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BACKGROUND: Diaphragmatic paralysis is typically associated with phrenic nerve injury. Neonatal diaphragmatic paralysis diagnosis is easily missed because its manifestations are variable and usually nonspecific. CASE SUMMARY: We report a 39-week-old newborn delivered via vaginal forceps who presented with tachypnea but without showing other birth-trauma-related manifestations. The infant was initially diagnosed with pneumonia. However, the newborn still exhibited tachypnea despite effective antibiotic treatment. Chest radiography revealed right diaphragmatic elevation. M-mode ultrasonography revealed decreased movement of the right diaphragm. The infant was subsequently diagnosed with diaphragmatic paralysis. After 4 weeks, tachypnea improved. Upon re-examination using M-mode ultrasonography, the difference in bilateral diaphragmatic muscle movement was smaller than before. CONCLUSION: Appropriate use of M-mode ultrasound to quantify diaphragmatic excursions could facilitate timely diagnosis and provide objective evaluation.
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Metal-based chemoimmunotherapy has recently garnered significant attention for its capacity to stimulate tumor-specific immunity beyond direct cytotoxic effects. Such effects are usually caused by ICD via the activation of DAMP signals. However, metal complexes that can elicit antitumor immune responses other than ICD have not yet been described. Herein, we report that a rhodium complex (Rh-1) triggers potent antitumor immune responses by downregulating Wnt/ß-catenin signaling with subsequent activation of T lymphocyte infiltration to the tumor site. The results of mechanistic experiments suggest that ROS accumulation following Rh-1 treatment is a critical trigger of a decrease in ß-catenin and enhanced secretion of CCL4, a key mediator of T cell infiltration. Through these properties, Rh-1 exerts a synergistic effect in combination with PD-1 inhibitors against tumor growth in vivo. Taken together, our work describes a promising metal-based antitumor agent with a noncanonical mode of action to sensitize tumor tissues to ICB therapy.
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Developing anticancer drugs with low side effects is an ongoing challenge. Immunogenic cell death (ICD) has received extensive attention as a potential synergistic modality for cancer immunotherapy. However, only a limited set of drugs or treatment modalities can trigger an ICD response and none of them have cytotoxic selectivity. This provides an incentive to explore strategies that might provide more effective ICD inducers free of adverse side effects. Here, we report a metal-based complex (Cu-1) that disrupts cellular redox homeostasis and effectively stimulates an antitumor immune response with high cytotoxic specificity. Upon entering tumor cells, this Cu(II) complex enhances the production of intracellular radical oxidative species while concurrently depleting glutathione (GSH). As the result of heightening cellular oxidative stress, Cu-1 gives rise to a relatively high cytotoxicity to cancer cells, whereas normal cells with low levels of GSH are relatively unaffected. The present Cu(II) complex initiates a potent ferroptosis-dependent ICD response and effectively inhibits in vivo tumor growth in an animal model (c57BL/6 mice challenged with colorectal cancer). This study presents a strategy to develop metal-based drugs that could synergistically potentiate cytotoxic selectivity and promote apoptosis-independent ICD responses through perturbations in redox homeostasis.
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Cobre , Glutatión , Homeostasis , Oxidación-Reducción , Animales , Ratones , Humanos , Glutatión/metabolismo , Ratones Endogámicos C57BL , Antineoplásicos/farmacología , Línea Celular Tumoral , Estrés Oxidativo/efectos de los fármacos , Sinergismo Farmacológico , Muerte Celular Inmunogénica/efectos de los fármacos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Ferroptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismoRESUMEN
The development and optimization of metal-based anticancer drugs with novel cytotoxic mechanisms have emerged as key strategies to overcome chemotherapeutic resistance and side effects. Agents that simultaneously induce ferroptosis and autophagic death have received extensive attention as potential modalities for cancer therapy. However, only a limited set of drugs or treatment modalities can synergistically induce ferroptosis and autophagic tumor cell death. In this work, we designed and synthesized four new cycloplatinated (II) complexes harboring an isoquinoline alkaloid Câ§N ligand. On screening the in vitro activity of these agents, we found that Pt-3 exhibited greater selectivity of cytotoxicity, decreased resistance factors, and improved anticancer activity compared to cisplatin. Furthermore, Pt-3, which we demonstrate can initiate potent ferritinophagy-dependent ferroptosis, exhibits less toxic and better therapeutic activity than cisplatin in vivo. Our results identify Pt-3 as a promising candidate or paradigm for further drug development in cancer treatment.
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Antineoplásicos , Ferroptosis , Isoquinolinas , Neoplasias de la Mama Triple Negativas , Ferroptosis/efectos de los fármacos , Humanos , Isoquinolinas/farmacología , Isoquinolinas/química , Isoquinolinas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Animales , Femenino , Línea Celular Tumoral , Ferritinas/metabolismo , Autofagia/efectos de los fármacos , Ratones , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Alcaloides/farmacología , Alcaloides/química , Alcaloides/síntesis química , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacos , Ratones DesnudosRESUMEN
A platinum(ii) complex containing an aminophosphonate ligand preferentially accumulates in the endoplamic reticulum (ER) in association with potent ER stress and reactive oxygen species generation, followed by the activation of damage-associated molecular pattern signals and immune responses. Importantly, the Pt complex exhibits potent anti-tumour activities in two independent mouse models via an immunogenic cell death pathway.
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Antineoplásicos Inmunológicos/farmacología , Ésteres/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Organofosfonatos/farmacología , Compuestos Organoplatinos/farmacología , Animales , Antineoplásicos Inmunológicos/química , Muerte Celular/efectos de los fármacos , Ésteres/química , Humanos , Ligandos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/patología , Organofosfonatos/química , Compuestos Organoplatinos/químicaRESUMEN
Agents with multiple modes of tumor cell death can be effective chemotherapeutic drugs. One example of a bimodal chemotherapeutic approach is an agent that can induce both apoptosis and autophagic death. Thus far, no clinical anticancer drug has been shown to simultaneously induce both these pathways. Mono-functional platinum complexes are potent anticancer drug candidates which act through mechanisms distinct from cisplatin. Here, we describe the synthesis and characterize of two mono-functional platinum complexes containing 8-substituted quinoline derivatives as ligands. In comparison to cisplatin, n-Mon-Pt-1 exhibited a greater in vitro cytotoxicity, was more effective in resistant cells and elicited a better anticancer effect. Mechanistic experiments indicate that n-Mon-Pt-1 mainly accumulates in mitochondria, and stimulates significant TrxR inhibition, ROS release and an ER stress response, ultimately resulting in a simultaneous induction of apoptosis and autophagy. Importantly, compared to cisplatin, n-Mon-Pt-1 exhibits lower acute toxicity and better anticancer activity in a murine tumor model.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos Organoplatinos/farmacología , Células A549 , Animales , Antineoplásicos/síntesis química , Apoptosis/genética , Autofagia/genética , Línea Celular , Línea Celular Tumoral , Cisplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Factor 2 Eucariótico de Iniciación/genética , Factor 2 Eucariótico de Iniciación/metabolismo , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Compuestos Organoplatinos/síntesis química , Quinolinas/química , Especies Reactivas de Oxígeno/agonistas , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Tiorredoxina Reductasa 1/genética , Tiorredoxina Reductasa 1/metabolismo , Factor de Transcripción CHOP/genética , Factor de Transcripción CHOP/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismoRESUMEN
Agents with multiple modes of tumor cell death can be effective chemotherapeutic drugs. One example of a bimodal chemotherapeutic approach is an agent that can induce both apoptosis and autophagic death. Thus far, no clinical anticancer drug has been shown to simultaneously induce both these pathways. Mono-functional platinum complexes are potent anticancer drug candidates which act through mechanisms distinct from cisplatin. Here, we describe the synthesis and characterize of two mono-functional platinum complexes containing 8-substituted quinoline derivatives as ligands, [PtL1Cl]Cl [L1 = (Z)-1-(pyridin-2-yl)-N-(quinolin-8-ylmethylene) methanamine] (Mon-Pt-1) and [PtL2Cl]Cl [L2 = (Z)-2-(pyridin-2-yl)-N-(quinolin-8-ylmethylene) ethanamine] (Mon-Pt-2). In comparison to cisplatin, Mon-Pt-2 exhibited a greater in vitro cytotoxicity, was more effective in resistant cells and elicited a better anticancer effect. Mechanistic experiments indicate that Mon-Pt-2 mainly accumulates in mitochondria, and stimulates significant TrxR inhibition ROS release and an ER stress response, mediated by mitochondrial dysfunction, ultimately resulting in a simultaneous induction of apoptosis and autophagy. Importantly, compared to cisplatin, Mon-Pt-2 exhibits lower acute toxicity and better anticancer activity in a murine tumor model. To the best of our knowledge, Mon-Pt-2 is the first mono-functional platinum complex inducing pro-death autophagy and apoptosis of cancer cells.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Retículo Endoplásmico/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Células A549 , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Ratones , Ratones Endogámicos , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Relación Estructura-ActividadRESUMEN
Agents inducing both apoptosis and autophagic death can be effective chemotherapeutic drugs. In our present work, we synthesized two organometallic gold(III) complexes harboring C^N ligands that structurally resemble tetrahydroisoquinoline (THIQ): Cyc-Au-1 (AuL1Cl2, L1 = 3,4-dimethoxyphenethylamine) and Cyc-Au-2 (AuL2Cl2, L2 = methylenedioxyphenethylamine). In screening their in vitro activity, we found both gold complexes exhibited lower toxicity, lower resistance factors, and better anticancer activity than those of cisplatin. The organometallic gold(III) complexes accumulate in mitochondria and induce elevated ROS and an ER stress response through mitochondrial dysfunction. These effects ultimately result in simultaneous apoptosis and autophagy. Importantly, compared to cisplatin, Cyc-Au-2 exhibits lower toxicity and better anticancer activity in a murine tumor model. To the best of our knowledge, Cyc-Au-2 is the first organometallic Au(III) compound that induces apoptosis and autophagic death. On the basis of our results, we believe Cyc-Au-2 to be a promising anticancer agent or lead compound for further anticancer drug development.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Complejos de Coordinación/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Tetrahidroisoquinolinas/farmacología , Células A549 , Adenocarcinoma Bronquioloalveolar/tratamiento farmacológico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Complejos de Coordinación/síntesis química , Complejos de Coordinación/uso terapéutico , Complejos de Coordinación/toxicidad , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ligandos , Masculino , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Estructura Molecular , Especies Reactivas de Oxígeno/metabolismo , Tetrahidroisoquinolinas/química , Tetrahidroisoquinolinas/uso terapéutico , Tetrahidroisoquinolinas/toxicidad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Four µ2-Cl bridged dinuclear metal complexes with isoquinoline ligands, (MPDQ)2Zn2Cl4 (1) (MPDQ=4.5-methylenedioxy-1-pyridinedihydroisoquinoline), (PYP)2Zn2Cl4 (2) (PYP=5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline), (MPDQ)2Mn2Cl4 (3),and (PYP)2Mn2Cl4 (4) were synthesized and characterized. All complexes exhibited strong proliferation inhibition activity against various cancer cells. The underlying molecular mechanisms through which they caused the cancer cell death were also elucidated. Induction of apoptosis in MGC-803 cells by complex 2 was evidenced by annexin V+/PI- detection and DiD/DAPI staining assay. Further investigation revealed that complex 2 was able to induce intrinsic pathway-dependent apoptosis in cancer cells by triggering DNA damage which was caused by the overproduction of reactive oxygen species. Based on these studies, we suggest that Zn(II) complexes containing isoquinoline ligands can be developed as candidates for anti-cancer chemotherapeutics.
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Antineoplásicos/química , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Isoquinolinas/química , Manganeso/química , Zinc/química , Células A549 , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Waste incineration is one of the important atmospheric mercury emission sources. The aim of this article is to explore the atmospheric mercury pollution level of waste incineration industry from Chongqing. This study investigated the mercury emissions from a municipal solid waste incineration plant and a medical waste incineration plant in Chongqing. The exhaust gas samples in these two incineration plants were obtained using USA EPA 30B method. The mercury concentrations in the fly ash and bottom ash samples were analyzed. The results indicated that the mercury concentrations of the municipal solid waste and medical waste incineration plant in Chongqing were (26.4 +/- 22.7) microg x m(-3) and (3.1 +/- 0.8) microg x m(-3) in exhaust gas respectively, (5279.2 +/- 798.0) microg x kg(-1) and (11,709.5 +/- 460.5) microg x kg(-1) in fly ash respectively. Besides, the distribution proportions of the mercury content from municipal solid waste and medical waste in exhaust gas, fly ash, and bottom ash were 34.0%, 65.3%, 0.7% and 32.3%, 67.5%, 0.2% respectively; The mercury removal efficiencies of municipal solid waste and medical waste incineration plants were 66.0% and 67.7% respectively. The atmospheric mercury emission factors of municipal solid waste and medical waste incineration plants were (126.7 +/- 109.0) microg x kg(-1) and (46.5 +/- 12.0) microg x kg(-1) respectively. Compared with domestic municipal solid waste incineration plants in the Pearl River Delta region, the atmospheric mercury emission factor of municipal solid waste incineration plant in Chongqing was lower.
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Contaminantes Atmosféricos/análisis , Atmósfera/análisis , Incineración , Mercurio/análisis , China , Ceniza del Carbón/análisis , Residuos Industriales , Residuos Sanitarios , Residuos SólidosRESUMEN
CONTEXT: As a component of the outer membrane in Gram-negative bacteria, lipopolysaccharide (LPS)-induced proliferation and cell cycle progression of monocytes/macrophages. It has been suggested that the proapoptotic T-cell death-associated gene 51 (TDAG51) might be associated with cell proliferation and cell cycle progression; however, its role in the interaction between LPS and macrophages remains unclear. OBJECTIVE: We attempted to elucidate the role(s) of TDAG51 played in the interaction between LPS and macrophages. MATERIALS AND METHODS: We investigated TDAG51 expression in RAW264.7 cells stimulated with LPS and examined the effects of RNA interference-mediated TDAG51 down-regulation. We used CCK-8 assay and flow cytometry analysis to evaluate the interaction between TDAG51 and LPS-induced proliferation and cell cycle progression in RAW264.7 cells. RESULTS: Our findings indicate that TDAG51 is up-regulated in LPS-stimulated RAW264.7 cells, the TDAG51 siRNA effectively reduced TDAG51 protein up-regulation following LPS stimulation in RAW264.7 cells, the significant changes of the proliferation and cell cycle progression of RAW264.7 cells in TDAG51 Knockdown RAW264.7 cells treated with LPS were observed. CONCLUSION: These findings suggested that TDAG51 up-regulation is a dependent event during LPS-mediated proliferation and cell cycle progression, and which increase our understanding of the interaction mechanism between LPS and macrophages.
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Ciclo Celular/efectos de los fármacos , Lipopolisacáridos/farmacología , Macrófagos/metabolismo , Factores de Transcripción/biosíntesis , Regulación hacia Arriba/efectos de los fármacos , Animales , Línea Celular , RatonesRESUMEN
Municipal solid waste (MSW) incineration is one of the most important atmospheric mercury emission sources. To investigate the mercury concentrations of MSW and mercury emission characteristics in incineration plants, this study analyzed the MSW sampled in 3 typical MSW incineration plants in Shanghai, Guangzhou and Wuhu respectively. The exhaust gas samples in incineration plants were sampled by using OH (Ontario Hydro) method. The mercury concentrations in fly ash, and bottom ash samples were also analyzed. The results indicated that mercury concentrations of MSW in Shanghai, Guangzhou, and Wuhu incineration plants were (0.39±0.04) mg·kg-1, (0.57±0.05) mg·kg-1, and (0.27±0.08) mg·kg-1 respectively. The mercury concentrations of exhaust gas in Guangzhou, Wuhu MSW incineration plants were (9.5±3.9) µg·m-3 and (24.1±6.0) µg·m-3 respectively; Particulate mercury (Hgp), gaseous oxidized mercury (Hg2+), and gaseous elemental mercury (Hg0) represented (0.9±0.8)%, (89.0±5.4)%, (10.1±4.6)% in Guangzhou MSW incineration plant, and (1.0±0.8)%, (65.4±27.6)%, (33.6±27.5)% in Wuhu MSW incineration plant, respectively. Gaseous oxidized mercury (Hg2+) of exhaust gas in different incineration process showed different distribution proportions. Besides, mercury removal efficiency of Guangzhou, Wuhu MWS incineration plants was 96.7% and 33.7%, respectively. The atmospheric mercury emission factors of Shanghai, Guangzhou, and Wuhu MSW incineration plants were (0.156±0.016) mg·kg-1, (0.019±0.002) mg·kg-1, (0.178±0.027) mg·kg-1 respectively. Compared with MSW incineration plants in Japan and Korea, the atmospheric mercury emission factor of Guangzhou incineration plant was slightly lower; Atmospheric mercury emission factors of Shanghai and Wuhu MSW incineration plants were close to those of domestic fractional MSW incineration plants.
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BACKGROUND: Angiotensin II (Ang II), a principal effector of renin-angiotensin system (RAS) and increased in aging tissues, can stimulate JAK/STAT pathway via the G-protein-coupled Ang II receptor type I (AT1) and induce nuclear translocation of signal transducers and activators of transcription (STAT). To further explore the role of Ang II in aging, we examined the effect of Ang II on human replicative senescent diploid fibroblast WI-38 cells. METHODS: Human senescent WI-38 cells were incubated with Ang II, receptor antagonist PD123319, valsartan, STAT3 sense plasmid, and/or STAT3 antisense plasmids. Methods were applied including electrophoretic mobility shift assay (EMSA), Western blot, transfection, and laser scanning confocal microscopy. RESULTS: It was found that cultured human senescent WI-38 cells constitutively expressed tissue inhibitor of metalloproteinase-1 (TIMP-1), and Ang II induced TIMP-1 protein expression in both time- and dose-dependent manners. Ang II induced STAT-DNA binding activity also in both time- and dose-dependent manners. And supershift assay showed that the sis-inducing factor (SIF) band contained STAT3 proteins. STAT3 antisense oligonucleotides could inhibit both Ang II-induced STAT3-DNA binding activity as well as TIMP-1 expression. CONCLUSION: Ang II could up-regulate TIMP-1 expression through activating STAT3 signal pathway in human senescent cells, indicating that Ang II-STAT3-TIMP-1 pathway may be involved in the mechanism of sclerosis in aging tissues.
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Angiotensina II/farmacología , Senescencia Celular , Factor de Transcripción STAT3/fisiología , Inhibidor Tisular de Metaloproteinasa-1/genética , Células Cultivadas , ADN/metabolismo , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Humanos , Sistema de Señalización de MAP Quinasas , Regulación hacia ArribaRESUMEN
The dorsal horn of the spinal cord consists of distinct laminae that serve as a pivotal region for relaying a variety of somatosensory signals such as temperature, pain, and touch. The molecular mechanisms underlying the development of the dorsal horn are poorly understood. To define a molecular map of the dorsal horn circuit, we have profiled dorsal horn-enriched (DHE) gene expression in dorsal spinal cords on embryonic day 15.5 (E15.5) by genome-wide microarray and smart subtractive screening based on polymerase chain reaction (PCR). High-throughput in situ hybridization (ISH) was carried out to validate the expression of 379 genes in the developing dorsal spinal cord. A total of 113 DHE genes were identified, of which 59% show lamina-specific expression patterns. Most lamina-specific genes were expressed across at least two laminae, however. About 32% of all DHE genes are transcription factors, which represent the largest percentage of the group of all DHE functional classifications. Importantly, several individual lamina-specific transcription factors such c-Maf, Rora, and Satb1 are identified for the first time. Epistasis studies revealed several putative effectors of known DHE transcription factors such as Drg11, Tlx3(Rnx), and Lmx1b. These effector genes, including Grp, Trpc3, Pcp4, and Enc1, have been implicated in synaptic transmission, calcium homeostasis, and structural function and thus may have similar roles in the dorsal horn. The identification of a large number of DHE genes, especially those that are lamina specific, lays a foundation for future studies on the molecular machinery that controls the development of the dorsal horn and on functional differences of these distinct laminae in the dorsal spinal cord.