional Chinesa , Proteínas de Checkpoint Imunológico/farmacologia , Receptor de Morte Celular Programada 1 , Neoplasias/patologia , Imunoterapia , Fatores de Necrose Tumoral/farmacologia , Microambiente TumoralRESUMO
Least squares reverse time migration (LSRTM) imaging is the one of the most accurate methods for migration imaging at present, and Polak-Ribiere-Polyak conjugate gradient (PRPCG) for LSRTM has the good numerical performance but weak convergence, so we construct an optimization factor to improve the iteration direction of the gradient, which can automatically generate a sufficient descent direction. The improved PRPCG (IPRPCG) can reduce the data residual values and speed up the iteration. And the illumination preconditioned (IP) operator is employed to IPRPCG-LSRTM which solves the problem of low resolution due to the insufficient iterative gradient information. In this paper, the experiments show that the imaging results of the proposed method (IPRPCG-IP-LSRTM) is improved greatly in detail characterization and events continuity, the iterative curve converged faster significantly, and the normalized data residual was reduced by 6.55% on average, which improved the accuracy of migration imaging effectively.
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The axiparabola is a novel reflective element proposed in recent years, which can generate a long focal line with high peak intensity, and has important applications in laser plasma accelerators. The off-axis design of an axiparabola has the advantage of separating the focus from incident rays. However, an off-axis axiparabola designed by the current method always produces a curved focal line. In this paper, we propose a new method to design its surface by combining geometric optics design and diffraction optics correction, which can effectively convert a curved focal line into a straight foal line. We reveal that the geometric optics design inevitably introduces an inclined wavefront, which leads to the bending of the focal line. To compensate for the tilt wavefront, we use an annealing algorithm to further correct the surface through diffraction integral operation. We also carry out numerical simulation verification based on scalar diffraction theory, which proves that the surface of this off-axis mirror designed by this method can always obtain a straight focal line. This new method has wide applicability in an axiparabola with any off-axis angle.
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Cotton is widely grown in many countries around the world due to the huge economic value of the total natural fiber. Verticillium wilt, caused by the soil-borne pathogen Verticillium dahliae, is the most devastating disease that led to extensive yield losses and fiber quality reduction in cotton crops. Developing resistant cotton varieties through genetic engineering is an effective, economical, and durable strategy to control Verticillium wilt. However, there are few resistance gene resources in the currently planted cotton varieties, which has brought great challenges and difficulties for breeding through genetic engineering. Further revealing the molecular mechanism between V. dahliae and cotton interaction is crucial to discovering genes related to disease resistance. In this review, we elaborated on the pathogenic mechanism of V. dahliae and the resistance mechanism of cotton to Verticillium wilt. V. dahliae has evolved complex mechanisms to achieve pathogenicity in cotton, mainly including five aspects: (1) germination and growth of microsclerotia; (2) infection and successful colonization; (3) adaptation to the nutrient-deficient environment and competition of nutrients; (4) suppression and manipulation of cotton immune responses; (5) rapid reproduction and secretion of toxins. Cotton has evolved multiple physiological and biochemical responses to cope with V. dahliae infection, including modification of tissue structures, accumulation of antifungal substances, homeostasis of reactive oxygen species (ROS), induction of Ca2+ signaling, the mitogen-activated protein kinase (MAPK) cascades, hormone signaling, and PAMPs/effectors-triggered immune response (PTI/ETI). This review will provide an important reference for the breeding of new cotton germplasm resistant to Verticillium wilt through genetic engineering.
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BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of cancer-associated mortality worldwide. Myosin-9's role in HCC and the anti-HCC effect of the drugs targeting Myosin-9 remain poorly understood so far. Candidate antitumor agents obtained from natural products have attracted worldwide attention. Usenamine A is a novel product, which was first extracted in our laboratory from the lichen Usnea longissima. According to published reports, usenamine A exhibits good antitumor activity, while the mechanisms underlying its antitumor effects remain to be elucidated. PURPOSE: The present study investigated the anti-hepatoma effect of usenamine A and the underlying molecular mechanisms, along with evaluating the therapeutic potential of targeting Myosin-9 in HCC. METHODS: The CCK-8, Hoechst staining, and FACS assays were conducted in the present study to investigate how usenamine A affected the growth and apoptosis of human hepatoma cells. Moreover, TEM, acridine orange staining, and immunofluorescence assay were performed to explore the induction of autophagy by usenamine A in human hepatoma cells. The usenamine A-mediated regulation of protein expression in human hepatoma cells was analyzed using immunoblotting. MS analysis, SPR assay, CETSA, and molecular modeling were performed to identify the direct target of usenamine A. Immunofluorescence assay and co-immunoprecipitation assay were conducted to determine whether usenamine A affected the interaction between Myosin-9 and the actin present in human hepatoma cells. In addition, the anti-hepatoma effect of usenamine A was investigated in vivo using a xenograft tumor model and the IHC analysis. RESULTS: The present study initially revealed that usenamine A could suppress the proliferation of HepG2 and SK-HEP-1 cells (hepatoma cell lines). Furthermore, usenamine A induced cell apoptosis via the activation of caspase-3. In addition, usenamine A enhanced autophagy. Moreover, usenamine A administration could dramatically suppress the carcinogenic ability of HepG2 cells, as evidenced by the nude mouse xenograft tumor model. Importantly, it was initially revealed that Myosin-9 was a direct target of usenamine A. Usenamine A could block cytoskeleton remodeling through the disruption of the interaction between Myosin-9 and actin. Myosin-9 participated in suppressing proliferation while inducing apoptosis and autophagy in response to treatment with usenamine A. In addition, Myosin-9 was revealed as a potential oncogene in HCC. CONCLUSIONS: Usenamine A was initially revealed to suppress human hepatoma cells growth by interfering with the Myosin-9/actin-dependent cytoskeleton remodeling through the direct targeting of Myosin-9. Myosin-9 is, therefore, a promising candidate target for HCC treatment, while usenamine A may be utilized as a possible anti-HCC therapeutic, particularly in the treatment of HCC with aberrant Myosin-9.
Assuntos
Morte Celular Autofágica , Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Humanos , Carcinoma Hepatocelular/patologia , Actinas , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Hepáticas/patologia , Apoptose , Células Hep G2 , Proteínas do Citoesqueleto/farmacologia , Proteínas do Citoesqueleto/uso terapêutico , Citoesqueleto/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is extremely malignant in nature. It is an important way to discover anti-cancer drugs from natural products at present. (R)-7,3'-dihydroxy-4'-methoxy-8-methylflavane (DHMMF), a natural flavonoid, was isolated from Resina Draconis which is the red resin from Dracaena cochinchinensis (Lour.) S. C. Chen. However, the anti-hepatoma effect and underlying mechanisms of DHMMF remain unclear. Herein, we demonstrated that DHMMF treatment significantly inhibited the proliferation of human hepatoma HepG2 and SK-HEP-1 cells. The IC50 value of DHMMF for HepG2 and SK-HEP-1 cells were 0.67 µM and 0.66 µM, respectively, while the IC50 value of DHMMF for human normal liver LO2 cells was 120.60 µM. DHMMF induced DNA damage, apoptosis, and G2/M phase arrest in HepG2 and SK-HEP-1 cells. Furthermore, the anti-proliferative and pro-apoptotic effects of DHMMF in human hepatoma cells were mediated by the upregulation of p21. Importantly, DHMMF exhibited potent anti-HCC efficacy in a xenograft mice model and an orthotopic mice model of liver cancer. Additionally, the combined administration of DHMMF and polo-like kinase 1 (PLK1) inhibitor BI 6727 showed a synergistic anti-HCC efficacy. Collectively, we demonstrated that DHMMF treatment induced apoptosis and G2/M phase arrest via DNA damage-driven upregulation of p21 expression in human hepatoma cells. DHMMF may serve as a promising drug candidate for HCC treatment, especially for patients of HCC with low p21 expression. Our results also suggested that DHMMF treatment in combination with PLK1 inhibitor may serve as a potential treatment strategy for patients with HCC.
Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Regulação para Cima , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Proliferação de Células , Células Hep G2 , Antineoplásicos/farmacologia , Apoptose , Dano ao DNA , Divisão CelularRESUMO
The long-focal-depth mirror is a novel reflective element proposed in recent years. Due to the advantages of negligible dependence on wavelength and high damage threshold, it is suitable to focus ultra-short laser pulses with broadband spectra and high intensity with a focal depth of centimeter scale. To the best of our knowledge, the focusing properties of this mirror has been only studied under low numerical aperture (NA). In this paper, we extend it to the case of high NA and it is proved that an accelerating superluminal laser focus can be always generated by this extension, in which the degree of acceleration increases with the increase of NA. And the velocity of laser focus increases approximately linearly from c to 1.6c for NA = 0.707. Due to its properties of tight focusing, the Richards-Wolf integrals have been used to study the intensity distribution of each polarization component for different kinds of incident light. And these are linearly polarized light, radially polarized light, azimuthally polarized light, linearly polarized light with spiral phase, and linearly polarized light with ultrashort pulses. From comparisons of numerical results, the intensity distributions are obviously different for different kind of incident light, and accelerating superluminal laser focus with special structure (such as the hollow conical beam) can be produced under appropriate condition. We believe this study can expand the fields of application for the long-focal-depth mirror.
RESUMO
Gastric cancer (GC) is a malignancy with high morbidity and mortality. Chinese dragon's blood is a traditional Chinese medicine derived from the red resin of Dracaena cochinchinensis (Lour.) S. C. Chen. However, the antigastric cancer effect of Chinese dragon's blood has not yet been reported. Herein, we demonstrated that Chinese dragon's blood ethyl acetate extract (CDBEE) suppressed the proliferative and metastatic potential of human gastric cancer MGC-803 and HGC-27 cells. CDBEE suppressed epithelial-mesenchymal transition in MGC-803 and HGC-27 cells. Moreover, CDBEE induced apoptotic and autophagic cell death in MGC-803 and HGC-27 cells. The cytotoxicity of CDBEE in human gastric epithelial GES-1 cells was dramatically weaker than that in human gastric cancer cells. Mechanistically, the activation of the mitogen-activated protein kinase (MAPK) signalling pathway was involved in the growth inhibition of MGC-803 and HGC-27 cells by CDBEE. Additionally, CDBEE-induced autophagic cell death was mediated by downregulation of the mammalian target of rapamycin (mTOR)-Beclin1 signalling cascade and upregulation of the ATG3/ATG7-LC3 signalling cascade. Importantly, CDBEE exhibited potent anti-GC efficacy in vivo without obvious toxicity or side effects. Therefore, CDBEE may be a promising candidate drug for the treatment of gastric cancer, especially for GC patients with aberrant MAPK signalling or mTOR signalling.