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BACKGROUND AND AIMS: Although the benefits of vertical sleeve gastrectomy (VSG) surgery are well known, the molecular mechanisms by which VSG alleviates obesity and its complications remain unclear. We aim to determine the role of CYP8B1 (cytochrome P450, family 8, subfamily B, polypeptide 1) in mediating the metabolic benefits of VSG. APPROACH AND RESULTS: We found that expression of CYP8B1, a key enzyme in controlling the 12α-hydroxylated (12α-OH) bile acid (BA) to non-12α-OH BA ratio, was strongly downregulated after VSG. Using genetic mouse models of CYP8B1 overexpression, knockdown, and knockout, we demonstrated that overexpression of CYP8B1 dampened the metabolic improvements associated with VSG. In contrast, short hairpin RNA-mediated CYP8B1 knockdown improved metabolism similar to those observed after VSG. Cyp8b1 deficiency diminished the metabolic effects of VSG. Further, VSG-induced alterations to the 12α-OH/non-12α-OH BA ratio in the BA pool depended on CYP8B1 expression level. Consequently, intestinal lipid absorption was restricted, and the gut microbiota (GM) profile was altered. Fecal microbiota transplantation from wild type-VSG mice (vs. fecal microbiota transplantation from wild-type-sham mice) improved metabolism in recipient mice, while there were no differences between mice that received fecal microbiota transplantation from knockout-sham and knockout-VSG mice. CONCLUSIONS: CYP8B1 is a critical downstream target of VSG. Modulation of BA composition and gut microbiota profile by targeting CYP8B1 may provide novel insight into the development of therapies that noninvasively mimic bariatric surgery to treat obesity and its complications.
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Cirurgia Bariátrica , Esteroide 12-alfa-Hidroxilase , Camundongos , Animais , Esteroide 12-alfa-Hidroxilase/metabolismo , Regulação para Baixo , Obesidade/metabolismo , Gastrectomia , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVE: To develop an AI-assisted MRI model to identify surgical target areas in pediatric hip and periarticular infections. METHODS: A retrospective study was conducted on the pediatric patients with hip and periarticular infections who underwent Magnetic Resonance Imaging(MRI)examinations from January 2010 to January 2023 in three hospitals in China. A total of 7970 axial Short Tau Inversion Recovery (STIR) images were selected, and the corresponding regions of osteomyelitis (label 1) and abscess (label 2) were labeled using the Labelme software. The images were randomly divided into training group, validation group, and test group at a ratio of 7:2:1. A Mask R-CNN model was constructed and optimized, and the performance of identifying label 1 and label 2 was evaluated using receiver operating characteristic (ROC) curves. Calculation of the average time it took for the model and specialists to process an image in the test group. Comparison of the accuracy of the model in the interpretation of MRI images with four orthopaedic surgeons, with statistical significance set at P < 0.05. RESULTS: A total of 275 patients were enrolled, comprising 197 males and 78 females, with an average age of 7.10 ± 3.59 years, ranging from 0.00 to 14.00 years. The area under curve (AUC), accuracy, sensitivity, specificity, precision, and F1 score for the model to identify label 1 were 0.810, 0.976, 0.995, 0.969, 0.922, and 0.957, respectively. The AUC, accuracy, sensitivity, specificity, precision, and F1 score for the model to identify label 2 were 0.890, 0.957, 0.969, 0.915, 0.976, and 0.972, respectively. The model demonstrated a significant speed advantage, taking only 0.2 s to process an image compared to average 10 s required by the specialists. The model identified osteomyelitis with an accuracy of 0.976 and abscess with an accuracy of 0.957, both statistically better than the four orthopaedic surgeons, P < 0.05. CONCLUSION: The Mask R-CNN model is reliable for identifying surgical target areas in pediatric hip and periarticular infections, offering a more convenient and rapid option. It can assist unexperienced physicians in pre-treatment assessments, reducing the risk of missed and misdiagnosis.
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Imageamento por Ressonância Magnética , Osteomielite , Humanos , Masculino , Feminino , Imageamento por Ressonância Magnética/métodos , Criança , Estudos Retrospectivos , Adolescente , Osteomielite/diagnóstico por imagem , Pré-Escolar , Lactente , Articulação do Quadril/diagnóstico por imagem , Articulação do Quadril/cirurgia , Articulação do Quadril/patologia , China , Abscesso/diagnóstico por imagem , Abscesso/cirurgia , Curva ROCRESUMO
The regulation of bile acid pathways has become a particularly promising therapeutic strategy for a variety of metabolic disorders, cancers, and diseases. However, the hydrophobicity of bile acids has been an obstacle to clinical efficacy due to off-target effects from rapid drug absorption. In this report, we explored a novel strategy to design new structure fragments based on lithocholic acid (LCA) with improved hydrophilicity by introducing a polar "oxygen atom" into the side chain of LCA, then (i) either retaining the carboxylic acid group or replacing the carboxylic acid group with (ii) a diol group or (iii) a vinyl group. These novel fragments were evaluated using luciferase-based reporter assays and the MTS assay. Compared to LCA, the result revealed that the two lead compounds 1a-1b were well tolerated in vitro, maintaining similar potency and efficacy to LCA. The MTS assay results indicated that cell viability was not affected by dose dependence (under 25 µM). Additionally, computational model analysis demonstrated that compounds 1a-1b formed more extensive hydrogen bond networks with Takeda G protein-coupled receptor 5 (TGR5) than LCA. This strategy displayed a potential approach to explore the development of novel endogenous bile acids fragments. Further evaluation on the biological activities of the two lead compounds is ongoing.
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Ácidos e Sais Biliares , Ácido Litocólico , Ácido Litocólico/farmacologia , Ácidos e Sais Biliares/farmacologiaRESUMO
Concurrent translocations of MYC and BCL2 lead to abnormal expression of both oncoproteins, which contribute to the aggressive clinical characteristics of double-hit lymphoma (DHL). An effective therapy for DHL remains an unmet clinical need. In this study, we showed that both Ca2+ /calmodulin-dependent protein kinase II δ (CAMKIIδ) and γ (CAMKIIγ) were highly expressed in DHL. Both isoforms of CAMKII stabilize c-Myc protein by phosphorylating it at Ser62, increase BCL2 expression, and promote DHL tumor growth. Inhibition of CAMKIIδ and CAMKIIγ by either berbamine (BBM) or one of its derivatives (PA4) led to the down regulation of c-Myc and BCL2 proteins. BBM/PA4 also exhibited anti-tumor efficacy in DHL cell lines and NSG xenograft models. Altogether, CAMKIIδ and CAMKIIγ appear to be critical for DHL tumor development and are promising therapeutic targets for DHL.
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Linfoma de Células B , Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Proto-Oncogênicas c-myc , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Rearranjo Gênico , Humanos , Linfoma de Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismoRESUMO
MnO2/C composite with ordered submicron pore array structure was obtained by using Atrophaneura horishana butterfly wings as template and carbon source for high performance supercapacitor electrode. Micro/nanostructured carbon substrate was firstly constructed by calcining the wing specimen under nitrogen atmosphere. Then, amorphous MnO2 was formed on the structure via surface solution reaction. The as-prepared composite shows a high specific capacitance of 1342 F g-1 at 1 A g-1 with good rate capability and stability. The excellent charge-discharge performance should be attributed to the coupling effect of pseudocapacitive amorphous MnO2 and robust porous carbon. The pore array structured substrate not only provides high specific surface area for sufficient active sites, but also exhibits good connectivity for efficient charge and mass transport.
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The liver is able to regenerate itself in response to partial hepatectomy or liver injury. This is accomplished by a complex network of different cell types and signals both inside and outside the liver. Bile acids (BAs) are recently identified as liver-specific metabolic signals and promote liver regeneration by activating their receptors: Farnesoid X Receptor (FXR) and G-protein-coupled BA receptor 1 (GPBAR1, or TGR5). FXR is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. FXR promotes liver regeneration after 70% partial hepatectomy (PHx) or liver injury. Moreover, activation of FXR is able to alleviate age-related liver regeneration defects. Both liver- and intestine-FXR are activated by BAs after liver resection or injury and promote liver regeneration through distinct mechanism. TGR5 is a membrane-bound BA receptor and it is also activated during liver regeneration. TGR5 regulates BA hydrophobicity and stimulates BA excretion in urine during liver regeneration. BA signaling thus represents a novel metabolic pathway during liver regeneration. This article is part of a Special Issue entitled: Nuclear receptors in animal development.
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Ácidos e Sais Biliares/metabolismo , Regeneração Hepática , Fígado/fisiologia , Animais , Humanos , Mucosa Intestinal/metabolismo , Fígado/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
In this report, we investigated the molecular genetic mechanism underlying the deafness-associated mitochondrial tRNAHis 12201T>C mutation. The destabilization of a highly conserved base-pairing (5A-68U) by the m.12201T>C mutation alters structure and function of tRNAHis. Using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from a Chinese family into mtDNA-less (ρo) cells, we showed â¼70% decrease in the steady-state level of tRNAHis in mutant cybrids, compared with control cybrids. The mutation changed the conformation of tRNAHis, as suggested by slower electrophoretic mobility of mutated tRNA with respect to the wild-type molecule. However, â¼60% increase in aminoacylated level of tRNAHis was observed in mutant cells. The failure in tRNAHis metabolism was responsible for the variable reductions in seven mtDNA-encoded polypeptides in mutant cells, ranging from 37 to 81%, with the average of â¼46% reduction, as compared with those of control cells. The impaired mitochondrial translation caused defects in respiratory capacity in mutant cells. Furthermore, marked decreases in the levels of mitochondrial ATP and membrane potential were observed in mutant cells. These mitochondrial dysfunctions caused an increase in the production of reactive oxygen species in the mutant cells. The data provide the evidence for a mitochondrial tRNAHis mutation leading to deafness.
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Surdez/genética , Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Mutação , RNA de Transferência de Histidina/genética , Espécies Reativas de Oxigênio/metabolismo , Trifosfato de Adenosina/biossíntese , Linhagem Celular , Respiração Celular , Humanos , Proteínas Mitocondriais/metabolismo , RNA de Transferência de Histidina/química , RNA de Transferência de Histidina/metabolismo , Aminoacilação de RNA de TransferênciaRESUMO
A cellulose-based carbon aerogel (CTN) loaded with titanium dioxide (TiO2) and graphitic carbon nitride (g-C3N4) was prepared using sol-gel, freeze-drying, and high-temperature carbonization methods. The formation of the sol-gel was carried out through a one-pot method using refining papermaking pulp, tetrabutyl titanate, and urea as raw materials and hectorite as a cross-linking and reinforcing agent. Due to the cross-linking ability of hectorite, the carbonized aerogel maintained a porous structure and had a large specific surface area with low density (0.0209 g/cm3). The analysis of XRD, XPS, and Raman spectra revealed that the titanium dioxide (TiO2) and graphitic carbon nitride (g-C3N4) were uniformly distributed in the CTN, while TEM and SEM observations demonstrated the uniformly distributed three-dimensional porous structure of CTN. The photocatalytic activity of the CTN was determined according to its ability to degrade rhodamine B. The removal rate reached 89% under visible light after 120 min. In addition, the CTN was still stable after five reuse cycles. The proposed catalyst exhibits excellent photocatalytic performance under visible light conditions.
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The hypoxic environment is among the most important factors that complicates the healing of chronic wounds, such as venous leg ulcers, pressure injuries and diabetic foot ulcers, which seriously affects the quality of life of patients. Various oxygen supply treatments are used in clinical practice to improve the hypoxic environment at the wound site. However, problems still occur, such as insufficient oxygen supply, short oxygen infusion time and potential biosafety risks. In recent years, artificial photosynthetic systems have become a research hotspot in the fields of materials and energy. Photosynthesis is expected to improve the oxygen level at wound sites and promote wound healing because the method provides a continuous oxygen supply and has good biosafety. In this paper, oxygen treatment methods for wounds are reviewed, and the oxygen supply principle and construction of artificial photosynthesis systems are described. Finally, research progress on the photosynthetic oxygen production system to promote wound healing is summarized.
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Delayed wound healing caused by bacterial infection remains a major challenge in clinical treatment. Exotoxins incorporated in bacterial extracellular vesicles play a key role as the disease-causing virulence factors. Safe and specific antivirulence agents are expected to be developed as an effective anti-bacterial infection strategy, instead of single antibiotic therapy. Plant-derived extracellular vesicle-like nanoparticles have emerged as promising therapeutic agents for skin diseases, but the elucidations of specific mechanisms of action and clinical transformation still need to be advanced. Here, dandelion-derived extracellular vesicle-like nanoparticles (TH-EVNs) are isolated and exert antivirulence activity through specifically binding to Staphylococcus aureus (S. aureus) exotoxins, thereby protecting the host cell from attack. The neutralization of TH-EVNs against exotoxins has considerable binding force and stability, showing complete detoxification effect in vivo. Then gelatin methacryloyl hydrogel is developed as TH-EVNs-loaded dressing for S. aureus exotoxin-invasive wounds. Hydrogel dressings demonstrate good physical and mechanical properties, thus achieving wound retention and controlled release of TH-EVNs, in addition to promoting cell proliferation and migration. In vivo results show accelerated re-epithelialization, promotion of collagen maturity and reduction of inflammation after treatment. Collectively, the developed TH-EVNs-laden hydrogel dressings provide a potential therapeutic approach for S. aureus exotoxin- associated trauma.
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Anti-Infecciosos , Infecções Estafilocócicas , Taraxacum , Hidrogéis/química , Staphylococcus aureus , Cicatrização , Exotoxinas , Antibacterianos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , BandagensRESUMO
ABSTRACT: Ca2+/calmodulin-dependent protein kinase II γ (CAMKIIγ) has been identified as a potential target for treating cancer. Based on our previous study of berbamine (BBM) as a CAMKIIγ inhibitor, we have synthesized a new BBM derivative termed PA4. Compared with BBM, PA4 showed improved potency and specificity and was more cytotoxic against lymphoma and leukemia than against other types of cancer. In addition to indirectly targeting c-Myc protein stability, we demonstrated that its cytotoxic effects were also mediated via increased reactive oxygen species production in lymphoma cells. PA4 significantly impeded tumor growth in vivo in a xenograft T-cell lymphoma mouse model. Pharmacokinetics studies demonstrated quick absorption into plasma after oral administration, with a maximum concentration of 1680 ± 479 ng/mL at 5.33 ± 2.31 hours. The calculated oral absolute bioavailability was 34.1%. Toxicity assessment of PA4 showed that the therapeutic window used in our experiments was safe for future development. Given its efficacy, safety, and favorable pharmacokinetic profile, PA4 is a potential lead candidate for treating lymphoma.
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Antineoplásicos , Benzilisoquinolinas , Leucemia , Linfoma de Células T , Humanos , Camundongos , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Benzilisoquinolinas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
Loser-out tournament-based fireworks algorithm (LoTFWA) is a new baseline of fireworks algorithm (FWA). However, its ability to search deeply in local areas and communicate among fireworks is not satisfying enough. Therefore, this paper proposes a new triple-spark guiding strategy for LoTFWA to deal with the mentioned problems. Among the three sparks generated for guiding, one is exactly the same as the original one in LoTFWA, the second one uses the centroid of good sparks to enhance the local exploitation, and the last one is based on Differential evolution (DE) mutation and used to enhance cooperation and exploration. Experimental results show that with low computational cost, the proposed guiding strategy attains significantly better results than LoTFWA and is competitive with state-of-the-art FWA variants. Furthermore, comprehensive experiments show that the proposed strategy has the potential to combine with other FWA variants to achieve better results.
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Hexavalent chromium (Cr(VI)) is a typical heavy metal pollutant, making its removal from wastewater imperative. Although nanosized zero-valent iron (nZVI) and graphene-based materials are excellent remediation materials, they have drawbacks, such as agglomeration and being difficult to recycle. A facile synthesis method for decorating reduced graphene oxide (rGO) with ultrathin nZVI (within 10 nm) was explored in this study in order to develop an effective tool for Cr(VI) detoxication. Cu particles were doped in these composites for electron-transfer enhancement and were verified to improve the rate by 2.4~3.4 times. Batch experiments were conducted at different pHs, initial concentrations, ionic strengths, and humic acid (HA) concentrations. From these observations, it was found that the acid condition and appearance of Cu and rGO enhanced the treatment capacity. This procedure was fitted with a pseudo-second-order model, and the existence of NaCl and HA impeded it to some extent. Cr(VI) could be detoxified into Cr(III) and precipitated on the surface. Combining these analyses, a kinetics study, and the characterizations before and after the reaction, the removal mechanism of Cr(VI) was further discussed as a complex process involving adsorption, reduction, and precipitation. The maximum removal capacity of 156.25 mg g-1 occurred in the acid condition, providing a potential Cr(VI) remediation method.
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BACKGROUND: Hepatocellular carcinoma (HCC) is a multifactor-driven malignant tumor with rapid progression, which causes the difficulty to substantially improve the prognosis of HCC. Limited understanding of the mechanisms in HCC impedes the development of efficacious therapies. Despite Krüpple-Like factors (KLFs) were reported to be participated in HCC pathogenesis, the function of KLF14 in HCC remains largely unexplored. METHODS: We generated KLF14 overexpressed and silenced liver cancer cells, and nude mouse xenograft models for the in vitro and in vivo study. Luciferase reporter assay, ChIP-qPCR, Co-IP, immunofluorescence were performed for mechanism research. The expression of KLF14 in HCC samples was analyzed by quantitative RT-PCR, Western blotting, and immunohistochemistry (IHC) analysis. RESULTS: KLF14 was significantly downregulated in human HCC tissues, which was highly correlated with poor prognosis. Inhibition of KLF14 promoted liver cancer cells proliferation and overexpression of KLF14 suppressed cells growth. KLF14 exerts its anti-tumor function by inhibiting Iron-responsive element-binding protein 2 (IRP2), which then causes transferrin receptor-1(TfR1) downregulation and ferritin upregulation on the basis of IRP-IREs system. This then leading to cellular iron deficiency and HCC cells growth suppression in vitro and in vivo. Interestingly, KLF14 suppressed the transcription of IRP2 via recruiting SIRT1 to reduce the histone acetylation of the IRP2 promoter, resulting in iron depletion and cell growth suppression. More important, we found fluphenazine is an activator of KLF14, inhibiting HCC cells growth through inducing iron deficiency. CONCLUSION: KLF14 acts as a tumor suppressor which inhibits the proliferation of HCC cells by modulating cellular iron metabolism via the repression of IRP2. We identified Fluphenazine, as an activator of KLF14, could be a potential compound for HCC therapy. Our findings therefore provide an innovative insight into the pathogenesis of HCC and a promising therapeutic target.
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Carcinoma Hepatocelular , Proteína 2 Reguladora do Ferro , Ferro , Fatores de Transcrição Kruppel-Like , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Flufenazina , Regulação Neoplásica da Expressão Gênica , Homeostase , Ferro/metabolismo , Proteína 2 Reguladora do Ferro/genética , Proteína 2 Reguladora do Ferro/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismoRESUMO
Long non-coding RNAs (lncRNAs) are emerging important epigenetic regulators in metabolic processes. Whether they contribute to the metabolic effects of vertical sleeve gastrectomy (VSG), one of the most effective treatments for sustainable weight loss and metabolic improvement, is unknown. Herein, we identify a hepatic lncRNA Gm19619, which is strongly repressed by VSG but highly up-regulated by diet-induced obesity and overnight-fasting in mice. Forced transcription of Gm19619 in the mouse liver significantly promotes hepatic gluconeogenesis with the elevated expression of G6pc and Pck1. In contrast, AAV-CasRx mediated knockdown of Gm19619 in high-fat diet-fed mice significantly improves hepatic glucose and lipid metabolism. Mechanistically, Gm19619 is enriched along genomic regions encoding leptin receptor (Lepr) and transcription factor Foxo1, as revealed in chromatin isolation by RNA purification (ChIRP) assay and is confirmed to modulate their transcription in the mouse liver. In conclusion, Gm19619 may enhance gluconeogenesis and lipid accumulation in the liver.
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Lipogênese , RNA Longo não Codificante , Animais , Camundongos , Dieta Hiperlipídica , Regulação para Baixo , Gastrectomia , Gluconeogênese/genética , Lipogênese/genética , Fígado/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
Auditory neuropathy spectrum disorder (ANSD) represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function, but with the preservation of outer hair cell function. ANSD represents up to 15% of individuals with hearing impairments. Through mutation screening, bioinformatic analysis and expression studies, we have previously identified several apoptosis-inducing factor (AIF) mitochondria-associated 1 (AIFM1) variants in ANSD families and in some other sporadic cases. Here, to elucidate the pathogenic mechanisms underlying each AIFM1 variant, we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and constructed AIF-wild type (WT) and AIF-mutant (mut) (p.|T260A, p.|R422W, and p.|R451Q) stable transfection cell lines. We then analyzed AIF structure, coenzyme-binding affinity, apoptosis, and other aspects. Results revealed that these variants resulted in impaired dimerization, compromising AIF function. The reduction reaction of AIF variants had proceeded slower than that of AIF-WT. The average levels of AIF dimerization in AIF variant cells were only 34.5%|â|49.7% of that of AIF-WT cells, resulting in caspase-independent apoptosis. The average percentage of apoptotic cells in the variants was 12.3%|â|17.9%, which was significantly higher than that (6.9%|â|7.4%) in controls. However, nicotinamide adenine dinucleotide (NADH) treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells. Our findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD, and introduce NADH as a potential drug for ANSD treatment. Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies.
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Fator de Indução de Apoptose , NAD , Humanos , Fator de Indução de Apoptose/química , Fator de Indução de Apoptose/genética , Fator de Indução de Apoptose/metabolismo , NAD/metabolismo , Dimerização , ApoptoseRESUMO
Auditory neuropathy spectrum disorder (ANSD) is a hearing impairment caused by dysfunction of inner hair cells, ribbon synapses, spiral ganglion neurons and/or the auditory nerve itself. Approximately 1/7000 newborns have abnormal auditory nerve function, accounting for 10%-14% of cases of permanent hearing loss in children. Although we previously identified the AIFM1 c.1265 G > A variant to be associated with ANSD, the mechanism by which ANSD is associated with AIFM1 is poorly understood. We generated induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells (PBMCs) via nucleofection with episomal plasmids. The patient-specific iPSCs were edited via CRISPR/Cas9 technology to generate gene-corrected isogenic iPSCs. These iPSCs were further differentiated into neurons via neural stem cells (NSCs). The pathogenic mechanism was explored in these neurons. In patient cells (PBMCs, iPSCs, and neurons), the AIFM1 c.1265 G > A variant caused a novel splicing variant (c.1267-1305del), resulting in AIF p.R422Q and p.423-435del proteins, which impaired AIF dimerization. Such impaired AIF dimerization then weakened the interaction between AIF and coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4). On the one hand, the mitochondrial import of ETC complex subunits was inhibited, subsequently leading to an increased ADP/ATP ratio and elevated ROS levels. On the other hand, MICU1-MICU2 heterodimerization was impaired, leading to mCa2+ overload. Calpain was activated by mCa2+ and subsequently cleaved AIF for its translocation into the nucleus, ultimately resulting in caspase-independent apoptosis. Interestingly, correction of the AIFM1 variant significantly restored the structure and function of AIF, further improving the physiological state of patient-specific iPSC-derived neurons. This study demonstrates that the AIFM1 variant is one of the molecular bases of ANSD. Mitochondrial dysfunction, especially mCa2+ overload, plays a prominent role in ANSD associated with AIFM1. Our findings help elucidate the mechanism of ANSD and may lead to the provision of novel therapies.
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Fator de Indução de Apoptose , Cálcio , Células-Tronco Pluripotentes Induzidas , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Criança , Humanos , Recém-Nascido , Fator de Indução de Apoptose/genética , Fator de Indução de Apoptose/metabolismo , Cálcio/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucócitos Mononucleares/metabolismo , Mitocôndrias/metabolismo , Neurônios/metabolismo , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial/genética , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial/metabolismoRESUMO
Hypertrophic cardiomyopathy (HCM) is the most prominent cause of sudden cardiac death in young people. Due to heterogeneity in clinical manifestations, conventional HCM drugs have limitations for mitochondrial hypertrophic cardiomyopathy. Discovering more effective compounds would be of substantial benefit for further elucidating the pathogenic mechanisms of HCM and treating patients with this condition. We previously reported the MT-RNR2 variant associated with HCM that results in mitochondrial dysfunction. Here, we screened a mitochondria-associated compound library by quantifying the mitochondrial membrane potential of HCM cybrids and the survival rate of HCM-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in galactose media. 1-Deoxynojirimycin (DNJ) was identified to rescue mitochondrial function by targeting optic atrophy protein 1 (OPA1) to promote its oligomerization, leading to reconstruction of the mitochondrial cristae. DNJ treatment further recovered the physiological properties of HCM iPSC-CMs by improving Ca2+ homeostasis and electrophysiological properties. An angiotensin II-induced cardiac hypertrophy mouse model further verified the efficacy of DNJ in promoting cardiac mitochondrial function and alleviating cardiac hypertrophy in vivo. These results demonstrated that DNJ could be a potential mitochondrial rescue agent for mitochondrial hypertrophic cardiomyopathy. Our findings will help elucidate the mechanism of HCM and provide a potential therapeutic strategy.
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1-Desoxinojirimicina , Cardiomiopatia Hipertrófica , Animais , Camundongos , 1-Desoxinojirimicina/farmacologia , 1-Desoxinojirimicina/metabolismo , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Cardiomegalia/tratamento farmacológico , Cardiomegalia/genética , Cardiomegalia/metabolismoRESUMO
Nuclear receptor farnesoid X receptor (FXR) is generally considered a cell protector of enterohepatic tissues and a suppressor of liver cancer and colorectal carcinoma (CRC). Loss or reduction of FXR expression occurs during carcinogenesis, and the FXR level is inversely associated with the aggressive behaviors of the malignancy. Global deletion of FXR and tissue-specific deletion of FXR display distinct effects on tumorigenesis. Epigenetic silencing and inflammatory context are two main contributors to impaired FXR expression and activity. FXR exerts its antitumorigenic function via the following mechanisms: 1) FXR regulates multiple metabolic processes, notably bile acid homeostasis; 2) FXR antagonizes hepatic and enteric inflammation; 3) FXR impedes aberrant activation of some cancer-related pathways; and 4) FXR downregulates a number of oncogenes while upregulating some tumor suppressor genes. Restoring FXR functions via its agonists provides a therapeutic approach for patients with liver cancer and CRC. However, an in-depth understanding of the species-specific pharmacological effects is a prerequisite for assessing the clinical safety and efficacy of FXR agonists in human cancer treatment.
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Neoplasias Colorretais , Neoplasias Hepáticas , Receptores Citoplasmáticos e Nucleares/metabolismo , Ácidos e Sais Biliares/metabolismo , Neoplasias Colorretais/metabolismo , Humanos , Fígado/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Receptores Citoplasmáticos e Nucleares/genéticaRESUMO
Combinatorial auction is an important type of market mechanism, which can help bidders to bid on the combination of items more efficiently. The winner determination problem (WDP) is one of the most challenging research topics on the combinatorial auction, which has been proven to be NP-hard. It has more attention from researchers in recent years and has a wide range of real-world applications. To solve the winner determination problem effectively, this paper proposes a hybrid ant colony algorithm called DHS-ACO, which combines an effective local search for exploitation and an ant colony algorithm for exploration, with two effective strategies. One is a hash tabu search strategy adopted to reduce the cycling problem in the local search procedure. Another is a deep scoring strategy which is introduced to consider the profound effects of the local operators. The experimental results on a broad range of benchmarks show that DHS-ACO outperforms the existing algorithms.