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1.
Mol Neurobiol ; 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38965172

RESUMO

A pathological hallmark of Alzheimer's disease (AD) is the region-specific accumulation of the amyloid-beta protein (Aß), which triggers aberrant neuronal excitability, synaptic impairment, and progressive cognitive decline. Previous works have demonstrated that Aß pathology induced aberrant elevation in the levels and excessive enzymatic hydrolysis of voltage-gated sodium channel type 2 beta subunit (Navß2) in the brain of AD models, accompanied by alteration in excitability of hippocampal neurons, synaptic deficits, and subsequently, cognitive dysfunction. However, the mechanism is unclear. In this research, by employing cell models treated with toxic Aß1-42 and AD mice, the possible effects and potential mechanisms induced by Navß2. The results reveal that Aß1-42 induces remarkable increases in Navß2 intracellular domain (Navß2-ICD) and decreases in both BDNF exons and protein levels, as well as phosphorylated tropomyosin-related kinase B (pTrkB) expression in cells and mice, coupled with cognitive impairments, synaptic deficits, and aberrant neuronal excitability. Administration with exogenous Navß2-ICD further enhances these effects induced by Aß1-42, while interfering the generation of Navß2-ICD and/or complementing BDNF neutralize the Navß2-ICD-conducted effects. Luciferase reporter assay verifies that Navß2-ICD regulates BDNF transcription and expression by targeting its promoter. Collectively, our findings partially elucidate that abnormal enzymatic hydrolysis of Navß2 induced by Aß1-42-associated AD pathology leads to intracellular Navß2-ICD overload, which may responsible to abnormal neuronal excitability, synaptic deficit, and cognition dysfunction, through its transcriptional suppression on BDNF. Therefore, this work supplies novel evidences that Navß2 plays crucial roles in the occurrence and progression of cognitive impairment of AD by transcriptional regulatory activity of its cleaved ICD.

2.
Molecules ; 29(12)2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38930839

RESUMO

A tumor-targeting fluorescent probe has attracted increasing interest in fluorescent imaging for the noninvasive detection of cancers in recent years. Sulfonamide-containing naphthalimide derivatives (SN-2NI, SD-NI) were synthesized by the incorporation of N-butyl-4-ethyldiamino-1,8-naphthalene imide (NI) into sulfonamide (SN) and sulfadiazine (SD) as the tumor-targeting groups, respectively. These derivatives were further characterized by mass spectrometry (MS), nuclear magnetic resonance spectroscopy (1H NMR), Fourier transform infrared spectroscopy (FT-IR), ultraviolet-visible spectroscopy (UV), and a fluorescence assay. In vitro properties, including cell cytotoxicity and the cell uptake of tumor cells, were also evaluated. Sulfonamide-containing naphthalimide derivatives possessed low cell cytotoxicity to B16F10 melanoma cells. Moreover, SN-2NI and SD-NI can be taken up highly by B16F10 cells and then achieve good green fluorescent images in B16F10 cells. Therefore, sulfonamide-containing naphthalimide derivatives can be considered to be the potential probes used to target fluorescent imaging in tumors.


Assuntos
Corantes Fluorescentes , Naftalimidas , Sulfonamidas , Naftalimidas/química , Naftalimidas/síntese química , Sulfonamidas/química , Sulfonamidas/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Animais , Camundongos , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Espectroscopia de Infravermelho com Transformada de Fourier , Sobrevivência Celular/efeitos dos fármacos
3.
Mar Pollut Bull ; 205: 116547, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38875965

RESUMO

The shallow hydrothermal vents (HVs) of Kueishan Island are considered as a template for studying the extremes of sulfide-polluted and acidified water. The present study examined the biological and spatiotemporal aspects of mesozooplankton mortality in waters around this extreme HV environment. Zooplankton sample collection was carried out in three monsoonal periods and the results revealed that there was a significant decrease in the mortality of total mesozooplankton with increasing distance from the HVs. The overall mortality of mesozooplankton showed a significant negative correlation with sea surface temperature and pH. Particularly, mortality of copepods showed a significant negative correlation with pH, whereas it was significantly positive correlated with sea surface temperature in the southwest monsoon prevailing period. Overall, the results may imply a situation that zooplankton will encounter in the more acidified environment of a future ocean.

4.
Front Neurol ; 15: 1330102, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38715687

RESUMO

Objective: Temporal lobe epilepsy (TLE) is a prevalent refractory partial epilepsy seen in clinical practice, with most cases originating from the hippocampus and being characterized by impaired learning and memory. Oxidative stress plays a direct role in the development of epilepsy and neurodegeneration while promoting cognitive dysfunction. Previous research indicates that benzyl isothiocyanate (BITC) has antioxidative stress properties and contributes to neuroprotection. In this study, we aimed to investigate the neuroprotective effect of BITC on a lithium-pilocarpine-induced temporal lobe epileptic mice model. Methods: We conducted Intellicage learning tests, Morris water maze, open field test, and step-down-type passive avoidance tests, respectively. In addition, body weight and brain-to-body ratio were calculated. Nissl staining, real-time quantitative PCR detection of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1) and NAD(P)H dehydrogenase quinone 1(NQO1) were performed. Content of malondialdehyde (MDA) and activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and total antioxidant capacity (T-AOC) were determined. Results: Our results demonstrate that BITC enhances cognitive function and motor ability in mice, as determined by Intellicage learning tests, Morris water maze, open field test, and step-down-type passive avoidance tests, respectively. Epilepsy leads to the loss of neurons in the CA3 region, while BITC treatment plays a positive role in neuroprotection, especially in the cortex. In comparison to the control group, the EP group exhibited decreased transcription levels of HO-1 and NQO1, alongside reduced GSH-Px activity, while MDA content was elevated. Conversely, the BITC treatment group, when compared to the EP group, showed enhanced transcription levels of Nrf2, HO-1, and NQO1, along with increased GSH-Px activity, and a decrease in MDA content. Conclusion: In summary, our study provides evidence that BITC can improve cognitive impairments in pilocarpine-induced epileptic mice, demonstrating significant antioxidant effects and neuroprotective properties. This highlights its potential as a phytochemical for managing the sequelae of epilepsy.

5.
J Sci Food Agric ; 104(11): 6778-6786, 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-38567792

RESUMO

BACKGROUND: This study explored the denaturation of 11S globulin, a protein known for its diverse functional properties in soy protein applications, at pH 3.0 and pH 10.0, followed by a gradual return to pH 7.0 to facilitate renaturation. It investigated the structural and functional changes during renaturation induced by a change in pH, revealing the stabilization mechanism of 11S globulin. RESULTS: The findings revealed that during pH adjustment to neutral, the denatured soybean 11S globulin - resulting from alkaline (pH 10.0) or acidic (pH 3.0) treatments - experienced a refolding of its extended tertiary structure to varying extents. The particle size and the proportions of α-helix and ß-sheet in the secondary structure aligned progressively with those of the natural-state protein. However, for the alkali-denatured 11S, the ß-sheet content decreased upon adjustment to neutral, whereas an increase was observed for the acid-denatured 11S. In terms of functional properties, after alkaline denaturation, the foaming capacity (FC) and emulsifying activity index (EAI) of 11S increased by 1.4 and 1.2 times, respectively, in comparison with its native state. The solubility, foamability, and emulsifiability of the alkali-denatured 11S gradually diminished during renaturation but remained superior to those of the native state. Conversely, these properties showed an initial decline, followed by an increase during renaturation triggered by pH neutralization. CONCLUSIONS: This research contributes to the enhancement of protein functionality, offering a theoretical foundation for the development of functional soy protein products and expanding their potential applications. © 2024 Society of Chemical Industry.


Assuntos
Globulinas , Glycine max , Desnaturação Proteica , Proteínas de Soja , Concentração de Íons de Hidrogênio , Globulinas/química , Glycine max/química , Proteínas de Soja/química , Solubilidade , Estrutura Secundária de Proteína
6.
RSC Adv ; 14(13): 9020-9031, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38500630

RESUMO

Integrase plays an important role in the life cycle of HIV-1, and integrase strand transfer inhibitors (INSTIs) can effectively impair the viral replication. However, drug resistance mutations have been confirmed to decrease the efficacy of INSTI during the antiviral therapy. Herein, indole-2-carboxylic acid (1) was found to inhibit the strand transfer of integrase, and the indole nucleus of compound 1 was observed to chelate with two Mg2+ ions within the active site of integrase. Through optimization of compound 1, a series of indole-2-carboxylic acid derivatives were designed and synthesized, and compound 17a was proved to markedly inhibit the effect of integrase, with IC50 value of 3.11 µM. Binding mode analysis of 17a demonstrated that the introduced C6 halogenated benzene ring could effectively bind with the viral DNA (dC20) through π-π stacking interaction. These results indicated that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.

7.
Osteoporos Int ; 35(6): 1049-1059, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38459138

RESUMO

PURPOSE: This study aimed to apply a newly developed semi-automatic phantom-less QCT (PL-QCT) to measure proximal humerus trabecular bone density based on chest CT and verify its accuracy and precision. METHODS: Subcutaneous fat of the shoulder joint and trapezius muscle were used as calibration references for PL-QCT BMD measurement. A self-developed algorithm based on a convolution map was utilized in PL-QCT for semi-automatic BMD measurements. CT values of ROIs used in PL-QCT measurements were directly used for phantom-based quantitative computed tomography (PB-QCT) BMD assessment. The study included 376 proximal humerus for comparison between PB-QCT and PL-QCT. Two sports medicine doctors measured the proximal humerus with PB-QCT and PL-QCT without knowing each other's results. Among them, 100 proximal humerus were included in the inter-operative and intra-operative BMD measurements for evaluating the repeatability and reproducibility of PL-QCT and PB-QCT. RESULTS: A total of 188 patients with 376 shoulders were involved in this study. The consistency analysis indicated that the average bias between proximal humerus BMDs measured by PB-QCT and PL-QCT was 1.0 mg/cc (agreement range - 9.4 to 11.4; P > 0.05, no significant difference). Regression analysis between PB-QCT and PL-QCT indicated a good correlation (R-square is 0.9723). Short-term repeatability and reproducibility of proximal humerus BMDs measured by PB-QCT (CV: 5.10% and 3.41%) were slightly better than those of PL-QCT (CV: 6.17% and 5.64%). CONCLUSIONS: We evaluated the bone quality of the proximal humeral using chest CT through the semi-automatic PL-QCT system for the first time. Comparison between it and PB-QCT indicated that it could be a reliable shoulder BMD assessment tool with acceptable accuracy and precision. This study developed and verify a semi-automatic PL-QCT for assessment of proximal humeral bone density based on CT to assist in the assessment of proximal humeral osteoporosis and development of individualized treatment plans for shoulders.


Assuntos
Densidade Óssea , Osso Esponjoso , Úmero , Tomografia Computadorizada por Raios X , Humanos , Densidade Óssea/fisiologia , Masculino , Feminino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X/métodos , Idoso , Reprodutibilidade dos Testes , Úmero/diagnóstico por imagem , Úmero/fisiologia , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/fisiopatologia , Osso Esponjoso/fisiologia , Algoritmos , Imagens de Fantasmas , Adulto , Osteoporose/fisiopatologia , Osteoporose/diagnóstico por imagem , Idoso de 80 Anos ou mais
9.
Mol Pharm ; 21(3): 1537-1547, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38356224

RESUMO

Mitochondria-targeting photothermal therapy could significantly enhance the tumor cell killing effect. However, since therapeutic reagents need to overcome a series of physiological obstacles to arrive at mitochondria accurately, precise mitochondria-targeting photothermal therapy still faces great challenges. In this study, we developed a self-delivery nanoplatform that specifically targeted the mitochondria of tumor cells for precise photothermal therapy. Photothermal agent IR780 was encapsulated by amphiphilic apoptotic peptide KLA with mitochondria-targeting ability to form nanomicelle KI by self-assembly through hydrophilic and hydrophobic interactions. Subsequently, negatively charged tumor-targeting polymer HA was coated on the surface of KI through electrostatic interactions, to obtain tumor mitochondria-targeting self-delivery nanoplatform HKI. Through CD44 receptor-mediated recognition, HKI was internalizated by tumor cells and then disassembled in an acidic environment with hyaluronidase in endosomes, resulting in the release of apoptotic peptide KLA and photothermal agent IR780 with mitochondria anchoring capacity, which achieved precise mitochondria guidance and destruction. This tumor mitochondria-targeting self-delivery nanoplatform was able to effectively deliver photothermal agents and apoptotic peptides to tumor cell mitochondria, resulting in precise destruction to mitochondria and enhancing tumor cell inhibition at the subcellular organelle level.


Assuntos
Nanopartículas , Neoplasias , Humanos , Terapia Fototérmica , Peptídeos , Mitocôndrias , Apoptose , Nanopartículas/química , Linhagem Celular Tumoral , Fototerapia
10.
Sci Adv ; 10(3): eadf8666, 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38241376

RESUMO

Fiber-optic distributed acoustic sensing (DAS) has proven to be a revolutionary technology for the detection of seismic and acoustic waves with ultralarge scale and ultrahigh sensitivity, and is widely used in oil/gas industry and intrusion monitoring. Nowadays, the single-frequency laser source in DAS becomes one of the bottlenecks limiting its advance. Here, we report a dual-comb-based coherently parallel DAS concept, enabling linear superposition of sensing signals scaling with the comb-line number to result in unprecedented sensitivity enhancement, straightforward fading suppression, and high-power Brillouin-free transmission that can extend the detection distance considerably. Leveraging 10-line comb pairs, a world-class detection limit of 560 fε/√Hz@1 kHz with 5 m spatial resolution is achieved. Such a combination of dual-comb metrology and DAS technology may open an era of extremely sensitive DAS at the fε/√Hz level, leading to the creation of next-generation distributed geophones and sonars.

11.
Mol Pharm ; 21(2): 467-480, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38266250

RESUMO

Photothermal therapy (PTT) is an effective cancer treatment method. Due to its easy focusing and tunability of the irradiation light, direct and accurate local treatment can be performed in a noninvasive manner by PTT. This treatment strategy requires the use of photothermal agents to convert light energy into heat energy, thereby achieving local heating and triggering biochemical processes to kill tumor cells. As a key factor in PTT, the photothermal conversion ability of photothermal agents directly determines the efficacy of PTT. In addition, photothermal agents generally have photothermal imaging (PTI) and photoacoustic imaging (PAI) functions, which can not only guide the optimization of irradiation conditions but also achieve the integration of disease diagnosis. If the photothermal agents have function of fluorescence imaging (FLI) or fluorescence enhancement, they can not only further improve the accuracy in disease diagnosis but also accurately determine the tumor location through multimodal imaging for corresponding treatment. In this paper, we summarize recent advances in photothermal agents with FLI or fluorescence enhancement functions for PTT and tumor diagnosis. According to the different recognition sites, the application of specific targeting photothermal agents is introduced. Finally, limitations and challenges of photothermal agents with fluorescence imaging/enhancement in the field of PTT and tumor diagnosis are prospected.


Assuntos
Nanopartículas , Neoplasias , Humanos , Fototerapia/métodos , Terapia Fototérmica , Linhagem Celular Tumoral , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Nanomedicina Teranóstica/métodos , Imagem Óptica
12.
World J Clin Cases ; 12(1): 86-94, 2024 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-38292647

RESUMO

BACKGROUND: The obesity rate of adolescents is gradually increasing, which seriously affects their mental health, and sleep plays an important role in adolescent obesity. AIM: To investigate the relationship between sleep rhythm and obesity among adolescents and further explores the interactive effect of sleep rhythm and gender on adolescent obesity, providing a theoretical basis for developing interventions for adolescent obesity. METHODS: Research data source Tianjin Mental Health Promotion Program for Students. From April to June 2022, this study selected 14201 students from 13 middle schools in a certain district of Tianjin as the research subject using the convenient cluster sampling method. Among these students, 13374 accepted and completed the survey, with an effective rate of 94.2%.The demographic data and basic information of adolescents, such as height and weight, were collected through a general situation questionnaire. The sleep rhythm of adolescents was evaluated using the reduced version of the morningness-eveningness questionnaire. RESULTS: A total of 13374 participants (6629 females, accounting for 49.56%; the average age is 15.21 ± 1.433 years) were analyzed. Among them, the survey showed that 2942 adolescent were obesity, accounting for 22% and 2104 adolescent were overweight, accounting for 15.7%. Among them, 1692 male adolescents are obese, with an obesity rate of 25.1%, higher than 18.9% of female adolescents. There is a statistically significant difference between the three groups (χ2 = 231.522, P < 0.000). The obesity group has the smallest age (14.94 ± 1.442 years), and there is a statistical difference in age among the three groups (F = 69.996, P < 0.000).Obesity rates are higher among individuals who are not-only-child, have residential experience within six months, have family economic poverty, and have evening-type sleep (P < 0.05). Logistic regression analysis shows a correlation between sleep rhythm and adolescent obesity. Evening-type sleep rhythm can increase the risk of obesity in male adolescents [1.250 (1.067-1.468)], but the effect on female obesity is not remarkable. Further logistic regression analysis in the overall population demonstrates that the interaction between evening-type sleep rhythm and the male gender poses a risk of adolescent obesity [1.122 (1.043-1.208)]. CONCLUSION: Among adolescents, the incidence of obesity in males is higher than in females. Evening-type sleep rhythm plays an important role in male obesity but has no significant effect on female obesity. Progressive analysis suggests an interactive effect of sleep rhythm and gender on adolescent obesity, and the combination of evening-type sleep and the male gender promotes the development of adolescent obesity. In formulating precautions against adolescent obesity, obesity in male adolescents with evening-type sleep should be a critical concern.

13.
Orthod Craniofac Res ; 27(2): 276-286, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37904627

RESUMO

OBJECTIVES: The midpalatal suture acts as the growth centre of the maxilla. Colony-stimulating factor 1 receptor (CSF1R) is essential for osteoclastogenesis. Deletion of CSF1R, and its ligand, results in significant craniofacial phenotypes but has not been studied in detail in the midpalatal suture. MATERIALS AND METHODS: Pregnant ICR mice were treated with the CSF1R inhibitor PLX5622 at embryo Day 14.5 (E14.5) to E17.5. Pups at E18.5, postnatal Day 3 (P3) and P7 were collected for skeletal and histological staining. Osteoclasts were labelled using TRAP staining. PHH3 and TUNEL were employed to detect cell proliferation and apoptosis. Sox9, Ihh, and Col10a1 and Runx2, Col1a1, and DMP1 were used to detect chondrogenic differentiation and osteogenic differentiation, respectively. CD31, MMP9 and CTSK were utilized to assess vascular invasion and osteoclast secretion enzymes, respectively. RESULTS: Embryonic inhibition of CSF1R resulted in a depletion of TRAP-positive cells and an enlarged cartilage zone of the midpalatal suture of postnatal mice. Compared to those in the control group, Sox9, Ihh, Col10a1, Runx2 and Col1a1 were upregulated, whereas TUNEL and DMP1 were decreased in this zone. In the trabecular region, Col10a1 was upregulated, while TUNEL, Col1a1 and DMP1 were downregulated. Moreover, the expression of MMP9, CTSK and CD31 was decreased, and invasion into the cartilage zone was delayed. CONCLUSIONS: Embryonic inhibition of CSF1R led to an abnormally enlarged cartilaginous zone in the midpalatal suture, potentially due to delayed endochondral ossification caused by the depletion of osteoclasts. Additionally, we established a novel model of midpalatal suture dysplasia, offering prospects for future research.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core , Osteogênese , Camundongos , Animais , Osteogênese/fisiologia , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Fator Estimulador de Colônias de Macrófagos , Metaloproteinase 9 da Matriz , Camundongos Endogâmicos ICR , Cartilagem/metabolismo , Suturas
14.
Int J Biol Macromol ; 256(Pt 1): 128372, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38000588

RESUMO

Chronic diabetic wounds represent the most common diabetes complication. Wound healing depends on scavenging reactive oxygen species (ROS), neovascularization, and controlling infection. A naturally derived gelatin-based hydrogel is biocompatible, biodegradable, does not promote inflammation, and can remove ROS, but strategies for developing a gelatin-based hydrogel currently require careful chemical modification of gelatin and time-consuming purification and post-crosslinking processing. Herein, a facile method of combining zirconium (Zr4+), gelatin, and quercetin (QCN) to generate an injectable gelatin-based hydrogel (QCN@Gel-Zr) for diabetic wound treatment was presented. Adding QCN improved the mechanical, injection, and adhesive performance of the Gel-Zr hydrogel and conferred antibacterial and free radical-scavenging abilities. These properties induced cellular proliferation and migration, protection against oxidative stress, and reduction in inflammatory expression. In vivo models of acute and chronic diabetic skin wounds were used to demonstrate biocompatibility and the ability of the gelatin hydrogels to promote wound healing. The histological analysis showed that the QCN@Gel-Zr hydrogel promoted angiogenesis, collagen deposition, and hair follicle regeneration with no detectable cytotoxicity. This study demonstrates the preparation of gelatin-based hydrogel with various flexible functions to address the complex biological requirements of diabetic wound repair.


Assuntos
Diabetes Mellitus , Gelatina , Humanos , Hidrogéis/farmacologia , Espécies Reativas de Oxigênio , Cicatrização , Antibacterianos
15.
Exp Brain Res ; 242(1): 205-224, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37994916

RESUMO

Traumatic brain injury (TBI) leads to disturbed brain discharge rhythm, elevated excitability, anxiety-like behaviors, and decreased learning and memory capabilities. Cognitive dysfunctions severely affect the quality of life and prognosis of TBI patients, requiring effective rehabilitation treatment. Evidence indicates that moderate exercise after brain injury decreases TBI-induced cognitive decline. However, the underlying mechanism remains unelucidated. Our results demonstrate that TBI causes cognitive impairment behavior abnormalities and overexpression of Nav1.1, Nav1.3 and Nav1.6 proteins inside the hippocampus of mice models. Three weeks of voluntary running wheel (RW) exercise treatments before or/and post-injury effectively redressed the aberrant changes caused by TBI. Additionally, a 10% exercise-conditioned medium helped recover cell viability, neuronal sodium current and expressions of Nav1.1, Nav1.3 and Nav1.6 proteins across cultured neurons after injury. Therefore, the results validate the neuroprotection induced by voluntary RW exercise treatment before or/and post-TBI. The RW exercise-induced improvement in cognitive behaviors and neuronal excitability could be associated with correcting the Nav1.1, Nav1.3, and Nav1.6 expression levels. The current study proves that voluntary exercise is an effective treatment strategy against TBI. The study also highlights novel potential targets for rehabilitating TBI, including the Navs proteins.


Assuntos
Lesões Encefálicas Traumáticas , Lesões Encefálicas , Canais de Sódio Disparados por Voltagem , Humanos , Camundongos , Animais , Qualidade de Vida , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/terapia , Cognição
16.
Acta Pharmaceutica Sinica B ; (6): 256-272, 2024.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wpr-1011250

RESUMO

Liver regeneration following injury aids the restoration of liver mass and the recovery of liver function. In the present study we investigated the contribution of megakaryocytic leukemia 1 (MKL1), a transcriptional modulator, to liver regeneration. We report that both MKL1 expression and its nuclear translocation correlated with hepatocyte proliferation in cell and animal models of liver regeneration and in liver failure patients. Mice with MKL1 deletion exhibited defective regenerative response in the liver. Transcriptomic analysis revealed that MKL1 interacted with E2F1 to program pro-regenerative transcription. MAPKAPK2 mediated phosphorylation primed MKL1 for its interaction with E2F1. Of interest, phospholipase d2 promoted MKL1 nuclear accumulation and liver regeneration by catalyzing production of phosphatidic acid (PA). PA administration stimulated hepatocyte proliferation and enhanced survival in a MKL1-dependent manner in a pre-clinical model of liver failure. Finally, PA levels was detected to be positively correlated with expression of pro-regenerative genes and inversely correlated with liver injury in liver failure patients. In conclusion, our data reveal a novel mechanism whereby MKL1 contributes to liver regeneration. Screening for small-molecule compounds boosting MKL1 activity may be considered as a reasonable approach to treat acute liver failure.

17.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-1005902

RESUMO

Objective To analyze the data of prostate cancer in Wuhan from 2010 to 2019, understand the characteristics and trends of incidence, mortality, and YLL, and provide decision-making basis for Wuhan's cancer prevention and control strategies. Methods Data on deaths and incident cases of prostate cancer in Wuhan from 2010 to 2019 and from 2013 to 2017, respectively, were collected from the Wuhan Death Monitoring System. Indicators such as incidence rate, mortality rate, and years of life lost due to premature death (YLL) of prostate cancer in Wuhan were calculated using Excel 2016 and Python. The Bayesian Age-Period-Cohort Model (BAPC) was used to predict the mortality rate of prostate cancer in Wuhan from 2020 to 2024. The trend changes were described using the annual average percentage change (AAPC). Results From 2010 to 2019, the incidence, mortality, and YLL rates of prostate cancer in Wuhan showed an overall increasing trend (AAPC >0, P <0.05). The standardized mortality and incidence rates in the central urban area were significantly higher than those in the outer urban area, and the age group of 85 and above had the highest incidence and mortality rates. The age group of 0-54 had the largest increase in incidence and mortality rates. From 2020 to 2024, prostate cancer in Wuhan is expected to continue to increase slightly (an increase of 0.94%). Conclusion The incidence, mortality, and YLL rates of prostate cancer in Wuhan are showing an overall increasing trend, and this trend may continue. The characteristics are higher in the central urban area than in the outer urban area, and higher in the older age group than in the younger age group. Targeted measures need to be taken, and screening for high-risk populations should be strengthened.

18.
Molecules ; 28(24)2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38138510

RESUMO

As an important antiviral target, HIV-1 integrase plays a key role in the viral life cycle, and five integrase strand transfer inhibitors (INSTIs) have been approved for the treatment of HIV-1 infections so far. However, similar to other clinically used antiviral drugs, resistance-causing mutations have appeared, which have impaired the efficacy of INSTIs. In the current study, to identify novel integrase inhibitors, a set of molecular docking-based virtual screenings were performed, and indole-2-carboxylic acid was developed as a potent INSTI scaffold. Indole-2-carboxylic acid derivative 3 was proved to effectively inhibit the strand transfer of HIV-1 integrase, and binding conformation analysis showed that the indole core and C2 carboxyl group obviously chelated the two Mg2+ ions within the active site of integrase. Further structural optimizations on compound 3 provided the derivative 20a, which markedly increased the integrase inhibitory effect, with an IC50 value of 0.13 µM. Binding mode analysis revealed that the introduction of a long branch on C3 of the indole core improved the interaction with the hydrophobic cavity near the active site of integrase, indicating that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.


Assuntos
Infecções por HIV , Inibidores de Integrase de HIV , Integrase de HIV , HIV-1 , Humanos , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/química , Simulação de Acoplamento Molecular , Integrase de HIV/metabolismo , Infecções por HIV/tratamento farmacológico , Indóis/farmacologia , Indóis/uso terapêutico , Domínio Catalítico , Farmacorresistência Viral , Mutação
19.
J Vis Exp ; (200)2023 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-37930003

RESUMO

Knee osteoarthritis (KOA) is one of the most frequently encountered diseases in the orthopedic department, which seriously reduces the quality of life of people with KOA. Among several pathogenic factors, the biomechanical imbalance of the knee joint is one of the main causes of KOA. Acupotomology believes that restoring the mechanical balance of the knee joint is the key to treating KOA. Clinical studies have shown that acupotomy can effectively reduce pain and improve knee mobility by reducing adhesion, contracture of soft tissues, and stress concentration points in muscles and tendons around the knee joint. In this protocol, we used the modified Videman method to establish a KOA model by immobilizing the left hindlimb in a straight position. We have outlined the method of operation and the precautions related to acupotomy in detail and evaluated the efficacy of acupotomy in conjunction with the theory of "Modulating Muscles and Tendons to Treat Bone Disorders" through the detection of the mechanical properties of quadriceps femoris and tendon, as well as cartilage mechanics and morphology. The results show that acupotomy has a protective effect on cartilage by adjusting the mechanical properties of the soft tissues around the knee joint, improving the cartilage stress environment, and delaying cartilage degeneration.


Assuntos
Terapia por Acupuntura , Osteoartrite do Joelho , Humanos , Animais , Coelhos , Osteoartrite do Joelho/terapia , Qualidade de Vida , Terapia por Acupuntura/métodos , Articulação do Joelho/cirurgia , Cartilagem
20.
J Tradit Chin Med ; 43(4): 734-743, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37454258

RESUMO

OBJECTIVE: To investigate the effects of acupotomy on the subchondral bone absorption and mechanical properties in rabbits with knee osteoarthritis (KOA). METHODS: The rabbits were divided into blank control, model, acupotomy and electroacupuncture (EA) groups, with 12 rabbits in each. Modified Videman's method was used to prepare KOA model. The acupotomy and EA group were given indicated intervention for 3 weeks. The behavior of rabbits in each group was recorded. Subsequently, cartilage-subchondral bone units were obtained and morphological changes were observed by optical microscope and micro computed tomography. Compression test was used to detect the mechanical properties of subchondral bone, Western blot and real-time polymerase chain reaction (RT-PCR) were applied to detect the expression of bone morphogenetic protein 2-Smad1 (BMP2-Smad1) pathway in subchondral bone. RESULTS: Compared with the control group, rabbits in the KOA group showed lameness, knee pain, and cartilage degradation; the subchondral bone showed active resorption, the mechanical properties decreased significantly and the BMP2-Smad1 pathway downregulated significantly. Both acupotomy and EA intervention could increase the thickness of trabecular bone (Tb. Th), the bone volume fraction (BV/TV) and the thickness of subchondral bone plate, reduce the separation of trabecular bone (Tb. Sp), improve the maximum load and elastic modulus of subchondral bone, and effectively delay cartilage degeneration in KOA rabbits. This process may be achieved through upregulation the related proteins of BMP2-Smad1 pathway. The maximum load and elastic modulus of subchondral bone in the acupotomy group were slightly better than those in the EA group. CONCLUSIONS: Acupotomy could effectively protect cartilage by inhibiting abnormal bone resorption and improving mechanical properties of subchondral bone thorough the related proteins of BMP2-Smad1 pathway in KOA rabbits.


Assuntos
Terapia por Acupuntura , Cartilagem Articular , Osteoartrite do Joelho , Animais , Coelhos , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/terapia , Osteoartrite do Joelho/metabolismo , Microtomografia por Raio-X , Proteína Morfogenética Óssea 2/genética , Articulação do Joelho , Cartilagem Articular/metabolismo
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