RESUMO
HIV-1 Env mediates viral entry into host cells and is the sole target for neutralizing antibodies. However, Env structure and organization in its native virion context has eluded detailed characterization. Here, we used cryo-electron tomography to analyze Env in mature and immature HIV-1 particles. Immature particles showed distinct Env positioning relative to the underlying Gag lattice, providing insights into long-standing questions about Env incorporation. A 9.1-Å sub-tomogram-averaged reconstruction of virion-bound Env in conjunction with structural mass spectrometry revealed unexpected features, including a variable central core of the gp41 subunit, heterogeneous glycosylation between protomers, and a flexible stalk that allows Env tilting and variable exposure of neutralizing epitopes. Together, our results provide an integrative understanding of HIV assembly and structural variation in Env antigen presentation.
Assuntos
Microscopia Crioeletrônica , Tomografia com Microscopia Eletrônica , Vírion/ultraestrutura , Produtos do Gene env do Vírus da Imunodeficiência Humana/ultraestrutura , Produtos do Gene gag do Vírus da Imunodeficiência Humana/ultraestrutura , 2,2'-Dipiridil/análogos & derivados , 2,2'-Dipiridil/farmacologia , Sequência de Aminoácidos , Dissulfetos/farmacologia , Epitopos/química , Células HEK293 , Proteína gp41 do Envelope de HIV/química , Humanos , Espectrometria de Massa com Troca Hidrogênio-Deutério , Modelos Moleculares , Testes de Neutralização , Peptídeos/química , Polissacarídeos/química , Domínios Proteicos , Estrutura Secundária de Proteína , Subunidades Proteicas/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/químicaRESUMO
The vertebrate host's immune system and resident commensal bacteria deploy a range of highly reactive small molecules that provide a barrier against infections by microbial pathogens. Gut pathogens, such as Vibrio cholerae, sense and respond to these stressors by modulating the expression of exotoxins that are crucial for colonization. Here, we employ mass spectrometry-based profiling, metabolomics, expression assays, and biophysical approaches to show that transcriptional activation of the hemolysin gene hlyA in V. cholerae is regulated by intracellular forms of sulfur with sulfur-sulfur bonds, termed reactive sulfur species (RSS). We first present a comprehensive sequence similarity network analysis of the arsenic repressor superfamily of transcriptional regulators, where RSS and hydrogen peroxide sensors segregate into distinct clusters of sequences. We show that HlyU, transcriptional activator of hlyA in V. cholerae, belongs to the RSS-sensing cluster and readily reacts with organic persulfides, showing no reactivity or DNA dissociation following treatment with glutathione disulfide or hydrogen peroxide. Surprisingly, in V. cholerae cell cultures, both sulfide and peroxide treatment downregulate HlyU-dependent transcriptional activation of hlyA. However, RSS metabolite profiling shows that both sulfide and peroxide treatment raise the endogenous inorganic sulfide and disulfide levels to a similar extent, accounting for this crosstalk, and confirming that V. cholerae attenuates HlyU-mediated activation of hlyA in a specific response to intracellular RSS. These findings provide new evidence that gut pathogens may harness RSS-sensing as an evolutionary adaptation that allows them to overcome the gut inflammatory response by modulating the expression of exotoxins.
Assuntos
Proteínas de Bactérias , Dissulfetos , Exotoxinas , Regulação Bacteriana da Expressão Gênica , Proteínas Hemolisinas , Espaço Intracelular , Compostos de Sulfidrila , Ativação Transcricional , Vibrio cholerae , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Exotoxinas/genética , Exotoxinas/metabolismo , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/metabolismo , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Ativação Transcricional/efeitos dos fármacos , Vibrio cholerae/efeitos dos fármacos , Vibrio cholerae/genética , Vibrio cholerae/metabolismo , Dissulfetos/metabolismo , Dissulfetos/farmacologia , Compostos de Sulfidrila/metabolismo , Compostos de Sulfidrila/farmacologia , Espaço Intracelular/metabolismo , Espectrometria de Massas , Metabolômica , Dissulfeto de Glutationa/farmacologia , Microbioma Gastrointestinal/imunologiaRESUMO
Chemotherapy using a nanoscaled drug delivery system is an effective cancer therapy, but its high drug concentration often causes drug resistance in cancer cells and normal cell damage. Combination therapy involving two or more different cell signaling pathways can be a powerful tool to overcome the limitations of chemotherapy. Herein, this article presents nanogel (NG)-mediated co-delivery of a chemodrug camptothecin (CPT) and mitochondria-targeting monomer (MT monomer) for efficient activation of two modes of the programmed cell death pathway (apoptosis and necroptosis) and synergistic enhancement of cancer therapy. CPT and the monomer are incorporated together into the redox-degradable polymeric NGs for release in response to the intracellular glutathione. The MT monomer is shown to undergo reactive oxygen species (ROS)-triggered disulfide polymerization inside the cancerous mitochondria in cooperation with the chemotherapeutic CPT elevating the intracellular ROS level. The CPT/monomer interconnection in cell death mechanisms for mitochondrial dysfunction and enhanced cell death is evidenced by a series of cell analyses showing ROS generation, mitochondria damage, impacts on (non)cancerous or drug-resistant cells, and cell death modes. The presented work provides beneficial insights for utilizing combination therapy to facilitate a desired cell death mechanism and developing a novel nanosystem for more efficacious cancer treatment.
Assuntos
Dissulfetos , Neoplasias , Polietilenoglicóis , Polietilenoimina , Humanos , Nanogéis , Preparações Farmacêuticas , Dissulfetos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Polimerização , Morte Celular , Neoplasias/tratamento farmacológico , Linhagem Celular Tumoral , Camptotecina/farmacologia , Camptotecina/uso terapêuticoRESUMO
The issue of bacterial infectious diseases remains a significant concern worldwide, particularly due to the misuse of antibiotics, which has caused the emergence of antibiotic-resistant strains. Fortunately, the rapid development of nanomaterials has propelled significant progress in antimicrobial therapy, offering promising solutions. Among them, the utilization of nanoenzyme-based chemodynamic therapy (CDT) has become a highly hopeful approach to combating bacterial infectious diseases. Nevertheless, the application of CDT appears to be facing certain constraints for its low efficiency in the Fenton reaction at the infected site. In this study, we have successfully synthesized a versatile nanozyme, which was a composite of molybdenum sulfide (MoS2) and iron sulfide (FeS2), through the hydrothermal method. The results showed that iron/molybdenum sulfide nanozymes (Fe/Mo SNZs) with desirable peroxidase (POD) mimic activity can generate cytotoxic reactive oxygen species (ROS) by successfully triggering the Fenton reaction. The presence of MoS2 significantly accelerates the conversion of Fe2+/Fe3+ through a cocatalytic reaction that involves the participation of redox pairs of Mo4+/Mo6+, thereby enhancing the efficiency of CDT. Additionally, based on the excellent photothermal performance of Fe/Mo SNZs, a near-infrared (NIR) laser was used to induce localized temperature elevation for photothermal therapy (PTT) and enhance the POD-like nanoenzymatic activity. Notably, both in vitro and in vivo results demonstrated that Fe/Mo SNZs with good broad-spectrum antibacterial properties can help eradicate Gram-negative bacteria like Escherichia coli and Gram-positive bacteria like Staphylococcus aureus. The most exciting thing is that the synergistic PTT/CDT exhibited astonishing antibacterial ability and can achieve complete elimination of bacteria, which promoted wound healing after infection. Overall, this study presents a synergistic PTT/CDT strategy to address antibiotic resistance, providing avenues and directions for enhancing the efficacy of wound healing treatments and offering promising prospects for further clinical use in the near future.
Assuntos
Antibacterianos , Dissulfetos , Ferro , Molibdênio , Sulfetos , Cicatrização , Molibdênio/química , Molibdênio/farmacologia , Cicatrização/efeitos dos fármacos , Sulfetos/química , Sulfetos/farmacologia , Animais , Dissulfetos/química , Dissulfetos/farmacologia , Ferro/química , Ferro/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Catálise , Staphylococcus aureus/efeitos dos fármacos , Camundongos , Escherichia coli/efeitos dos fármacos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Nanoestruturas/química , Fototerapia , Testes de Sensibilidade Microbiana , Terapia Fototérmica , Compostos FerrososRESUMO
Human Hippo signaling pathway is an evolutionarily conserved regulator network that controls organ development and has been implicated in various cancers. Transcriptional enhanced associate domain-4 (TEAD4) is the final nuclear effector of Hippo pathway, which is activated by Yes-associated protein (YAP) through binding to two separated YAP regions of α1-helix and Ω-loop. Previous efforts have all been addressed on deriving peptide inhibitors from the YAP to target TEAD4. Instead, we herein attempted to rationally design a so-called 'YAP helixα1-trap' based on the TEAD4 to target YAP by using dynamics simulation and energetics analysis as well as experimental assays at molecular and cellular levels. The trap represents a native double-stranded helical hairpin covering a specific YAP-binding site on TEAD4 surface, which is expected to form a three-helix bundle with the α1-helical region of YAP, thus competitively disrupting TEAD4-YAP interaction. The hairpin was further stapled by a disulfide bridge across its two helical arms. Circular dichroism characterized that the stapling can effectively constrain the trap into a native-like structured conformation in free state, thus largely minimizing the entropy penalty upon its binding to YAP. Affinity assays revealed that the stapling can considerably improve the trap binding potency to YAP α1-helix by up to 8.5-fold at molecular level, which also exhibited a good tumor-suppressing effect at cellular level if fused with TAT cell permeation sequence. In this respect, it is considered that the YAP helixα1-trap-mediated blockade of Hippo pathway may be a new and promising therapeutic strategy against cancers.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Antineoplásicos , Proteínas de Ligação a DNA , Simulação de Dinâmica Molecular , Proteínas Musculares , Fatores de Transcrição de Domínio TEA , Fatores de Transcrição , Proteínas de Sinalização YAP , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Humanos , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Proteínas Musculares/química , Proteínas Musculares/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Dissulfetos/química , Dissulfetos/farmacologia , Ligação Proteica , Sítios de Ligação , Linhagem Celular Tumoral , Desenho Assistido por Computador , Desenho de FármacosRESUMO
BACKGROUND: Molybdenum disulfide (MoS2) has excellent physical and chemical properties. Further, chiral MoS2 (CMS) exhibits excellent chiroptical and enantioselective effects, and the enantioselective properties of CMS have been studied for the treatment of neurodegenerative diseases. Intriguingly, left- and right-handed materials have different effects on promoting the differentiation of neural stem cells into neurons. However, the effect of the enantioselectivity of chiral materials on peripheral nerve regeneration remains unclear. METHODS: In this study, CMS@bacterial cellulose (BC) scaffolds were fabricated using a hydrothermal approach. The CMS@BC films synthesized with L-2-amino-3-phenyl-1-propanol was defined as L-CMS. The CMS@BC films synthesized with D-2-amino-3-phenyl-1-propanol was defined as D-CMS. The biocompatibility of CMS@BC scaffolds and their effect on Schwann cells (SCs) were validated by cellular experiments. In addition, these scaffolds were implanted in rat sciatic nerve defect sites for three months. RESULTS: These chiral scaffolds displayed high hydrophilicity, good mechanical properties, and low cytotoxicity. Further, we found that the L-CMS scaffolds were superior to the D-CMS scaffolds in promoting SCs proliferation. After three months, the scaffolds showed good biocompatibility in vivo, and the nerve conducting velocities of the L-CMS and D-CMS scaffolds were 51.2 m/s and 26.8 m/s, respectively. The L-CMS scaffolds showed a better regenerative effect than the D-CMS scaffolds. Similarly, the sciatic nerve function index and effects on the motor and electrophysiological functions were higher for the L-CMS scaffolds than the D-CMS scaffolds. Finally, the axon diameter and myelin sheath thickness of the regenerated nerves were improved in the L-CMS group. CONCLUSION: We found that the CMS@BC can promote peripheral nerve regeneration, and in general, the L-CMS group exhibited superior repair performance. Overall, the findings of this study reveal that CMS@BC can be used as a chiral nanomaterial nerve scaffold for peripheral nerve repair.
Assuntos
Celulose , Dissulfetos , Molibdênio , Regeneração Nervosa , Células de Schwann , Alicerces Teciduais , Regeneração Nervosa/efeitos dos fármacos , Animais , Ratos , Alicerces Teciduais/química , Dissulfetos/química , Dissulfetos/farmacologia , Células de Schwann/efeitos dos fármacos , Molibdênio/química , Molibdênio/farmacologia , Celulose/química , Celulose/farmacologia , Celulose/análogos & derivados , Ratos Sprague-Dawley , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiologia , Proliferação de Células/efeitos dos fármacos , Engenharia Tecidual/métodos , Masculino , Traumatismos dos Nervos Periféricos , EstereoisomerismoRESUMO
Allicin (AL) is one of garlic-derived organosulfides and has a variety of pharmacological effects. Studies have reported that AL has notable inhibitory effects on liver cancer, gastric cancer, breast cancer, and other cancers. However, there are no relevant reports about its role in human nasopharyngeal carcinoma. Ferroptosis is an iron-dependent form of non-apoptotic regulated cell death. Increasing evidence indicates that induction of ferroptosis can inhibit the proliferation, migration, invasion, and survival of various cancer cells, which act as a tumor suppressor in cancer. In this study, we confirmed that AL can inhibit cell proliferation, migration, invasion, and survival in human nasopharyngeal carcinoma cells. Our finding shows that AL can induce the ferroptosis axis by decreasing the level of GSH and GPX4 and promoting the induction of toxic LPO and ROS. AL-mediated cytotoxicity in human nasopharyngeal carcinoma cells is dependent on ferroptosis. Therefore, AL has good anti-cancer properties and is expected to be a potential drug for the treatment of nasopharyngeal carcinoma.
Assuntos
Proliferação de Células , Dissulfetos , Ferroptose , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Espécies Reativas de Oxigênio , Ácidos Sulfínicos , Humanos , Ferroptose/efeitos dos fármacos , Dissulfetos/farmacologia , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/patologia , Proliferação de Células/efeitos dos fármacos , Ácidos Sulfínicos/farmacologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Movimento Celular/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Glutationa/metabolismo , Sobrevivência Celular/efeitos dos fármacosRESUMO
Garlic (Allium sativum L.), particularly its volatile essential oil, is widely recognized for medicinal properties. We have evaluated the efficacy of Indian Garlic Essential Oil (GEO) for antimicrobial and antibiofilm activity and its bioactive constituents. Allyl sulfur-rich compounds were identified as predominant phytochemicals in GEO, constituting 96.51% of total volatile oils, with 38% Diallyl trisulphide (DTS) as most abundant. GEO exhibited significant antibacterial activity against eleven bacteria, including three drug-resistant strains with minimum inhibitory concentrations (MICs) ranging from 78 to 1250 µg/mL. In bacterial growth kinetic assay GEO effectively inhibited growth of all tested strains at its ½ MIC. Antibiofilm activity was evident against two important human pathogens, S. aureus and P. aeruginosa. Mechanistic studies demonstrated that GEO disrupts bacterial cell membranes, leading to the release of nucleic acids, proteins, and reactive oxygen species. Additionally, GEO demonstrated potent antioxidant activity at IC50 31.18 mg/mL, while its isolated constituents, Diallyl disulphide (DDS) and Diallyl trisulphide (DTS), showed effective antibacterial activity ranging from 125 to 500 µg/mL and 250-1000 µg/mL respectively. Overall, GEO displayed promising antimicrobial and antibiofilm activity against enteric bacteria, suggesting its potential application in the food industry.
Assuntos
Antibacterianos , Antioxidantes , Biofilmes , Alho , Testes de Sensibilidade Microbiana , Óleos Voláteis , Alho/química , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Antioxidantes/farmacologia , Antioxidantes/química , Antibacterianos/farmacologia , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Compostos Alílicos/farmacologia , Compostos Alílicos/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Sulfetos/farmacologia , Bactérias/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Dissulfetos/farmacologia , Índia , Óleos de Plantas/farmacologia , Óleos de Plantas/química , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/químicaRESUMO
Aflatoxin B1 (AFB1) is known to inhibit growth, and inflict hepatic damage by interfering with protein synthesis. Allicin, has been acknowledged as an efficacious antioxidant capable of shielding the liver from oxidative harm. This study aimed to examine the damage caused by AFB1 on bovine hepatic cells and the protective role of allicin against AFB1-induced cytotoxicity. In this study, cells were pretreated with allicin before the addition of AFB1 for co-cultivation. Our findings indicate that AFB1 compromises cellular integrity, suppresses the expression of nuclear factor erythroid 2-related factor 2 (Nrf2). In addition, allicin attenuates oxidative damage to bovine hepatic cells caused by AFB1 by promoting the expression of the Nrf2 pathway and reducing cell apoptosis. In conclusion, the results of this study will help advance clinical research and applications, providing new options and directions for the prevention and treatment of liver diseases.
Assuntos
Aflatoxina B1 , Antioxidantes , Apoptose , Dissulfetos , Hepatócitos , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Transdução de Sinais , Ácidos Sulfínicos , Animais , Ácidos Sulfínicos/farmacologia , Aflatoxina B1/toxicidade , Bovinos , Dissulfetos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Antioxidantes/farmacologia , FemininoRESUMO
Environmental pollution, virus infection, allergens, and other factors may cause respiratory disease, which could be improved by dietary therapy. Allium species are common daily food seasoning and have high nutritional and medical value. Diallyl disulfide (DADS) is the major volatile oil compound of Allium species. The present study aims to explore the preventive effect and potential mechanism of DADS on pulmonary fibrosis. C57BL/6J mice were intratracheally injected with bleomycin (BLM) to establish pulmonary fibrosis and then administrated with DADS. Primary lung fibroblasts or A549 were stimulated with BLM, followed by DADS, farnesoid X receptor (FXR) agonist (GW4064), yes-associated protein 1 (YAP1) inhibitor (verteporfin), or silencing of FXR and YAP1. In BLM-stimulated mice, DADS significantly ameliorated histopathological changes and interleukin-1ß levels in bronchoalveolar lavage fluid. DADS decreased fibrosis markers, HIF-1α, inflammatory cytokines, and epithelial-mesenchymal transition in pulmonary mice and activated fibroblasts. DADS significantly enhanced FXR expression and inhibited YAP1 activation, which functions as GW4064 and verteporfin. A deficiency of FXR or YAP1 could result in the increase of these two protein expressions, respectively. DADS ameliorated extracellular matrix deposition, hypoxia, epithelial-mesenchymal transition, and inflammation in FXR or YAP1 knockdown A549. Taken together, targeting the crosstalk of FXR and YAP1 might be the potential mechanism for DADS against pulmonary fibrosis. DADS can serve as a potential candidate or dietary nutraceutical supplement for the treatment of pulmonary fibrosis.
Assuntos
Compostos Alílicos , Dissulfetos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar , Receptores Citoplasmáticos e Nucleares , Transdução de Sinais , Proteínas de Sinalização YAP , Animais , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/induzido quimicamente , Camundongos , Dissulfetos/farmacologia , Humanos , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Compostos Alílicos/farmacologia , Células A549 , Masculino , Allium/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Bleomicina , Pulmão/efeitos dos fármacos , Pulmão/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismoRESUMO
BACKGROUND: Myelodysplastic syndrome (MDS) is a prevalent hematological neoplastic disorder in clinics and its immunopathogenesis has garnered growing interest. Oral and intravenous arsenic agents have long been used to treat hematological malignancies. The main component of oral arsenic is realgar (arsenic disulfide), while arsenic trioxide is the main component of intravenous arsenic. METHODS: This study aimed to assess the effects of ATO and Realgar on the enhancement of peripheral blood, drug safety, and T cell immune status in the NUP98-HOXD13 (NHD13) mice model of MDS, specifically in the peripheral blood, spleen, and liver. RESULTS: The study findings indicate that realgar and arsenic trioxide (ATO) can improve peripheral hemogram in mice, whereas realgar promotes higher peripheral blood cell production than ATO. Furthermore, the clinical administration method and dose did not cause significant toxicity or side effects and thus can be considered safe. Coexistence and interconversion of hyperimmune function and immunosuppression in mice were also observed in this study. In addition, there were interactions between immune cells in the peripheral blood, spleen, and liver to regulate the immune balance of the body and activate immunity via T-cell activation. CONCLUSION: In summary, oral and intravenous arsenic agents are beneficial in improving peripheral hemogram and immunity in mice.
Assuntos
Trióxido de Arsênio , Arsenicais , Modelos Animais de Doenças , Síndromes Mielodisplásicas , Animais , Trióxido de Arsênio/administração & dosagem , Trióxido de Arsênio/farmacologia , Arsenicais/farmacologia , Arsenicais/administração & dosagem , Camundongos , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/imunologia , Sulfetos/farmacologia , Sulfetos/administração & dosagem , Dissulfetos/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Baço/efeitos dos fármacos , Baço/imunologiaRESUMO
Diallyl disulfide (DADS), an organic component of allicin abstracted from garlic, possesses multi-target antitumor activity. DJ-1 performs a vital function in promoting AKT aberrant activation via down-regulating phosphatase and tensin homologue (PTEN) in tumors. It is unknown the involvement of DJ-1 in epithelial-mesenchymal transition (EMT) of gastric cancer (GC) cells. The purpose of this study is to investigate whether diallyl disulfide (DADS) intervenes in the role of DJ-1 in GC. Based on the identification that the correlation between high DJ-1 and low PTEN expression in GC was implicated in clinical progression, we illuminated that down-regulation of DJ-1 by DADS aided in an increase in PTEN expression and a decrease in phosphorylated AKT levels, which was in line with the results manifested in the DJ-1 knockdown and overexpressed cells, concurrently inhibiting proliferation, EMT, migration, and invasion. Furthermore, the antagonistic effects of DADS on DJ-1 were observed in in vivo experiments. Additionally, DADS mitigated the DJ-1-associated drug resistance. The current study revealed that DJ-1 is one of potential targets for DADS, which hopefully provides a promising strategy for prevention and adjuvant chemotherapy of GC.
Assuntos
Compostos Alílicos , Proliferação de Células , Dissulfetos , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Proteína Desglicase DJ-1 , Neoplasias Gástricas , Dissulfetos/farmacologia , Proteína Desglicase DJ-1/metabolismo , Proteína Desglicase DJ-1/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Compostos Alílicos/farmacologia , Humanos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linhagem Celular Tumoral , Animais , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , Movimento Celular/efeitos dos fármacos , Camundongos , Camundongos Nus , Camundongos Endogâmicos BALB CRESUMO
Garlic is a vegetable with numerous pro-health properties, showing high antioxidant capacity, and cytotoxicity for various malignant cells. The inhibition of cell proliferation by garlic is mainly attributed to the organosulfur compounds (OSCs), but it is far from obvious which constituents of garlic indeed participate in the antioxidant and cytotoxic action of garlic extracts. This study aimed to obtain insight into this question by examining the antioxidant activity and cytotoxicity of six OSCs and five phenolics present in garlic. Three common assays of antioxidant activity were employed (ABTSâ decolorization, DPPHâ decolorization, and FRAP). Cytotoxicity of both classes of compounds to PEO1 and SKOV-3 ovarian cancer cells, and MRC-5 fibroblasts was compared. Negligible antioxidant activities of the studied OSCs (alliin, allicin, S-allyl-D-cysteine, allyl sulfide, diallyl disulfide, and diallyl trisulfide) were observed, excluding the possibility of any significant contribution of these compounds to the total antioxidant capacity (TAC) of garlic extracts estimated by the commonly used reductive assays. Comparable cytotoxic activities of OSCs and phenolics (caffeic, p-coumaric, ferulic, gallic acids, and quercetin) indicate that both classes of compounds may contribute to the cytotoxic action of garlic.
Assuntos
Compostos Alílicos , Antioxidantes , Dissulfetos , Alho , Fenóis , Extratos Vegetais , Sulfetos , Ácidos Sulfínicos , Alho/química , Humanos , Antioxidantes/farmacologia , Antioxidantes/química , Fenóis/farmacologia , Fenóis/química , Dissulfetos/farmacologia , Dissulfetos/química , Linhagem Celular Tumoral , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Ácidos Sulfínicos/farmacologia , Ácidos Sulfínicos/química , Sulfetos/farmacologia , Sulfetos/química , Compostos Alílicos/farmacologia , Compostos Alílicos/química , Compostos de Enxofre/farmacologia , Compostos de Enxofre/química , Cisteína/análogos & derivados , Cisteína/química , Cisteína/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismoRESUMO
µ-Conotoxins are components of cone snail venom, well-known for their analgesic activity through potent inhibition of voltage-gated sodium channel (NaV) subtypes, including NaV1.7. These small, disulfide-rich peptides are typically stabilized by three disulfide bonds arranged in a 'native' CysI-CysIV, CysII-CysV, CysIII-CysVI pattern of disulfide connectivity. However, µ-conotoxin KIIIA, the smallest and most studied µ-conotoxin with inhibitory activity at NaV1.7, forms two distinct disulfide bond isomers during thermodynamic oxidative folding, including Isomer 1 (CysI-CysV, CysII-CysIV, CysIII-CysVI) and Isomer 2 (CysI-CysVI, CysII-CysIV, CysIII-CysV), but not the native µ-conotoxin arrangement. To date, there has been no study on the structure and activity of KIIIA comprising the native µ-conotoxin disulfide bond arrangement. Here, we evaluated the synthesis, potency, sodium channel subtype selectivity, and 3D structure of the three isomers of KIIIA. Using a regioselective disulfide bond-forming strategy, we synthetically produced the three µ-conotoxin KIIIA isomers displaying distinct bioactivity and NaV subtype selectivity across human NaV channel subtypes 1.2, 1.4, and 1.7. We show that Isomer 1 inhibits NaV subtypes with a rank order of potency of NaV1.4 > 1.2 > 1.7 and Isomer 2 in the order of NaV1.4≈1.2 > 1.7, while the native isomer inhibited NaV1.4 > 1.7≈1.2. The three KIIIA isomers were further evaluated by NMR solution structure analysis and molecular docking with hNaV1.2. Our study highlights the importance of investigating alternate disulfide isomers, as disulfide connectivity affects not only the overall structure of the peptides but also the potency and subtype selectivity of µ-conotoxins targeting therapeutically relevant NaV subtypes.
Assuntos
Conotoxinas , Bloqueadores do Canal de Sódio Disparado por Voltagem , Canais de Sódio Disparados por Voltagem , Conotoxinas/química , Conotoxinas/farmacologia , Dissulfetos/química , Dissulfetos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Canais de Sódio Disparados por Voltagem/química , Canais de Sódio Disparados por Voltagem/metabolismoRESUMO
Chemotherapeutics can induce immunogenic cell death (ICD) by triggering autophagy and mediate antitumor immunotherapy. However, using chemotherapeutics alone can only cause mild cell-protective autophagy and be incapable of inducing sufficient ICD efficacy. The participation of autophagy inducer is competent to enhance autophagy, so the level of ICD is promoted and the effect of antitumor immunotherapy is highly increased. Herein, tailor-made autophagy cascade amplification polymeric nanoparticles STF@AHPPE are constructed to enhance tumor immunotherapy. Arginine (Arg), polyethyleneglycol-polycaprolactone, and epirubicin (EPI) are grafted onto hyaluronic acid (HA) via disulfide bond to form the AHPPE nanoparticles and autophagy inducer STF-62247 (STF) is loaded. When STF@AHPPE nanoparticles target to tumor tissues and efficiently enter into tumor cells with the help of HA and Arg, the high glutathione concentration leads to the cleavage of disulfide bond and the release of EPI and STF. Finally, STF@AHPPE induces violent cytotoxic autophagy and strong ICD efficacy. As compared to AHPPE nanoparticles, STF@AHPPE nanoparticles kill the most tumor cells and show the more obvious ICD efficacy and immune activation ability. This work provides a novel strategy for combining tumor chemo-immunotherapy with autophagy induction.
Assuntos
Antineoplásicos , Nanopartículas , Neoplasias , Humanos , Antineoplásicos/farmacologia , Autofagia , Imunoterapia , Dissulfetos/farmacologia , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Triple-negative breast cancer (TNBC) displays a highly aggressive nature that originates from a small subpopulation of TNBC stem cells (TNBCSCs), and these TNBCSCs give rise to chemoresistance, tumor metastasis, and recurrence. Unfortunately, traditional chemotherapy eradicates normal TNBC cells but fails to kill quiescent TNBCSCs. To explore a new strategy for eradicating TNBCSCs, a disulfide-mediated self-assembly nano-prodrug that can achieve the co-delivery of ferroptosis drug, differentiation-inducing agent, and chemotherapeutics for simultaneous TNBCSCs and TNBC treatment, is reported. In this nano-prodrug, the disulfide bond not only induces self-assembly behavior of different small molecular drug but also serves as a glutathione (GSH)-responsive trigger in controlled drug release. More importantly, the differentiation-inducing agent can transform TNBCSCs into normal TNBC cells, and this differentiation with chemotherapeutics provides an effective approach to indirectly eradicate TNBCSCs. In addition, ferroptosis therapy is essentially different from the apoptosis-induced cell death of differentiation or chemotherapeutic, which causes cell death to both TNBCSCs and normal TNBC cells. In different TNBC mouse models, this nano-prodrug significantly improves anti-tumor efficacy and effectively inhibits the tumor metastasis. This all-in-one strategy enables controlled drug release and reduces stemness-related drug resistance, enhancing the chemotherapeutic sensitivity in TNBC treatment.
Assuntos
Antineoplásicos , Pró-Fármacos , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Antineoplásicos/farmacologia , Pró-Fármacos/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Células-Tronco Neoplásicas/patologia , Dissulfetos/farmacologiaRESUMO
Allicin, a thiosulfonate extract from freshly minced garlic, has been reported to have various biological effects on different organs and systems of animals and human. It can reduce oxidative stress, inhibit inflammatory response, resist pathogen infection and regulate intestinal flora. In addition, dozens of studies also demonstrated allicin could reduce blood glucose level, protect cardiovascular system and nervous system, and fight against cancers. Allicin was widely used in disease prevention and health care. However, more investigations on human cohort study are needed to verify the biological or clinical effects of allicin in the future. In this review, we summarized the biological effects of allicin from previous outstanding and valuable studies and provided useful information for future studies on the health effects of allicin.
Assuntos
Dissulfetos , Alho , Animais , Humanos , Dissulfetos/farmacologia , Ácidos Sulfínicos/farmacologia , Ácidos Sulfínicos/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêuticoRESUMO
It is well established that the quorum sensing (QS) in Pseudomonas aeruginosa is primarily responsible for the synthesis and the release of several virulence factors including pyocyanin and are involved in biofilm formation. In the Pseudomonas quinolone signal (PQS) system, autoinducers such as PQS and HHQ bind and activate the transcription regulator protein receptor PqsR (MvfR). Targeting PqsR with competitive inhibitors could be a promising strategy to inhibit QS in P. aeruginosa to overcome antimicrobial resistance. In this study, we have designed and synthesized a series of novel quinazolinone disulfide-containing competitive inhibitor of PqsR. The most potent analogue 8q efficiently inhibited the pqs system with an IC50 value of 4.5 µM. It also showed complete suppression of pyocyanin production and a significant reduction in biofilm formation by P. aeruginosa (PAO1) with low cytotoxicity. Additionally, 8q produced synergy in combination with known antibiotics such as ciprofloxacin and tobramycin. Finally, molecular docking analysis suggested that compound 8q could bind with the ligand-binding domain of PqsR in a similar fashion to the native ligand.
Assuntos
Pseudomonas aeruginosa , Percepção de Quorum , Pseudomonas aeruginosa/fisiologia , Piocianina , Ligantes , Simulação de Acoplamento Molecular , Quinazolinonas/farmacologia , Quinazolinonas/metabolismo , Dissulfetos/farmacologia , Biofilmes , Proteínas de Bactérias/metabolismoRESUMO
Leukemia is a type of disease in which hematopoietic stem cells proliferate clonally at the genetic level. We discovered previously by high-resolution mass spectrometry that diallyl disulfide (DADS), which is one of the effective ingredients of garlic, reduces the performance of RhoGDI2 from APL HL-60 cells. Although RhoGDI2 is oversubscribed in several cancer categories, the effect of RhoGDI2 in HL-60 cells has remained unexplained. We aimed to investigate the influence of RhoGDI2 on DADS-induced differentiation of HL-60 cells to elucidate the association among the effect of inhibition or over-expression of RhoGDI2 with HL-60 cell polarization, migration and invasion, which is important for establishing a novel generation of inducers to elicit leukemia cell polarization. Co-transfection with RhoGDI2-targeted miRNAs apparently decreases the malignant biological behavior of cells and upregulates cytopenias in DADS-treated HL-60 cell lines, which increases CD11b and decreases CD33 and mRNA levels of Rac1, PAK1 and LIMK1. Meanwhile, we generated HL-60 cell lines with high-expressing RhoGDI2. The proliferation, migration and invasion capacity of such cells were significantly increased by the treated with DADS, while the reduction capacity of the cells was decreased. There was a reduction in CD11b and an increase in CD33 production, as well as an increase in the mRNA levels of Rac1, PAK1 and LIMK1. It also confirmed that inhibition of RhoGDI2 attenuates the EMT cascade via the Rac1/Pak1/LIMK1 pathway, thereby inhibiting the malignant biological behavior of HL-60 cells. Thus, we considered that inhibition of RhoGDI2 expression might be a new therapeutic direction for the treatment of human promyelocytic leukemia. The anti-cancer property of DADS against HL-60 leukemia cells might be regulated by RhoGDI2 through the Rac1-Pak1-LIMK1 pathway, which provides new evidence for DADS as a clinical anti-cancer medicine.
Assuntos
Leucemia , Inibidor beta de Dissociação do Nucleotídeo Guanina rho , Humanos , Compostos Alílicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Dissulfetos/farmacologia , Células HL-60/efeitos dos fármacos , Células HL-60/metabolismo , Leucemia/metabolismo , Leucemia/patologia , Quinases Lim/genética , Quinases Lim/metabolismo , Quinases Ativadas por p21/metabolismo , Quinases Ativadas por p21/farmacologia , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/farmacologia , Inibidor beta de Dissociação do Nucleotídeo Guanina rho/efeitos dos fármacos , Inibidor beta de Dissociação do Nucleotídeo Guanina rho/metabolismo , RNA Mensageiro , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologiaRESUMO
Hypoxia is a characteristic feature of solid tumors, including oral squamous cell carcinoma (OSCC), which causes therapeutic resistance. The hypoxia-inducible factor 1-alpha (HIF-1α) is a key regulator of hypoxic tumor microenvironment (TME) and a promising therapeutic target against solid tumors. Among other HIF-1α inhibitors, vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor (HDACi) targeting the stability of HIF-1α, and PX-12 (1-methylpropyl 2-imidazolyl disulfide) is a thioredoxin-1 (Trx-1) inhibitor preventing accumulation of HIF-1α. HDACis are effective against cancers; however, they are accompanied by several side effects along with an emerging resistance against it. This can be overcome by using HDACi in a combination regimen with Trx-1 inhibitor, as their inhibitory mechanisms are interconnected. HDACis inhibit Trx-1, leading to an increase in the production of reactive oxygen species (ROS) and inducing apoptosis in cancer cells; thus, the efficacy of HDACi can be elevated by using a Trx-1 inhibitor. In this study, we have tested the EC50 (half maximal effective concentration) doses of vorinostat and PX-12 on CAL-27 (an OSCC cell line) under both normoxic and hypoxic conditions. The combined EC50 dose of vorinostat and PX-12 is significantly reduced under hypoxia, and the interaction of PX-12 with vorinostat was evaluated by combination index (CI). An additive interaction between vorinostat and PX-12 was observed in normoxia, while a synergistic interaction was observed under hypoxia. This study provides the first evidence for vorinostat and PX-12 synergism under hypoxic TME, at the same time highlighting the therapeutically effective combination of vorinostat and PX-12 against OSCC in vitro.