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1.
Contrast Media Mol Imaging ; 2022: 6814140, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36072635

RESUMO

The aim was to analyze the infection, influencing factors, and clinical manifestations of Helicobacter pylori infection, coronary heart disease, and cytotoxin-associated protein A infection, so as to provide reference for the improvement of clinical diagnosis and treatment level of in-depth treatment. This paper presents a clinical observation method based on Helicobacter pylori infection, risk factors, and cytotoxin-associated protein A in patients with coronary heart disease. Methods. 237 patients with CHD diagnosed and tested by 14C breath test were selected from inpatients of cardiovascular diseases in a hospital for retrospective analysis. The clinical data, serum deepening indicators, Hcy, and other factors were analyzed through general condition investigation, previous history investigation, and physical examination. The patients were observed by the SPSS22.0 statistical data processing method. The results showed that among the respondents, 175 cases were HP-positive, the infection rate was 73.8%, 77 patients with stable angina pectoris were 64.9%, and 160 patients with acute coronary heart disease were 78.1%. The difference between the groups was statistically significant (P < 0.05). Conclusion. Helicobacter pylori cytotoxic-associated protein A can increase the risk of gastric cancer, and Helicobacter pylori eradication treatment is more conducive to reduce the incidence of gastric cancer and ensure the safety of patients.


Assuntos
Doença das Coronárias , Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Doença das Coronárias/complicações , Doença das Coronárias/diagnóstico , Doença das Coronárias/epidemiologia , Citotoxinas/metabolismo , Infecções por Helicobacter/complicações , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/epidemiologia , Helicobacter pylori/metabolismo , Humanos , Estudos Retrospectivos , Fatores de Risco
2.
Int J Mol Sci ; 23(17)2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36077085

RESUMO

The synthesis of alkyl 2-(4-hydroxyquinolin-2-yl) acetates and 1-phenyl-4-(phenylamino)pyridine-2,6(1H,3H)-dione was optimised. Starting from 4-hydroxyquinolines (4HQs), aminomethylation was carried out via the modified Mannich reaction (mMr) applying formaldehyde and piperidine, but a second paraformaldehyde molecule was incorporated into the Mannich product. The reaction also afforded the formation of bisquinoline derivatives. A new 1H-azeto [1,2-a]quinoline derivative was synthesised in two different ways; namely starting from the aminomethylated product or from the ester-hydrolysed 4HQ. When the aldehyde component was replaced with aromatic aldehydes, Knoevenagel condensation took place affording the formation of the corresponding benzylidene derivatives, with the concomitant generation of bisquinolines. The reactivity of salicylaldehyde and hydroxynaphthaldehydes was tested; under these conditions, partially saturated lactones were formed through spontaneous ring closure. The activity of the derivatives was assessed using doxorubicin-sensitive and -resistant colon adenocarcinoma cell lines and normal human fibroblasts. Some derivatives possessed selective toxicity towards resistant cancer cells compared to doxorubicin-sensitive cancer cells and normal fibroblasts. Cytotoxic activity of the benzylidene derivatives and the corresponding Hammett-Brown substituent were correlated.


Assuntos
Adenocarcinoma , Antineoplásicos , Neoplasias do Colo , Hidroxiquinolinas , Antineoplásicos/farmacologia , Compostos de Benzilideno , Citotoxinas , Doxorrubicina/farmacologia , Humanos
3.
PLoS One ; 17(9): e0270697, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36170255

RESUMO

Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor for cellular metabolism and serves as a substrate in enzymatic processes. NAD+ is produced by de novo synthesis or salvage pathways in nearly all bacterial species. Haemophilus influenzae lacks the capacity for de novo synthesis, so it is dependent on import of NAD+ from the external environment or salvage biosynthetic pathways for recycling of NAD+ precursors and breakdown products. However, the actual sources of NAD+ utilized by H. influenzae in the respiratory tract are not well defined. In this study, we found that a variety of bacteria, including species found in the upper airway of humans, released NAD+ that was readily detectable in extracellular culture fluid, and which supported growth of H. influenzae in vitro. By contrast, certain strains of Streptococcus pyogenes (group A streptococcus or GAS) inhibited growth of H. influenzae in vitro by secreting NAD+-glycohydrolase (NADase), which degraded extracellular NAD+. Conversely, GAS strains that lacked enzymatically active NADase released extracellular NAD+, which could support H. influenzae growth. Our results suggest that many bacterial species, including normal flora of the upper airway, release NAD+ into the environment. GAS is distinctive in its ability to both release and degrade NAD+. Thus, colonization of the airway with H. influenzae may be promoted or restricted by co-colonization with GAS in a strain-specific manner that depends, respectively, on release of NAD+ or secretion of active NADase. We suggest that, in addition to its role as a cytotoxin for host cells, NADase may serve a separate function by restricting growth of H. influenzae in the human respiratory tract.


Assuntos
NAD , Streptococcus pyogenes , Citotoxinas/metabolismo , Haemophilus influenzae/metabolismo , Humanos , NAD/metabolismo , NAD+ Nucleosidase/metabolismo , Streptococcus pyogenes/metabolismo
4.
Med Oncol ; 39(12): 233, 2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36175588

RESUMO

Patients with platinum-resistant ovarian cancer (PROC) have limited therapeutic options and poor survival. There is a need for the development of newer therapies. Sodium valproic acid (VPA) is a short-chain fatty acid histone deacetylase (HDAC) inhibitor with antitumor activity in preclinical models of PROC. Synergism with conventional cytotoxic agents like etoposide has been demonstrated. In this prospective, single-arm, open-label, phase 2 study, we included patients ≥ 18 years with histologically or cytologically confirmed PROC and Eastern Cooperative Oncology Group performance status (ECOG-PS) 0-3. Patients received oral VPA 60 mg/kg/day in three divided doses for 3 days (D1-D3), followed by oral etoposide 50 mg once daily for two consecutive weeks (D4-D17). Serum samples were collected to assess peak VPA drug levels. The primary endpoint was the overall response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. We sought to show an improvement in response rate from 25% (historically with oral etoposide) to 40% with the addition of VPA. 27 patients were enrolled in the study, and 18 [median age: 52 (45-59) years; serous histology:17 (94%); ECOG-PS 2 or 3: 14 (78%)] were evaluable for the response after 4 months. Nine patients were lost from follow-up before achieving the primary endpoint (mainly due to Covid-related lockdown issues). The median number of prior lines of treatment was 2 (1-3). ORR was 0% according to GCIG criteria. The disease was stable in two patients [clinical benefit rate (CBR) of 11%]. The median OS and PFS were 7 months and 2 months, respectively. Grade ≥ 3 adverse events were reported in 6 (33%) patients. The addition of valproic acid to oral etoposide in patients with PROC and poor general condition was not helpful and failed to improve responses compared to those historically achieved with single-agent etoposide. However, further phase 2 randomized controlled trials with larger sample size can be done to confirm the findings.


Assuntos
COVID-19 , Linfoma Folicular , Neoplasias Ovarianas , Carcinoma Epitelial do Ovário , Controle de Doenças Transmissíveis , Citotoxinas , Etoposídeo , Feminino , Inibidores de Histona Desacetilases , Histona Desacetilases , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Estudos Prospectivos , Sódio , Ácido Valproico/uso terapêutico
5.
Biochem Biophys Res Commun ; 629: 95-100, 2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36115284

RESUMO

Subtilase cytotoxin (SubAB) is a major virulence factor produced by eae-negative Shiga-toxigenic Escherichia coli (STEC) that can cause fatal systemic complications. SubAB binds to target cells through multivalent interactions between its B-subunit pentamer and receptor molecules such as glycoproteins with a terminal N-glycolylneuraminic acid (Neu5Gc). We screened randomized multivalent peptide libraries synthesized on a cellulose membrane and identified a series of tetravalent peptides that efficiently bind to the receptor-binding region of the SubAB B-subunit pentamer. These peptides competitively inhibited the binding of the B-subunit to a receptor-mimic molecule containing clustered Neu5Gc (Neu5Gc-polymer). We selected the peptide with the highest inhibitory efficacy, FFP-tet, and covalently bound it to beads to synthesize FFP-tet-beads, a highly clustered SubAB absorber that displayed potency to absorb SubAB cytotoxicity through direct binding to the toxin. The efficacy of FFP-tet-beads to absorb SubAB cytotoxicity in solution was similar to that of Neu5Gc-polymer, suggesting that FFP-tet-beads might be an effective therapeutic agent against complications arising from eae-negative STEC infection.


Assuntos
Proteínas de Escherichia coli , Escherichia coli Shiga Toxigênica , Proteínas de Transporte/metabolismo , Celulose/metabolismo , Citotoxinas , Proteínas de Escherichia coli/metabolismo , Biblioteca de Peptídeos , Polímeros/metabolismo , Escherichia coli Shiga Toxigênica/genética , Escherichia coli Shiga Toxigênica/metabolismo , Subtilisinas/toxicidade , Fatores de Virulência/metabolismo
6.
J Enzyme Inhib Med Chem ; 37(1): 2710-2724, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36168121

RESUMO

Multidrug resistance (MDR) is a leading cause for treatment failure in cancer patients. One of the reasons of MDR is drug efflux by ATP-binding cassette (ABC) transporters in eukaryotic cells especially ABCB1 (P-glycoprotein). In this study, certain novel 1,2,5-trisubstituted benzimidazole derivatives were designed utilising ligand based pharmacophore approach. The designed benzimidazoles were synthesised and evaluated for their cytotoxic activity towards doxorubicin-sensitive cell lines (CCRF/CEM and MCF7), as well as against doxorubicin-resistant cancer cells (CEM/ADR 5000 and Caco-2). In particular, compound VIII showed a substantial cytotoxic effect in all previously mentioned cell lines especially in doxorubicin-resistant CEM/ADR5000 cells (IC50 = 8.13 µM). Furthermore, the most promising derivatives VII, VIII and XI were tested for their ABCB1 inhibitory action in the doxorubicin-resistant CEM/ADR 5000 subline which is known for overexpression of ABCB1 transporters. The results showed that compound VII exhibited the best ABCB1 inhibitory activity at three tested concentrations (22.02 µM (IC50), 50 µM and 100 µM) in comparison to verapamil as a reference ABCB1 inhibitor. Such inhibition resulted in a synergistic effect and a massive decrease in the IC50 of doxorubicin (34.5 µM) when compound VII was used in a non-toxic dose in combination with doxorubicin in doxorubicin-resistant cells CEM/ADR 5000 (IC50(Dox+VII) = 3.81 µM). Molecular modelling studies were also carried out to explain the key interactions of the target benzimidazoles at the ABCB1 binding site. Overall the obtained results from this study suggest that 1,2,5-trisubstituted benzimidazoles possibly are promising candidates for further optimisation and development of potential anticancer agents with ABCB1 inhibitory activity and therefore overcome MDR in cancer cells.


Assuntos
Antineoplásicos , Neoplasias , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/farmacologia , Trifosfato de Adenosina , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Células CACO-2 , Linhagem Celular Tumoral , Citotoxinas/farmacologia , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Ligantes , Verapamil/farmacologia
7.
FASEB J ; 36(10): e22557, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36125006

RESUMO

Vibrio cholerae cytolysin (VCC) is a ß-barrel pore-forming toxin (ß-PFT). It exhibits potent hemolytic activity against erythrocytes that appears to be a direct outcome of its pore-forming functionality. However, VCC-mediated cell-killing mechanism is more complicated in the case of nucleated mammalian cells. It induces apoptosis in the target nucleated cells, mechanistic details of which are still unclear. Furthermore, it has never been explored whether the ability of VCC to trigger programmed cell death is stringently dependent on its pore-forming activity. Here, we show that VCC can evoke hallmark features of the caspase-dependent apoptotic cell death even in the absence of the pore-forming ability. Our study demonstrates that VCC mutants with abortive pore-forming hemolytic activity can trigger apoptotic cell death responses and cytotoxicity, similar to those elicited by the wild-type toxin. VCC as well as its pore formation-deficient mutants display prominent propensity to translocate to the target cell mitochondria and cause mitochondrial membrane damage. Therefore, our results for the first time reveal that VCC, despite being an archetypical ß-PFT, can kill target nucleated cells independent of its pore-forming functionality. These findings are intriguing for a ß-PFT, whose destination is generally expected to remain limited on the target cell membranes, and whose mode of action is commonly attributed to the membrane-damaging pore-forming ability. Taken together, our study provides critical new insights regarding distinct implications of the two important virulence functionalities of VCC for the V. cholerae pathogenesis process: hemolytic activity for iron acquisition and cytotoxicity for tissue damage by the bacteria.


Assuntos
Toxinas Biológicas , Vibrio cholerae , Animais , Caspases/metabolismo , Morte Celular , Citotoxinas/metabolismo , Ferro/metabolismo , Mamíferos/metabolismo , Toxinas Biológicas/metabolismo , Vibrio cholerae/metabolismo
8.
Medicina (Kaunas) ; 58(9)2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36143975

RESUMO

Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide. Unfortunately, therapeutic gains in the treatment of other cancers have not successfully translated to pancreatic cancer treatments. Management of pancreatic cancer is difficult due to the lack of effective therapies and the rapid development of drug resistance. The cytotoxic agent gemcitabine has historically been the first-line treatment, but combinations of other immunomodulating and stroma-depleting drugs are currently undergoing clinical testing. Moreover, the treatment of pancreatic cancer is complicated by its heterogeneity: analysis of genomic alterations and expression patterns has led to the definition of multiple subtypes, but their usefulness in the clinical setting is limited by inter-tumoral and inter-personal variability. In addition, various cell types in the tumor microenvironment exert immunosuppressive effects that worsen prognosis. In this review, we discuss current perceptions of molecular features and the tumor microenvironment in pancreatic cancer, and we summarize emerging drug options that can complement traditional chemotherapies.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Citotoxinas/farmacologia , Humanos , Neoplasias Pancreáticas/genética , Microambiente Tumoral
9.
Chem Commun (Camb) ; 58(77): 10797-10800, 2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36069382

RESUMO

A photo-activated aptamer-drug conjugate, HG1-9-DNP, was developed based on an aptamer HG1-9 and a photolabile naphthalimide derivative DNP. HG1-9-DNP could be internalized into cells mediated by TfR, then photocleaved, and released a promising cytotoxic agent, DNNH, which arrested the cell cycle at the G2/M phase, resulting in high photo-induced cytotoxicity.


Assuntos
Aptâmeros de Nucleotídeos , Doxorrubicina , Aptâmeros de Nucleotídeos/metabolismo , Aptâmeros de Nucleotídeos/farmacologia , Linhagem Celular Tumoral , Citotoxinas , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Naftalimidas , Oligonucleotídeos , Preparações Farmacêuticas
10.
Nat Chem ; 14(10): 1193-1201, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36064972

RESUMO

Host-associated bacteria are increasingly being recognized as underexplored sources of bioactive natural products with unprecedented chemical scaffolds. A recently identified example is the plant-root-associated marine bacterium Gynuella sunshinyii of the chemically underexplored order Oceanospirillales. Its genome contains at least 22 biosynthetic gene clusters, suggesting a rich and mostly uncharacterized specialized metabolism. Here, in silico chemical prediction of a non-canonical polyketide synthase cluster has led to the discovery of janustatins, structurally unprecedented polyketide alkaloids with potent cytotoxicity that are produced in minute quantities. A combination of MS and two-dimensional NMR experiments, density functional theory calculations of 13C chemical shifts and semiquantitative interpretation of transverse rotating-frame Overhauser effect spectroscopy data were conducted to determine the relative configuration, which enabled the total synthesis of both enantiomers and assignment of the absolute configuration. Janustatins feature a previously unknown pyridodihydropyranone heterocycle and an unusual biological activity consisting of delayed, synchronized cell death at subnanomolar concentrations.


Assuntos
Produtos Biológicos , Policetídeos , Bactérias/metabolismo , Produtos Biológicos/química , Citotoxinas/metabolismo , Citotoxinas/farmacologia , Policetídeo Sintases/metabolismo , Policetídeos/metabolismo
11.
Dalton Trans ; 51(38): 14686-14699, 2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36098266

RESUMO

We report the controlled growth of biologically active compounds: gold nanoparticles (AuNPs) in various shapes, including their green synthesis, characterization, and studies of their applications towards biological, degradation and recycling. Using spectroscopic methods, studies on responsive binding mechanisms of AuNPs with biopolymers herring sperm deoxyribonucleic acid (hsDNA), bovine serum albumin (BSA), dyes degradation study, and exquisitely gold separation studies/recovery from nanowaste, COVID-19 testing kits, and pregnancy testing kits are discussed. The sensing ability of the AuNPs with biopolymers was investigated via various analytical techniques. The rate of degradation of various dyes in the presence and absence of AuNPs was studied by deploying stirring, IR, solar, and UV-Vis methods. AuNPs were found to be the most active cytotoxic agent against human breast cancer cell lines such as MCF-7 and MDAMB-468. Furthermore, an economical process for the recovery of gold traces from nanowaste, COVID-19 detection kits, and pregnancy testing kits was developed using inexpensive and eco-friendly α-cyclodextrin sugar. This method was found to be easy and safest in comparison with the universally accepted cyanidation process. In the future, small gold jewelry makers and related industries would benefit from the proposed gold-recycling process and it might contribute to their socio-economic growth. The methodologies proposed are also beneficial for trace-level forensic investigation.


Assuntos
COVID-19 , Nanopartículas Metálicas , alfa-Ciclodextrinas , COVID-19/diagnóstico , Teste para COVID-19 , Corantes , Citotoxinas , DNA , Ouro/química , Humanos , Masculino , Nanopartículas Metálicas/química , Sêmen , Soroalbumina Bovina/química , Açúcares
12.
J Cancer Res Ther ; 18(4): 1061-1072, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36149162

RESUMO

Background: Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor-2 targeted antibody-drug conjugate that contains a monoclonal antibody, trastuzumab, covalently linked to DM1, a small molecule cytotoxin. Methods: We conducted a systematic review and meta-analysis of published trials to examine the efficacy and safety of T-DM1 for patients with HER2-positive metastatic breast cancer. In addition, we systematically reviewed existing economic evaluations of T-DM1. An electronic literature search of online databases (Medline, CENTRAL, and Embase) was performed. Randomized controlled trials that compared T-DM1 with other active treatment agents were eligible for inclusion. In addition, studies that involved T-DM1 as one of the treatment comparators in an economic evaluation were included. Four trials with a total of 2462 participants were included in this meta-analysis. Results: Pooled results showed T-DM1 substantially improved overall survival (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.67-0.85; I2 = 0%) and progression-free survival (HR, 0.67; 95% CI, 0.52-0.85; I2 = 75%). In addition, T-DM1 showed greater association with severe thrombocytopenia and liver dysfunction than other regimens, but a lower rate of neutropenia, leukopenia, febrile neutropenia, asthenia, and diarrhea. All four trials included in the meta-analysis overall had a low risk of bias. Two cost-utility analyses involving T-DM1 were identified, and the overall quality was high. Conclusions: T-DM1 is effective for the treatment of patients with HER2-positive metastatic breast cancer, and it demonstrates a tolerable safety profile compared with other active controls. Little evidence was available regarding the cost-effectiveness of T-DM1 so no conclusions can be drawn.


Assuntos
Neoplasias da Mama , Imunoconjugados , Maitansina , Ado-Trastuzumab Emtansina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Análise Custo-Benefício , Citotoxinas , Intervalo Livre de Doença , Feminino , Humanos , Imunoconjugados/uso terapêutico , Maitansina/uso terapêutico , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico
13.
Mar Drugs ; 20(8)2022 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-36005497

RESUMO

Antibody-drug conjugates (ADCs) are an important class of therapeutics for the treatment of cancer. Structurally, an ADC comprises an antibody, which serves as the delivery system, a payload drug that is a potent cytotoxin that kills cancer cells, and a chemical linker that connects the payload with the antibody. Unlike conventional chemotherapy methods, an ADC couples the selective targeting and pharmacokinetic characteristics related to the antibody with the potent cytotoxicity of the payload. This results in high specificity and potency by reducing off-target toxicities in patients by limiting the exposure of healthy tissues to the cytotoxic drug. As a consequence of these outstanding features, significant research efforts have been devoted to the design, synthesis, and development of ADCs, and several ADCs have been approved for clinical use. The ADC field not only relies upon biology and biochemistry (antibody) but also upon organic chemistry (linker and payload). In the latter, total synthesis of natural and designed cytotoxic compounds, together with the development of novel synthetic strategies, have been key aspects of the consecution of clinical ADCs. In the case of payloads from marine origin, impressive structural architectures and biological properties are observed, thus making them prime targets for chemical synthesis and the development of ADCs. In this review, we explore the molecular and biological diversity of ADCs, with particular emphasis on those containing marine cytotoxic drugs as the payload.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias , Antineoplásicos/química , Antineoplásicos/farmacologia , Citotoxinas , Humanos , Imunoconjugados/química , Imunoconjugados/farmacologia , Neoplasias/tratamento farmacológico
14.
Int J Mol Sci ; 23(16)2022 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-36012321

RESUMO

While the fungal metabolite illudin M (1) is indiscriminately cytotoxic in cancer and non-malignant cells, its retinoate 2 showed a greater selectivity for the former, especially in a cerebral context. Illudin M killed malignant glioma cells as well as primary neurons and astrocytes at similarly low concentrations and destroyed their microtubule and glial fibrillary acidic protein (GFAP) networks. In contrast, the ester 2 was distinctly more cytotoxic in highly dedifferentiated U87 glioma cells than in neurons, which were even stimulated to enhanced growth. This was also observed in co-cultures of neurons with U87 cells where conjugate 2 eventually killed them by induction of differentiation based on the activation of nuclear receptors, which bind to retinoid-responsive elements (RARE). Hence, illudin M retinoate 2 appears to be a promising drug candidate.


Assuntos
Neoplasias Encefálicas , Glioma , Astrócitos/metabolismo , Neoplasias Encefálicas/metabolismo , Citotoxinas , Proteína Glial Fibrilar Ácida/metabolismo , Glioma/metabolismo , Humanos , Sesquiterpenos Policíclicos , Tretinoína/metabolismo
15.
Biomolecules ; 12(8)2022 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-36009005

RESUMO

Protein aggregation is a well-recognized problem in industrial preparation, including biotherapeutics. These low-energy states constantly compete with a native-like conformation, which is more pronounced in the case of macromolecules of low stability in the solution. A better understanding of the structure and function of such aggregates is generally required for the more rational development of therapeutic proteins, including single-chain fusion cytotoxins to target specific receptors on cancer cells. Here, we identified and purified such particles as side products of the renaturation process of the single-chain fusion cytotoxin, composed of two diphtheria toxin (DT) domains and interleukin 13 (IL-13), and applied various experimental techniques to comprehensively understand their molecular architecture and function. Importantly, we distinguished soluble purified dimeric and fractionated oligomeric particles from aggregates. The oligomers are polydisperse and multimodal, with a distribution favoring lower and even stoichiometries, suggesting they are composed of dimeric building units. Importantly, all these oligomeric particles and the monomer are cystine-dependent as their innate disulfide bonds have structural and functional roles. Their reduction triggers aggregation. Presumably the dimer and lower oligomers represent the metastable state, retaining the native disulfide bond. Although significantly reduced in contrast to the monomer, they preserve some fraction of bioactivity, manifested by their IL-13RA2 receptor affinity and selective cytotoxic potency towards the U-251 glioblastoma cell line. These molecular assemblies probably preserve structural integrity and native-like fold, at least to some extent. As our study demonstrated, the dimeric and oligomeric cytotoxin may be an exciting model protein, introducing a new understanding of its monomeric counterpart's molecular characteristics.


Assuntos
Antineoplásicos , Toxina Diftérica , Citotoxinas , Toxina Diftérica/química , Toxina Diftérica/metabolismo , Toxina Diftérica/toxicidade , Dissulfetos , Substâncias Macromoleculares , Relação Estrutura-Atividade
16.
Urol Oncol ; 40(10): 413-423, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35973928

RESUMO

INTRODUCTION: Metastatic urothelial cancer (mUC) is an aggressive disease with limited overall survival and treatment options. Antibody-drug conjugates (ADCs) were designed with the intent to deliver potent cytotoxic drugs selectively to antigen-expressing tumor cells by linking cytotoxins to monoclonal antibodies (mAbs) and have emerged as new treatment options in mUC, mainly in chemotherapy (CT) and immune-checkpoint inhibitors (ICI)-exposed patients. We aimed to perform a scoping review to assess activity, efficacy, treatment-related adverse events (TRAEs), and impact on quality of life of ADCs in mUC. METHODS: A review of the literature was performed in January 2022 using Pubmed and Embase databases according to the recommendations of the Joanna Briggs Institute. The search method involved querying for the terms "bladder carcinoma" or "urothelial carcinoma" with any of the following: "enfortumab vedotin" (EV), "sacituzumab govitecan" (SG), antibody-drug conjugate. Only prospective clinical trials were included. RESULTS: Ultimately, eleven clinical trials with 1417 patients were selected for inclusion, and five drugs were identified: enfortumab vedotin (EV), sacituzumab govitecan (SG), disitamab vedotin (RC48-ADC), ASG-15ME (anti-SLITRK6), and trastuzumab deruxtecan. The different ADCs have been tested mainly in phase 1 or phase 2 trials, as monotherapy or in combination with ICI. Response rate ranged from 27% with SG in previously treated patients to 73.3% with EV plus pembrolizumab in cisplatin-ineligible patients as first-line treatment. The phase 3 trial, EV-301, confirmed EV superiority over investigator-chosen CT after failure to platinum-based CT and ICI, improving overall survival (12.88 vs. 8.97 months; HR 0.70; 95% CI, 0.56-0.89; P=0.001). TRAEs of any grade occurred in more than 90% of patients in phase 2 or 3 trials, with high rates of grade 3 ≥ events ranging from 51.4 to 73.5% in different trials. TRAEs of particular interest related to EV were rash, neuropathy, and hyperglycemia. SG was associated with diarrhea and hematologic toxicity. Data from phase 2 and 3 trials of EV suggest no impact on quality of life but an improvement in pain symptoms compared to the control arm. CONCLUSIONS: ACDs represent a new therapeutic option for the treatment of mUC. Level-1 evidence has already been achieved by EV in the post-CT and post-ICI settings. A high incidence of potential adverse events was observed in phase 2 and 3 trials, including rash, neutropenia, hematologic toxicity, and neuropathy. Clinicians should be aware of possible adverse events and their optimal management.


Assuntos
Antineoplásicos , Carcinoma de Células de Transição , Exantema , Imunoconjugados , Neoplasias da Bexiga Urinária , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/induzido quimicamente , Carcinoma de Células de Transição/tratamento farmacológico , Cisplatino/uso terapêutico , Citotoxinas/uso terapêutico , Exantema/induzido quimicamente , Humanos , Inibidores de Checkpoint Imunológico , Imunoconjugados/efeitos adversos , Estudos Prospectivos , Qualidade de Vida , Neoplasias da Bexiga Urinária/patologia
17.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 47(7): 942-951, 2022 Jul 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-36039592

RESUMO

Cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) are the keys to the pathogenic role of Helicobacter pylori and the high-risk factors for the progression of gastric precancerous lesions. Autophagy can stabilize the intracellular environment, resist Helicobacter pylori infection, prevent the accumulation of damaged DNA, and inhibit the proliferation of gastric precancerous variant cells. However, CagA and VacA can inhibit the activation of upstream signals of autophagy and the maturation of autophagy-lysosomes in various ways, thus inhibiting the autophagy of gastric mucosal cells in precancerous lesions of gastric cancer. This change can cause Helicobacter pylori to be unable to be effectively cleared by autophagy, so CagA and VacA can persist and promote the inflammation, oxidative stress, apoptosis of gastric mucosal tissue cells, and the glycolytic activity and proliferation of variant cells in gastric precancerous lesions and a series of malignant biological processes. In recent years, the research on drugs specifically inhibiting the activities of CagA and VacA has become a new direction for the prevention and treatment of Helicobacter pylori-related severe gastric diseases, and a variety of drugs or components that can precisely and effectively regulate the factors for the treatment of gastric precancerous lesions are emerged, which opens a new strategy for the treatment of gastric precancerous lesions in the future.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Lesões Pré-Cancerosas , Antígenos de Bactérias/genética , Autofagia , Proteínas de Bactérias/genética , Citotoxinas , Células Epiteliais/patologia , Helicobacter pylori/genética , Humanos , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia
18.
Nat Commun ; 13(1): 5032, 2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-36028511

RESUMO

In pneumococcal meningitis, bacterial growth in the cerebrospinal fluid results in lysis, the release of toxic factors, and subsequent neuroinflammation. Exposure of primary murine glia to Streptococcus pneumoniae lysates leads to strong proinflammatory cytokine and chemokine production, blocked by inhibition of the intracellular innate receptor Nod1. Lysates enhance dynamin-dependent endocytosis, and dynamin inhibition reduces neuroinflammation, blocking ligand internalization. Here we identify the cholesterol-dependent cytolysin pneumolysin as a pro-endocytotic factor in lysates, its elimination reduces their proinflammatory effect. Only pore-competent pneumolysin enhances endocytosis in a dynamin-, phosphatidylinositol-3-kinase- and potassium-dependent manner. Endocytic enhancement is limited to toxin-exposed parts of the membrane, the effect is rapid and pneumolysin permanently alters membrane dynamics. In a murine model of pneumococcal meningitis, mice treated with chlorpromazine, a neuroleptic with a complementary endocytosis inhibitory effect show reduced neuroinflammation. Thus, the dynamin-dependent endocytosis emerges as a factor in pneumococcal neuroinflammation, and its enhancement by a cytolysin represents a proinflammatory control mechanism.


Assuntos
Meningite Pneumocócica , Streptococcus pneumoniae , Animais , Proteínas de Bactérias , Citotoxinas , Endocitose , Inflamação , Camundongos , Estreptolisinas
19.
STAR Protoc ; 3(3): 101595, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-35928004

RESUMO

CRISPR screening is a powerful tool to identify host factors for pathogenic agents including viruses and bacterial toxins. Here, we present a protocol to conduct a genome-scale CRISPR screen on HeLa cells for host factors involved in the toxin action of Clostridioides difficile TcdB4. We describe in detail how to prepare the library, set up the screen, obtain the gene sequences, and analyze the results. This protocol can also be modified for other genome-scale libraries, cell lines, and cytotoxins. For complete details on the use and execution of this protocol, please refer to Luo et al. (2022).


Assuntos
Toxinas Bacterianas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Toxinas Bacterianas/genética , Sistemas CRISPR-Cas/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Citotoxinas , Células HeLa , Humanos
20.
Org Lett ; 24(38): 6891-6896, 2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-35975906

RESUMO

While salarin C (SalaC) is a potent marine cytotoxin, Kashman demonstrated that congeners which had undergone Wasserman rearrangement exhibit little to no cytotoxicity. Given that thiazoles are known to undergo Wasserman rearrangement at a significantly reduced rate, we hypothesized that a thiazole-containing SalaC would exhibit greater stability without significantly altering the macrocyclic conformation. Herein, we describe the synthesis of a simplified, thiazole-containing macrocycle which demonstrates significantly improved stability under identical aerobic conditions.


Assuntos
Antineoplásicos , Tiazóis , Antineoplásicos/farmacologia , Citotoxinas , Macrolídeos , Tiazóis/farmacologia
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