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Targeting ferroptosis for cancer therapy has slowed because of an incomplete understanding of ferroptosis mechanisms under specific pathological contexts such as tumorigenesis and cancer treatment. Here, we identify TRPML1-mediated lysosomal exocytosis as a potential anti-ferroptotic process through genome-wide CRISPR-Cas9 activation and kinase inhibitor library screening. AKT directly phosphorylated TRPML1 at Ser343 and inhibited K552 ubiquitination and proteasome degradation of TRPML1, thereby promoting TRPML1 binding to ARL8B to trigger lysosomal exocytosis. This boosted ferroptosis defense of AKT-hyperactivated cancer cells by reducing intracellular ferrous iron and enhancing membrane repair. Correlation analysis and functional analysis revealed that TRPML1-mediated ferroptosis resistance is a previously unrecognized feature of AKT-hyperactivated cancers and is necessary for AKT-driven tumorigenesis and cancer therapeutic resistance. TRPML1 inactivation or blockade of the interaction between TRPML1 and ARL8B inhibited AKT-driven tumorigenesis and cancer therapeutic resistance in vitro and in vivo by promoting ferroptosis. A synthetic peptide targeting TRPML1 inhibited AKT-driven tumorigenesis and enhanced the sensitivity of AKT-hyperactivated tumors to ferroptosis inducers, radiotherapy, and immunotherapy by boosting ferroptosis in vivo. Together, our findings identified TRPML1 as a therapeutic target in AKT-hyperactivated cancer.
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Ferroptose , Neoplasias , Proteínas Proto-Oncogênicas c-akt , Animais , Humanos , Camundongos , Fatores de Ribosilação do ADP/metabolismo , Carcinogênese/patologia , Carcinogênese/genética , Linhagem Celular Tumoral , Ferroptose/efeitos dos fármacos , Lisossomos/metabolismo , Neoplasias/patologia , Neoplasias/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , UbiquitinaçãoRESUMO
A novel strategy for incorporating a trifluoroacetyl functionality into a range of structurally varied unsaturated bonds was developed by using PhI(OCOMe)2 as an oxidant with a masked trifluoroacyl reagent as a trifluoroacetyl radical precursor. The oxidative decarboxylation of the masked trifluoroacyl precursor followed by a tandem radical process provides versatile access to 5-exo-trig cyclization of N-arylacrylamides, direct C(sp2)-H trifluoroacetylation of quinolines, isoquinoline, 2H-indazole, and quinoxalin-2(1H)-ones, and C(sp)-H trifluoroacetylation of alkynes. This protocol is characterized by mild reaction conditions, operational simplicity, and broad functional group compatibility.
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Herein, a direct cross-dehydrogenative C-H amination of indoles has been successfully achieved, enabled by the merger of photocatalysis with nickel catalysis. This developed process does not require stoichiometric oxidants and prefunctionalization of amine partners, providing a concise platform for C-N bond formation. Moreover, the synthetic practicality of this transformation was well revealed by its high step- and atom-economy, high reaction efficiency, and broad functional group tolerance.
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A visible-light-induced radical relay strategy to access heterocycles bearing a monofluoromethylsufonyl moiety is reported, with PhI(OCOCH2F)2 as the CH2F radical precursor and DABSO as the SO2 source. A range of oxindoles, containing a CH2FSO2CH2- group at the C3 position, were synthesized from N-arylacrylamides in up to 97% yields. The protocol features catalyst-free photochemical tandem, mild reaction conditions, broad functional group compatibility, and good to excellent yields.
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Ferroptosis, an iron-dependent lipid peroxidation-driven programmed cell death, is closely related to cancer therapy. The development of druggable ferroptosis inducers and their rational application in cancer therapy are critical. Here, we identified Tubastatin A, an HDAC6 inhibitor as a novel druggable ferroptosis inducer through large-scale drug screening. Tubastatin A directly bonded to GPX4 and inhibited GPX4 enzymatic activity through biotin-linked Tubastatin A putdown and LC/MS analysis, which is independent of its inhibition of HDAC6. In addition, our results showed that radiotherapy not only activated Nrf2-mediated GPX4 transcription but also inhibited lysosome-mediated GPX4 degradation, subsequently inducing ferroptosis tolerance and radioresistance in cancer cells. Tubastatin A overcame ferroptosis resistance and radioresistance of cancer cells by inhibiting GPX4 enzymatic activity. More importantly, Tubastatin A has excellent bioavailability, as demonstrated by its ability to significantly promote radiotherapy-induced lipid peroxidation and tumour suppression in a mouse xenograft model. Our findings identify a novel druggable ferroptosis inducer, Tubastatin A, which enhances radiotherapy-mediated antitumor effects. This work provides a compelling rationale for the clinical evaluation of Tubastatin A, especially in combination with radiotherapy.
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Ferroptose , Neoplasias , Humanos , Animais , Camundongos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Apoptose , Peroxidação de LipídeosRESUMO
A visible-light-induced defluorinative dichloromethylation of α-CF3 alkenes was developed with cheap and readily accessible chloroform simultaneously as a dichloromethylation reagent and reaction medium, leading to the facile preparation of new polyhalogenated scaffolds. Notably, the change from CHCl3 to CDCl3 offers a straightforward pathway for accessing the deuterated analogues with excellent degrees of D incorporation. Mechanistic studies suggested the reaction underwent a radical addition of the dichloromethyl radical with alkenes, followed by sequential single-electron transfer and defluorination. This protocol features mild conditions, easy operation, facile scalability, and high efficiency, allowing convenient access to dichloronated gem-difluoroalkenes.
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An unprecedented photoredox-catalyzed phosphine-mediated deoxygenation of hexafluoroacetone hydrate was established to accomplish the hydroxylpolyfluoroalkylation of electron-deficient alkenes. A range of bis(trifluoromethyl)carbinols were facilely accessed by using readily available hexafluoroacetone hydrate, instead of toxic gaseous hexafluoroacetone. A range of electron-deficient alkenes are tolerated, giving the corresponding hydro-hydroxylpolyfluoroalkylated products in moderate to high yields. Remarkable features of this synthetic strategy include operational simplicity, mild reaction conditions, excellent regioselectivity, and broad functional group tolerance. The success of this strategy relies on the delicate utilization of aldehyde/ketone-gem-diol intrinsic equilibrium, which offers an innovated open-shell pathway for the assembly of synthetically challenging polyfluoroalkylated scaffolds.
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Alcenos , Fluorocarbonos , Catálise , AcetonaRESUMO
A metal-free photosensitized protocol for regioselective diamination of alkene feedstocks over a single step was developed based on the rationally designed bifunctional diamination reagent, thus affording a range of differentially protected 1,2-diamines in moderate to high yields. Mechanistic studies reveal that the reaction is initiated with a triplet-triplet energy transfer between thioxanthone catalyst and diamination reagent, followed by fragmentation to simultaneously generate long-lived iminyl radical and transient amidyl radical. The excellent regioselectivity presumably stems from the large reactivity difference between two different N-centered radical species. This protocol is characterized by excellent regioselectivity, broad functional group tolerance, and mild reaction conditions, which would enrich the diversity and versatility of facilitate the diversity-oriented synthesis of 1,2-diamine-containing complex molecule scaffolds.
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A photoinduced, photocatalyst-free cyanoalkylation of nitrostyenes was explored, affording a series of cyanoalkylated alkenes in moderate to good yields. Mechanistic studies reveal that an electron donor-acceptor complex formed between O-aryl oximes and DIPEA is presumably involved in this process. The excellent functional group compatibility of this newly designed synthetic protocol allows for cyanoalkylation of structurally varied substrates, which offers an eco-friendly pathway for the assembly of cyanoalkylated alkenes.
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The mechanism of the phosphine-catalysed domino sequence of alkynoates and activated methylenes has been computationally studied. The computational results revealed that the [3 + 2] annulation sequence could be ruled out, due to a difficult Knoevenagel condensation of aromatic aldehydes and active methylenes. The reaction proceeds through a [4 + 1] annulation pathway, which involves a phosphine-catalysed MBH-type reaction followed by a [1,5]-proton shift and dehydration to afford vinyl phosphonium intermediates as four-carbon synthons in the annulation reaction. Then 1,3-dicarbonyls act as nucleophiles to attack vinyl phosphonium intermediates, subsequently leading to a stepwise [1,3]-proton shift and an intramolecular nucleophilic attack to close the five-member ring.
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Reported herein is a visible-light-induced, catalyst-free intramolecular cyclization of 4-phenylsulfonyl-2,3,5,6-tetrachloropyridine, leading to rapid assembly of a series of unprecedented benzo[4,5]thieno[3,2-c]pyridine 5,5-dioxide scaffolds under mild conditions. The rational introduction of a perchloropyridin-4-yl module significantly facilitated this photoinduced process and offers a versatile platform for broad structural variation. Mechanistic studies revealed that a newly identified charge-transfer complex with carbonate is crucial to this photoinduced process.
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The accumulation of lipid peroxides is recognized as a determinant of the occurrence of ferroptosis. However, the sensors and amplifying process of lipid peroxidation linked to ferroptosis remain obscure. Here we identify PKCßII as a critical contributor of ferroptosis through independent genome-wide CRISPR-Cas9 and kinase inhibitor library screening. Our results show that PKCßII senses the initial lipid peroxides and amplifies lipid peroxidation linked to ferroptosis through phosphorylation and activation of ACSL4. Lipidomics analysis shows that activated ACSL4 catalyses polyunsaturated fatty acid-containing lipid biosynthesis and promotes the accumulation of lipid peroxidation products, leading to ferroptosis. Attenuation of the PKCßII-ACSL4 pathway effectively blocks ferroptosis in vitro and impairs ferroptosis-associated cancer immunotherapy in vivo. Our results identify PKCßII as a sensor of lipid peroxidation, and the lipid peroxidation-PKCßII-ACSL4 positive-feedback axis may provide potential targets for ferroptosis-associated disease treatment.
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Coenzima A Ligases/metabolismo , Ferroptose/fisiologia , Peroxidação de Lipídeos/fisiologia , Proteína Quinase C beta/metabolismo , Animais , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Técnicas de Inativação de Genes , Humanos , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/terapia , Fosforilação , Proteína Quinase C beta/genéticaRESUMO
A highly modular 1,4-difunctionalization of 1,3-dienes with bromodifluoroacetamides and sulfinates/amines through a photoinduced palladium-catalyzed radical relay process is described herein. This developed protocol offers a facile and general route to access a variety of value-added CF2-incorporated alkenes in moderate to good yields. The versatility and flexibility of this approach have been well illustrated by readily accessible starting materials, synthetic convenience, and wide functional group compatibility.
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A visible light-promoted radical relay of N-allylbromodifluoroacetamide with quinoxalin-2(1H)-ones was developed in which 5-exo-trig cyclization and C-C bond formation were involved. This protocol was performed under mild conditions to facilely offer a variety of hybrid molecules bearing both quinoxalin-2(1H)-one and 3,3-difluoro-γ-lactam motifs. These prepared novel skeletons would expand the accessible chemical space for structurally complex heterocycles with potential biological activities.
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Luz , Quinoxalinas , Ciclização , Lactamas , Estrutura MolecularRESUMO
An unprecedented electrochemical heterodifunctionalization of α-CF3 alkenes with benzenesulfonyl hydrazides was accomplished in this work, wherein a ß-sulfonyl and a α-hydroxyl group were simultaneously incorporated across the olefinic double bond in a single operation. Consequently, a series of potentially medicinally valuable and densely functionalized α-trifluoromethyl-ß-sulfonyl tertiary alcohols were assembled under mild conditions. Electrochemically-driven oxidative 1,2-difunctionlization of electron-deficient alkenes well obviates the need for oxidizing reagents, thus rendering this protocol more eco-friendly.
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Aiming at the valuable methylation process, readily available and inexpensive N,N,N',N'-tetramethylethylenediamine (TMEDA) was first identified as a new methyl source in photoredox-catalyzed transformation in this work. By virtue of this simple methylating reagent, a facile and practical protocol for the direct C-H methylation of N-heteroarenes was developed, featuring mild reaction conditions, broad substrate scope, and scalability. Mechanistic studies disclosed that a sequential photoredox, base-assisted proton shift, fragmentation, and tautomerization process was essentially involved.
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Etilenodiaminas , Prótons , Catálise , MetilaçãoRESUMO
We herein report an unprecedented photoinduced cyclization/defluorination domino process of N-allylbromodifluoroacetamide with cyclic secondary amines. Consequently, a wide array of valuable 3-fluoro-1,5-dihydro-2H-pyrrol-2-ones were facilely prepared from readily available starting materials under mild conditions. Preliminary mechanistic investigations suggest that a radical chain propagation and amine-promoted defluorination pathway are presumably involved in this transformation.
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OBJECTIVE: To evaluate and compare the clinical and radiographic outcomes of proximal fibular osteotomy (PFO) in treating medial knee osteoarthritis (KOA) patients with upper fibular curvature and non-curvature. METHODS: A retrospective cohort study was performed. From January 2016 to January 2017, a total of 51 patients (nine males and 42 females) at a mean age of 63.7 years (range 48-79 years) with medial KOA who underwent PFO procedure at the Third Hospital of Hebei Medical University were included in the study. The patients were divided into the two groups, namely curvature group (28 patients, six males and 22 females, aged 62.6 ± 7.7 years) and non-curvature group (23 patients, three males and 20 females, aged 64.5 ± 7.6 years). Perioperative parameters and Kellgren-Lawrence classification were recorded and analyzed in the two groups, respectively. All patients were followed up at 1, 3, 6, and 12 months at the first year of post-operation, and then every 6 months from the second year of post-operation. A telephone survey with standard questionnaire survey, including Visual Analog Scale (VAS) score and Hospital for Special Surgery (HSS) scoring system, was used to evaluate postoperative clinical outcomes. Radiological results were assessed using the femorotibial angle (FTA), hip-knee-ankle angle (HKA), and settlement value of medial tibial platform (MTP) in the two groups. RESULTS: The average follow-up periods of the curvature group and the non-curvature group were 34.8 ± 6.1 and 33.9 ± 5.4 months, respectively. There were no significant differences between the two groups of demographic data in terms of number of patients, age, body mass index (BMI), gender, KOA side, and Kellgren-Lawrence classification (P > 0.05). The VAS scores of the curvature group and non-curvature group were (3.53 ± 1.62 vs 3.68 ± 1.43 at 1 month, 3.46 ± 0.79 vs 3.57 ± 0.66 at 3 months, and 2.43 ± 0.88 vs 2.83 ± 0.94 at 6 months, both P > 0.05), while significant differences were found from 12 months post-operation (1.54 ± 0.72 vs 2.03 ± 0.85 at 12 months, and 1.04 ± 0.69 vs 1.74 ± 0.75 at 24 months, both P < 0.05). The HSS scores of the curvature group and non-curvature group were (79.67 ± 5.14 vs 78.25 ± 6.37 at 1 month, 84.65 ± 3.76 vs 83.18 ± 3.64 at 3 months, and 86.27 ± 3.13 vs 85.49 ± 3.25 at 6 months, both P > 0.05), while significant differences were found from 12 months post-operation (90.64 ± 4.32 vs 87.71 ± 5.63 at 12 months, and 92.93 ± 2.07 vs 90.06 ± 2.08 at 24 months, both P < 0.05). In addition, the FTA and settlement value of the curvature group were lower than the non-curvature group (177.18 ± 1.52 vs 178.35 ± 1.86, and 5.29 ± 1.74 vs 6.49 ± 2.09, both P < 0.05) while the HKA were higher than the non-curvature group (175.32 ± 2.34 vs 173.83 ± 2.64, P < 0.05) at the final follow-up. CONCLUSIONS: Medial KOA patients with upper fibular curvature is an optimal surgical indication for PFO surgery, with the advantages of pain relief, better functional recovery, and alignment correction.
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Fíbula/diagnóstico por imagem , Fíbula/cirurgia , Osteoartrite do Joelho/diagnóstico por imagem , Osteotomia/métodos , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Radiografia , Estudos RetrospectivosRESUMO
OBJECTIVE: To evaluate and analyze the potential relationship between periosteal reaction and medial compartment knee osteoarthritis (KOA), and to assess the independent risk factors for the development of periosteal reaction associated with medial compartment KOA. METHODS: This is a retrospective comparative study. From January 2019 to December 2019 at the Third Hospital of Hebei Medical University, a total of 363 patients (726 knees) with medial compartment KOA were enrolled in this study according to our inclusion and exclusion criteria, including 91 males and 272 females, with an mean age of 57.9 ± 12.8 years (range, 18-82 years). Among these patients, 206 patients (412 knees) were allocated to the periosteal reaction group (44 males and 162 females) and 157 patients (314 knees) were allocated to the non-periosteal reaction group (47 males and 110 females). The classification of KOA severity was based on Kellgren and Lawrence (K-L) grading system. The malalignment of the lower extremities in coronal plane was evaluated as medial proximal tibial angle (MPTA), hip-knee-ankle angle (HKA), and lateral distal femoral angle (LDFA). Patients demographics and radiographic parameters were recorded in the two groups. Intra-observer and inter-observer reliabilities of all radiological measurements were analyzed by intraclass correlation coefficients (ICCs). Univariate analyses were conducted for comparison of differences with continuous variables between patients with periosteal reaction and without periosteal reaction. Multivariate logistical regression analysis was performed to determine the independent risk factors of radiographic parameters for periosteal reaction. RESULTS: The overall incidence of periosteal reaction associated with medial compartment KOA was 56.7%. Furthermore, we observed that the incidence of periosteal reaction significantly increased with age and correlated with K-L grade progression (P < 0.05). There was a statistically significant difference between the two groups. In the multivariate logistical regression analysis, HKA and JLCA were identified as independent risk factors of the development of periosteal reaction in patients with medial compartment KOA (odds ratio [OR], 0.594; 95% confidence interval [CI] 0.544-0.648; P < 0.05; OR, 0.851; 95% confidence interval CI 0.737-0.983; P < 0.05; respectively), with other radiographic parameters including MTPA (OR 0.959; 95% CI 0.511-0.648; P > 0.05), LDFA (OR 0.990; 95% CI 0.899-1.089; P > 0.05), and JSW (OR 1.005; 95% CI 0.865-1.167; P > 0.05). CONCLUSIONS: In this retrospective study, patients with lower HKA and higher JLCA were identified as independent risk factors for the development of periosteal reaction, which occurred most commonly adjacent to the lateral of proximal tibia diaphysis, and thus we concluded that periosteal reaction may be an anatomical adaptation for medial compartment KOA based upon these results.
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Osteoartrite do Joelho/diagnóstico por imagem , Periósteo/diagnóstico por imagem , Tíbia/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/patologia , Periósteo/patologia , Radiografia , Estudos Retrospectivos , Tíbia/patologia , Adulto JovemRESUMO
Reported herein is the design and synthesis of new O-perhalopyridin-4-yl hydroxylamines as shelf-stable and versatile amidyl-radical precursors. The novel amination reagents can be easily prepared via a single synthetic step from inexpensive commercially available starting materials using monoprotected HONH2 as amino source. The synthetic potency of the developed reagents was well demonstrated by direct amination of a series of quinoxalin-2(1H)-ones and their analogues under photocatalytic conditions, even without any additive and photocatalysts.