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1.
Mol Cell ; 80(4): 607-620.e12, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33113344

RESUMO

Aberrant mitophagy has been implicated in a broad spectrum of disorders. PINK1, Parkin, and ubiquitin have pivotal roles in priming mitophagy. However, the entire regulatory landscape and the precise control mechanisms of mitophagy remain to be elucidated. Here, we uncover fundamental mitophagy regulation involving PINK1 and a non-canonical role of the mitochondrial Tu translation elongation factor (TUFm). The mitochondrion-cytosol dual-localized TUFm interacts with PINK1 biochemically and genetically, which is an evolutionarily conserved Parkin-independent route toward mitophagy. A PINK1-dependent TUFm phosphoswitch at Ser222 determines conversion from activating to suppressing mitophagy. PINK1 modulates differential translocation of TUFm because p-S222-TUFm is restricted predominantly to the cytosol, where it inhibits mitophagy by impeding Atg5-Atg12 formation. The self-antagonizing feature of PINK1/TUFm is critical for the robustness of mitophagy regulation, achieved by the unique kinetic parameters of p-S222-TUFm, p-S65-ubiquitin, and their common kinase PINK1. Our findings provide new mechanistic insights into mitophagy and mitophagy-associated disorders.


Assuntos
Drosophila melanogaster/crescimento & desenvolvimento , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Mitofagia , Fator Tu de Elongação de Peptídeos/metabolismo , Proteínas Quinases/metabolismo , Animais , Citosol/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Feminino , Células HeLa , Humanos , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Fator Tu de Elongação de Peptídeos/genética , Fosforilação , Domínios e Motivos de Interação entre Proteínas , Proteínas Quinases/genética , Transporte Proteico , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
2.
Langmuir ; 40(13): 6862-6868, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38385757

RESUMO

We report on a synthesis protocol, experimental characterization, and theoretical modeling of active pulsatile Belousov-Zhabotinsky (BZ) hydrogels. Our two-step synthesis technique allows independent optimization of the geometry, the chemical, and the mechanical properties of BZ gels. We identify the role of the surrounding medium chemistry and gel radius for the occurrence of BZ gel oscillations, quantified by the Damköhler number, which is the ratio of chemical reaction to diffusion rates. Tuning the BZ gel size to maximize its chemomechanical oscillation amplitude, we find that its oscillatory strain amplitude is limited by the time scale of gel swelling relative to the chemical oscillation period. Our experimental findings are in good agreement with a Vanag-Epstein model of BZ chemistry and a Tanaka Fillmore theory of gel swelling dynamics.

3.
BMC Pediatr ; 24(1): 104, 2024 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-38341530

RESUMO

BACKGROUND: Mitochondrial diseases are heterogeneous in terms of clinical manifestations and genetic characteristics. The dynamin 1-like gene (DNM1L) encodes dynamin-related protein 1 (DRP1), a member of the GTPases dynamin superfamily responsible for mitochondrial and peroxisomal fission. DNM1L variants can lead to mitochondrial fission dysfunction. CASE PRESENTATION: Herein, we report a distinctive clinical phenotype associated with a novel variant of DNM1L and review the relevant literature. A 5-year-old girl presented with paroxysmal hemiplegia, astigmatism, and strabismus. Levocarnitine and coenzyme Q10 supplement showed good efficacy. Based on the patient's clinical data, trio whole-exome sequencing (trio-WES) and mtDNA sequencing were performed to identify the potential causative genes, and Sanger sequencing was used to validate the specific variation in the proband and her family members. The results showed a novel de novo heterozygous nonsense variant in exon 20 of the DNM1L gene, c.2161C>T, p.Gln721Ter, which is predicted to be a pathogenic variant according to the ACMG guidelines. The proband has a previously undescribed clinical manifestation, namely hemiparesis, which may be an additional feature of the growing phenotypic spectrum of DNM1L-related diseases. CONCLUSION: Our findings elucidate a novel variant in DNM1L-related disease and reveal an expanding phenotypic spectrum associated with DNM1L variants. This report highlights the necessity of next generation sequencing for early diagnosis of patients, and that further clinical phenotypic and genotypic analysis may help to improve the understanding of DNM1L-related diseases.


Assuntos
Dinaminas , Proteínas Associadas aos Microtúbulos , Feminino , Humanos , Pré-Escolar , Proteínas Associadas aos Microtúbulos/genética , Dinaminas/genética , Dinaminas/metabolismo , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Fenótipo , Mitocôndrias
4.
FASEB J ; 36(8): e22446, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35816159

RESUMO

d-alanine (d-Ala) and several other d-amino acids (d-AAs) act as hormones and neuromodulators in nervous and endocrine systems. Unlike the endogenously synthesized d-serine in animals, d-Ala may be from exogenous sources, e.g., diet and intestinal microorganisms. However, it is unclear if the capability to produce d-Ala and other d-AAs varies among different microbial strains in the gut. We isolated individual microorganisms of rat gut microbiota and profiled their d-AA production in vitro, focusing on d-Ala. Serial dilutions of intestinal contents from adult male rats were plated on agar to obtain clonal cultures. Using MALDI-TOF MS for rapid strain typing, we identified 38 unique isolates, grouped into 11 species based on 16S rRNA gene sequences. We then used two-tier screening to profile bacterial d-AA production, combining a d-amino acid oxidase-based enzymatic assay for rapid assessment of non-acidic d-AA amount and chiral LC-MS/MS to quantify individual d-AAs, revealing 19 out of the 38 isolated strains as d-AA producers. LC-MS/MS analysis of the eight top d-AA producers showed high levels of d-Ala in all strains tested, with substantial inter- and intra-species variations. Though results from the enzymatic assay and LC-MS/MS analysis aligned well, LC-MS/MS further revealed the existence of d-glutamate and d-aspartate, which are poor substrates for this enzymatic assay. We observed large inter- and intra-species variation of d-AA production profiles from rat gut microbiome species, demonstrating the importance of chemical profiling of gut microbiota in addition to sequencing, furthering the idea that microbial metabolites modulate host physiology.


Assuntos
Microbioma Gastrointestinal , Alanina , Aminoácidos/metabolismo , Animais , Cromatografia Líquida , Microbioma Gastrointestinal/fisiologia , Masculino , RNA Ribossômico 16S/genética , Ratos , Espectrometria de Massas em Tandem
5.
Int J Clin Oncol ; 28(11): 1487-1500, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37634210

RESUMO

BACKGROUND: Aberrant expression of SWI/SNF complex subunits is closely associated with tumorigenesis. The clinicopathological and prognostic significance of altered SMARCA2 and SMARCA4 subunits has not been well evaluated in gastric adenocarcinoma. METHODS: We collected 1271 postoperative cases of gastric adenocarcinoma and then constructed tissue microarrays (TMA), from which we obtained the immunohistochemistry expression of SMARCA2 and SMARCA4. Next, we screened the variables related to the loss of SMARCA2 and SMARCA4 by univariate correlation analysis and multivariate logistic regression analysis. Then, we identified the variables related to prognosis by univariate and multivariate Cox regression analysis. Finally, we constructed a nomogram prognostic model and evaluated it. RESULTS: The loss of SMARCA2 and SMARCA4 occurred in 236 (18.57%) and 86 (6.77%) cases, respectively, including 26 cases of co-loss. After multivariate logistic regression, variables independently associated with SMARCA2 loss were T stage, differentiation status, WHO histological classification, and EBER. Variables independently associated with SMARCA4 loss were differentiation status, WHO histological classification, PD-L1, and MMR. Survival analysis revealed that the SMARCA2 and SMARCA4 lost groups showed worse survival than the corresponding present groups (P = 0.032 and P = 0.0048, respectively). Univariate and multivariate Cox analyses identified independent prognostic factors, including age, T stage, N stage, M stage, SMARCA2, and chemotherapy. CONCLUSION: The loss of SMARCA2 and SMARCA4 correlated with poor differentiation, leading to a worse prognosis. SMARCA2, as an independent prognostic factor, combined with other clinicopathological variables, established a novel nomogram prognostic model, which outperformed the AJCC TNM model.


Assuntos
Adenocarcinoma , Neoplasias Gástricas , Humanos , Prognóstico , Nomogramas , Adenocarcinoma/genética , Adenocarcinoma/patologia , Carcinogênese , Transformação Celular Neoplásica , Neoplasias Gástricas/genética , Fatores de Transcrição/genética , DNA Helicases/genética , Proteínas Nucleares/genética
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 40(7): 787-794, 2023 Jul 10.
Artigo em Zh | MEDLINE | ID: mdl-37368378

RESUMO

OBJECTIVE: To explore the clinical and genetic characteristics of four patients with medium-chain acyl-CoA dehydrogenase deficiency (MCADD). METHODS: Four children who had presented at the Children's Hospital Affiliated to Zhengzhou University between August 2019 and August 2021 were selected as the study subjects. Clinical data of the children were collected. The children were subjected to whole exome sequencing (WES). RESULTS: All of the four children were diagnosed with MCADD. Blood amino acid and ester acyl carnitine spectrum test showed that the concentration of octanoyl carnitine (C8) was significantly increased. The main clinical manifestations included poor mental response (3 cases), intermittent diarrhea with abdominal pain (1 case), vomiting (1 case), increased transaminase (3 cases), and metabolic acidosis (2 cases). Five variants were identified by genetic testing, among which c.341A>G (p.Y114C) was unreported previously. Three were missense variants, one was frameshift variant and one was splicing variant. CONCLUSION: The clinical heterogeneity of MCADD is obvious, and the severity of the disease may vary. WES can assist with the diagnosis. Delineation of the clinical symptoms and genetic characteristics of the disease can facilitate early diagnosis and treatment of the disease.


Assuntos
Erros Inatos do Metabolismo Lipídico , Triagem Neonatal , Criança , Humanos , Acil-CoA Desidrogenase/genética , Carnitina , Testes Genéticos , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 40(7): 842-846, 2023 Jul 10.
Artigo em Zh | MEDLINE | ID: mdl-37368387

RESUMO

OBJECTIVE: To explore the clinical features and genetic basis of a child with Galactosemia. METHODS: A child who had presented at the Children's Hospital Affiliated to Zhengzhou University on November 20, 2019 was selected as the study subject. Clinical data of the child was collected. Whole exome sequencing was carried out for the child. Candidate variants were validated by Sanger sequencing. RESULTS: Clinical manifestations of the child have included anemia, feeding difficulty, jaundice, hypomyotonia, abnormal liver function and coagulation abnormality. Tandem mass spectrometry showed increased citrulline, methionine, ornithine and tyrosine. Urine organic acid analysis showed increased phenyllactic acid, 4-hydroxyphenylacetic acid, 4-hydroxyphenyllactic acid, 4-hydroxyphenylpyruvate and N-acetyltyrosine. Genetic testing revealed that the child has harbored compound heterozygous variants of the GALT gene, namely c.627T>A (p.Y209*) and c.370G>C (p.G124R), which were respectively inherited from her healthy parents. Among these, c.627T>A (p.Y209*) was known as a likely pathogenic variant, while c.370G>C (p. G124R) was unreported previously and also predicted as a likely pathogenic variant(PM1+PM2_Supporting+PP3_Moderate+PPR). CONCLUSION: Above discovery has expanded the spectrum of the GALT gene variants underlying Galactosemia. Patients with thrombocytopenia, feeding difficulties, jaundice, abnormal liver function and coagulation abnormality without obvious causes should be analyzed by screening of metabolic diseases in combination with genetic testing.


Assuntos
Galactosemias , Criança , Feminino , Humanos , Galactosemias/genética , Testes Genéticos , Nível de Saúde , Metionina , Hipotonia Muscular , Mutação
8.
Langmuir ; 38(26): 8114-8124, 2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35731984

RESUMO

Many biological species combine the helical organization of cellulose or chitin microfibrils with broadband light absorption of black melanin to produce brilliant structural colors with metallic and glossy effects and other diverse functions. In this work, based on core-shell CNC@PDA chiral nanorods consisting of cellulose nanocrystals (CNCs) as the core and melanin-like polydopamine (PDA) as the shell that can form well-defined chiral liquid crystal phases, we report chiral photonic materials that closely mimic the unique coloration mechanisms and functionalities mastered by several biological species. The photonic films formed by such single CNC@PDA nanorods have brilliant iridescent structural colors originating from selective reflection of circularly polarized lights by the helical organization of CNC@PDAs across the films. Furthermore, the colors of such films have background-independent brightness, high visibility, and metallic effects that arise from the light absorption of the PDA component. Especially, the color ranges and metallic effects of the films can be conveniently tuned by varying the thickness of the PDA shell. In addition, the UV absorption and hygroscopic properties of PDA endow these CNC@PDA films with efficient broadband UV shielding and sensitive humidity-induced dynamic color changes. Due to the mussel-like superior adhesion of PDA, CNC@PDA-based photonic coatings can be formed conformably onto diverse kinds of substrates. A shiny eye shadow with viewing angle-dependent colorful patterns was used to demonstrate the potential applications. With combinations of multiple unique properties in one photonic material fabricated from a single building block, these CNC@PDA-based films are expected to have potential applications in cosmetics, UV protection, anticounterfeiting, chiral reflectors, etc.


Assuntos
Cosméticos , Nanotubos , Biomimética , Celulose/química , Umidade , Melaninas/química
9.
World J Surg Oncol ; 20(1): 383, 2022 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-36464671

RESUMO

BACKGROUND: The switch/sucrose nonfermentable (SWI/SNF) complex is an evolutionarily conserved chromatin remodeling complex that displays dysfunction in many tumors, especially undifferentiated carcinoma. Cancer stem cells (CSC), a special type of undifferentiated cancer cells with stem cell-like properties, play an essential role in tumor cell proliferation, invasion, and metastasis. In undifferentiated gastric carcinomas, the association of SWI/SNF complexes with clinicopathological features, CSC phenotype, and the prognosis is not fully understood. METHODS: We collected a cohort of 21 patients with undifferentiated/dedifferentiated gastric carcinoma. We next performed immunohistochemistry staining for the five subunits of the SWI/SNF complex (ARID1A, ARID1B, SMARCA2, SMARCA4, and SMARCB1), and four mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6), as well as other markers such as p53, PD-L1, and cancer stem cell (CSC) markers (SOX2, SALL4). Then, we investigated the correlation of SWI/SNF complex subunits with clinicopathological characters and performed prognostic analysis. RESULTS: We observed SMARCA2 loss in 12 cases (57.14%), followed by ARID1A (5 cases, 23.81%) and SMARCA4 (3 cases, 14.29%). Fourteen cases (66.67%) lost any one of the SWI/SNF complex subunits, including 3 cases with SMARCA2 and ARID1A co-loss, and 3 cases with SMARCA2 and SMARCA4 co-loss. Correlation analysis revealed that the CSC phenotype occurred more frequently in the SWI/SNF complex deficient group (P = 0.0158). Survival analysis revealed that SWI/WNF complex deficiency, undifferentiated status, CSC phenotype, and the loss of SMARCA2 and SMARCA4 resulted in worse survival. Univariate and multivariate Cox regression analyses screened out three independent factors associated with worse prognosis: undifferentiated status, SWI/SNF complex deficiency, and lymph node metastasis. CONCLUSIONS: The SWI/SNF complex deficiency was more likely to result in a CSC phenotype and worse survival and was an independent prognostic factor in undifferentiated/dedifferentiated gastric carcinoma.


Assuntos
Células-Tronco Neoplásicas , Neoplasias Gástricas , Humanos , Carcinoma/genética , Carcinoma/patologia , DNA Helicases , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Nucleares , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Sacarose , Fatores de Transcrição , Desdiferenciação Celular/genética
10.
Artigo em Inglês | MEDLINE | ID: mdl-35289322

RESUMO

BACKGROUND: SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily A, Member 2) is an important ATPase catalytic subunit in the switch-sucrose nonfermenting (SWI/SNF) complex. However, its relationship with the pathological features of NSCLC and its prognosis remain unclear. METHODS: We retrospectively reviewed 2390 patients with surgically resected NSCLC, constructed tissue microarrays (TMAs) and performed immunohistochemical assays. We analyzed the correlation of SAMRCA2 with clinicopathological features and evaluated its prognostic value. RESULTS: Among 2390 NSCLC cases, the negative expression ratios of SAMRCA2, SMARCA4, ARID1A, ARID1B and INI1 were 9.3%, 1.8%, 1.2%, 0.4% and 0%, respectively. In NSCLC, male sex, T3 and T4 stage, moderate and poor differentiation, tumor ≥ 2 cm, Ki67 ≥ 15%, SOX-2 negative expression, middle lobe lesion and adenocarcinoma were relative risk factors affecting SMARCA2-negative expression. In lung adenocarcinomas, high-grade nuclei, histological morphology of acinar and papillary, solid and micropapillary and TTF-1-negative expression were relative risk factors affecting SMARCA2-negative expression. Kaplan-Meier survival analysis showed that the OS was shorter in the SMARCA2-negative group. Multivariate survival analysis revealed that SMARCA2-negative expression was an independent factor correlated with a poor prognosis in NSCLC. CONCLUSION: In conclusion, SMARCA2-negative expression is an independent predictor of a poor outcome of NSCLC and is a potential target for NSCLC treatment.


Assuntos
Adenosina Trifosfatases , Carcinoma Pulmonar de Células não Pequenas/genética , Fatores de Transcrição , Adenosina Trifosfatases/metabolismo , Humanos , Masculino , Estudos Retrospectivos , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética
11.
Angew Chem Int Ed Engl ; 61(6): e202114414, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34889011

RESUMO

Lanthipeptides are a group of ribosomally synthesized and post-translationally modified peptides with diverse structural features and bioactivities. Gut-microbiota-derived lanthipeptides play important roles in gut homeostasis of the host. Herein, we report the discovery and biosynthesis of class III lantibiotics named amylopeptins, which are derived from the gut microbiota of Sprague-Dawley rats and display a narrow antimicrobial spectrum. In contrast to known class III lanthipeptides, the biosynthesis of amylopeptins employs AmyP, which belongs to a subgroup of S8 family serine proteases, to remove the leader of corresponding precursor peptides in a site-specific manner during the last step of their maturation. Overall, this study shows for the first time that S8 family proteases participate in the biosynthesis of class III lanthipeptides.


Assuntos
Bacillus amyloliquefaciens/genética , Bacteriocinas/biossíntese , Peptídeo Hidrolases/metabolismo , Animais , Bacillus amyloliquefaciens/metabolismo , Bacteriocinas/química , Bacteriocinas/genética , Microbioma Gastrointestinal , Peptídeo Hidrolases/genética , Ratos , Ratos Sprague-Dawley
12.
Cell Tissue Res ; 383(2): 809-821, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33159581

RESUMO

Stem cell transplantation is a promising therapy for wound healing, but the low retention and survival of transplanted stem cells limit their application. Injectable hydrogels exert beneficial effects in skin tissue engineering. In this study, an injectable hydrogel composed of sodium alginate (SA) and collagen type I (Col) was synthesized as a tissue scaffold to improve the efficacy of stem cells in a full-thickness excision wound model. Our results showed that SA/Col hydrogel was injectable, biodegradable, and exhibited low immunogenicity, which could promote the retention and survival of hUC-MSCs in vivo. SA/Col loaded with hUC-MSCs showed reduced wound size (p < 0.05). Histological and immunofluorescence results confirmed that SA/Col loaded with hUC-MSCs significantly promoted the formation of granulation, enhanced collagen deposition and angiogenesis, increased VEGF and TGF-ß1 expression (p < 0.05), and mitigated inflammation evidenced by lower production of TNF-α and IL-1ß and higher release of IL-4 and IL-10 (p < 0.05). Furthermore, SA/Col loaded with hUC-MSCs significantly lowered the expression of NLRP3 inflammasome-related proteins (p < 0.05). Taken together, our results suggest that SA/Col loaded with hUC-MSCs promotes skin wound healing via partly inhibiting NLRP3 pathway, which has potential to the treatment of skin wounds.


Assuntos
Alginatos/farmacologia , Colágeno/farmacologia , Hidrogéis/farmacologia , Células-Tronco Mesenquimais/citologia , Pele/efeitos dos fármacos , Cordão Umbilical/citologia , Cicatrização , Animais , Materiais Biocompatíveis/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Inflamação/patologia , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
13.
BMC Cancer ; 21(1): 999, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493229

RESUMO

BACKGROUND: There are differences in survival between high-and low-grade Upper Tract Urothelial Carcinoma (UTUC). Our study aimed to develop a nomogram to predict overall survival (OS) of patients with high- and low-grade UTUC after tumor resection, and to explore the difference between high- and low-grade patients. METHODS: Patients confirmed to have UTUC between 2004 and 2015 were selected from the Surveillance, Epidemiology and End Results (SEER) database. The UTUCs were identified and classified as high- and low-grade, and 1-, 3- and 5-year nomograms were established. The nomogram was then validated using the Chinese multicenter dataset (patients diagnosed in Shandong, China between January 2010 and October 2020). RESULTS: In the high-grade UTUC patients, nine important factors related to survival after tumor resection were identified to construct nomogram. The C index of training dataset was 0.740 (95% confidence interval [CI]: 0.727-0.754), showing good calibration. The C index of internal validation dataset was 0.729(95% CI:0.707-0.750). On the other hand, Two independent predictors were identified to construct nomogram of low-grade UTUC. The C index was 0.714 (95% CI: 0.671-0.758) for the training set,0.731(95% CI:0.670-0.791) for the internal validation dataset. Encouragingly, the nomogram was clinically useful and had a good discriminative ability to identify patients at high risk. CONCLUSION: We constructed a nomogram and a corresponding risk classification system predicting the OS of patients with an initial diagnosis of high-and low-grade UTUC.


Assuntos
Modelos Estatísticos , Nomogramas , Programa de SEER/estatística & dados numéricos , Neoplasias da Bexiga Urinária/mortalidade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia
14.
Biogerontology ; 22(2): 165-187, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33502634

RESUMO

Aging is a physiological process mediated by numerous biological and genetic pathways, which are directly linked to lifespan and are a driving force for all age-related diseases. Human life expectancy has greatly increased in the past few decades, but this has not been accompanied by a similar increase in their healthspan. At present, research on aging biology has focused on elucidating the biochemical and genetic pathways that contribute to aging over time. Several aging mechanisms have been identified, primarily including genomic instability, telomere shortening, and cellular senescence. Aging is a driving factor of various age-related diseases, including neurodegenerative diseases, cardiovascular diseases, cancer, immune system disorders, and musculoskeletal disorders. Efforts to find drugs that improve the healthspan by targeting the pathogenesis of aging have now become a hot topic in this field. In the present review, the status of aging research and the development of potential drugs for aging-related diseases, such as metformin, rapamycin, resveratrol, senolytics, as well as caloric restriction, are summarized. The feasibility, side effects, and future potential of these treatments are also discussed, which will provide a basis to develop novel anti-aging therapeutics for improving the healthspan and preventing aging-related diseases.


Assuntos
Envelhecimento , Longevidade , Restrição Calórica , Senescência Celular , Humanos , Expectativa de Vida
15.
Toxicol Appl Pharmacol ; 395: 114971, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32217144

RESUMO

MS-275 has been demonstrated to inhibit the growth of esophageal squamous cell carcinoma (ESCC) cells in our previous study, but its role in ESCC remains to be further explored. Cisplatin (cis-diamminedichloroplatinum II, DDP) is the first-line chemotherapeutic drug widely used in clinic for ESCC patients. However, the side effects of nephrotoxicity and drug resistance limit its clinical use. This study aimed to evaluate the anticancer effects of MS-275 combined with DDP on ESCC cell line EC9706 both in vitro and in vivo, and to investigate the possible mechanisms that mediate these effects. We found that MS-275 combined with DDP showed synergistic antitumor effects on EC9706 cells in vitro by decreasing cell proliferation, increasing apoptosis and oxidative damage, and inhibiting migration and stemness. The combination of MS-275 and DDP triggered pro-survival autophagy in EC9706. Moreover, MS-275 combined with DDP suppressed EC9706 xenografts growth and promoted apoptosis in vivo. Further study displayed that MS-275 combined with DDP suppressed Wnt/ß-catenin signaling in EC9706 cells and xenografts. These results indicate that MS-275 combined with DDP exerts synergistic antitumor effects by enhancing the chemosensitivity of EC9706 cells to DDP, which may be a potential therapeutic strategy for the treatment of patients with ESCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas/administração & dosagem , Cisplatino/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Piridinas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Biomacromolecules ; 21(6): 2376-2390, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32364722

RESUMO

The current work investigates how the nanoscale conformal coating layers of non-chiral polymeric materials can influence the chiral nematic liquid crystal (CLC) behaviors of the rodlike cellulose nanocrystals (CNCs), the bio-derived nanomaterials that have attracted significant attention. For this, we developed strategies to coat the CNC rods on the single-particle level with a homogeneous bioinspired polydopamine (PDA) layer, leading to well-defined core-shell CNC@PDA rods with various PDA coating thicknesses and excellent colloidal stability. Comprehensive investigation revealed that the CNC@PDA hybrid nanorods in concentrated suspensions form well-defined nematic liquid crystal phases with clear phase separation behavior that depend on the rod concentrations and ionic strengths, typical of charged rods. Most intriguingly, the nematic LC phases formed by the CNC@PDA rods with the PDA coating thickness achieved herein are indeed the perfect CLC phases, which form following the classic pathway of nucleation and coalesce of chiral tactoids and have colorful chiral fingerprints standing out from the dark suspensions. The pitches of the CLC phase increase sharply with increasing PDA coating thicknesses and are significantly larger than those of the pristine CNCs. Such observations can be attributed to the blurring effects of the PDA coating on the intrinsic surface chiral features of CNC of whatever origins that drive the formation of the CLC phases, resulting in weakening chiral interactions between CNC@PDA rods. Besides benefiting the understanding of the long-sought origin of the CLC phases of the pristine CNC, the current work demonstrates the possibility of controlling the CLC phase behaviors of CNC by tuning the thickness of the coating materials and also serves as the first example of directly transferring the unique chirality of CNC to other non-chiral materials.


Assuntos
Cristais Líquidos , Nanopartículas , Nanoestruturas , Celulose , Suspensões
17.
Bioorg Chem ; 104: 104246, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32911197

RESUMO

Cryptotanshinone (1), a major bioactive constituent in the traditional Chinese medicinal herb Dan-Shen Salvia miltiorrhiza Bunge, has been reported to possess remarkable pharmacological activities. To improve its bioactivities and physicochemical properties, in the present study, cryptotanshinone (1) was biotransformed with the fungus Cunninghamella elegans AS3.2028. Three oxygenated products (2-4) at C-3 of cryptotanshinone (1) were obtained, among them 2 was a new compound. Their structures were elucidated by comprehensive spectroscopic analysis including HRESIMS, NMR and ECD data. All of the biotransformation products (2-4) were found to inhibit significantly lipopolysaccharide-induced nitric oxide production in BV2 microglia cells with the IC50 values of 0.16-1.16 µM, approximately 2-20 folds stronger than the substrate (1). These biotransformation products also displayed remarkably improved inhibitory effects on the production of inflammatory cytokines (IL-1ß, IL-6, TNF-α, COX-2 and iNOS) in BV-2 cells via targeting TLR4 compared to substrate (1). The underlying mechanism of 2 was elucidated by comparative transcriptome analysis, which suggested that it reduced neuroinflammatory mainly through mitogen-activated protein kinase (MAPK) signaling pathway. Western blotting results revealed that 2 downregulated LPS-induced phosphorylation of JNK, ERK, and p38 in MAPK signaling pathway. These findings provide a basal material for the discovery of candidates in treating Alzheimer's disease.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores da Colinesterase/farmacologia , Cunninghamella/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Fenantrenos/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Acetilcolinesterase/metabolismo , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Biotransformação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Cunninghamella/química , Relação Dose-Resposta a Droga , Electrophorus , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estrutura Molecular , Oxigênio/metabolismo , Fenantrenos/química , Fenantrenos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Receptor 4 Toll-Like/metabolismo
18.
Soft Matter ; 15(32): 6504-6517, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31343046

RESUMO

Under external pressure compression, various kinds of artificial microcapsules can undergo buckling induced deformation and catastrophic rupturing failure, which needs to be understood for their diverse practical applications. For this, many theories and numerical simulations have recently emerged, leading to some intriguing but often debatable predictions and scaling laws. However, experimental testing of these predictions is very limited, due to challenges in realizing prescribed buckling pathways and in situ monitoring of the buckling procedure. Herein, we report the buckling behaviors of well-defined spherical polydopamine (PDA) capsules with tunable sizes and homogeneous nanoscale shells. Simple but controlled solvent evaporation was implemented inside a home-made optical chamber to induce buckling of PDA capsules by following a prescribed pathway toward targeted shapes that are only dictated by the inherent material properties of the capsules. In addition, the buckling speed was slowed down to the timescale of minutes, which can prevent buckling from being trapped at some metastable intermediate states as well as facilitating in situ optical monitoring of the whole buckling procedure in slow motion. In this way, several classic buckling behaviors were clearly observed, including the sudden appearance of spinodal-like dimples above critical pressures, transition of the indentation rim from the axisymmetric to polygonal shape, and evolution of multi-indented buckling into single indented buckling following Ostwald ripening. These observations are qualitatively comparable with recent predictions from numerical results. Furthermore, some novel buckling phenomena have been reported for the first time, which might stimulate further theories and numerical simulations.

19.
Soft Matter ; 15(5): 833-841, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30488939

RESUMO

The linear and nonlinear rheological behavior of two rod-like particle suspensions as a function of concentration is studied using small amplitude oscillatory shear, steady shear and capillary breakup extensional rheometry. The rod-like suspensions are composed of fd virus and its mutant fdY21M, which are perfectly monodisperse, with a length on the order of 900 nm. The particles are semiflexible yet differ in their persistence length. The effect of stiffness on the rheological behavior in both, shear and extensional flow, is investigated experimentally. The linear viscoelastic shear data is compared in detail with theoretical predictions for worm-like chains. The extensional properties are compared to Batchelor's theory, generalized for the shear thinning nature of the suspensions. Theoretical predictions agree well with the measured complex moduli at low concentrations as well as the nonlinear shear and elongational viscosities at high flow rates. The results in this work provide guidelines for enhancing the elongational viscosity based on purely frictional effects in the absence of strong normal forces which are characteristic for high molecular weight polymers.

20.
Appl Opt ; 58(4): 826-832, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30874126

RESUMO

We demonstrate a broadband aberration-corrected snapshot spectrometer by developing a toroidal slicer mirror as the focusing mirror. A collimating slicer mirror and an integrated grating divide the entire wavelength range into several windows. The toroidal sub-mirrors of the focusing mirror compensate for the coma and correct the astigmatism at different windows to compress the spectral spots over the waveband. From 200 to 1000 nm, the RMS spot radii are less than 30 µm and the spectral resolution at 600 nm is 151.8 pm. The optics have a small volume of 11 cm×11 cm×1.5 cm by employing a folded structure.

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