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1.
Int Wound J ; 21(4): e14758, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38629618

RESUMO

A meta-analysis was conducted to comprehensively explore the effects of platelet-rich plasma (PRP) combined with negative pressure wound therapy (NPWT) in treating patients with chronic wounds. Computer searches were conducted, from database infection to November 2023, in EMBASE, Google Scholar, Cochrane Library, PubMed, Wanfang and China National Knowledge Infrastructure databases for randomized controlled trials (RCTs) on the use of PRP combined with NPWT technology for treating chronic wounds. Two researchers independently screened the literature, extracted data and conducted quality assessments according to the inclusion and exclusion criteria. Stata 17.0 software was employed for data analysis. Overall, 18 RCTs involving 1294 patients with chronic wounds were included. The analysis revealed that, compared with NPWT alone, the use of PRP combined with NPWT technology significantly improved the healing rate (odds ratios [OR] = 1.92, 95% confidence intervals [CIs]: 1.43-2.58, p < 0.001) and total effective rate (OR = 1.31, 95% CI: 1.23-1.39, p < 0.001), and also significantly shortened the healing time of the wound (standardized mean difference = -2.01, 95% CI: -2.58 to -1.45, p < 0.001). This study indicates that the treatment of chronic wounds with PRP combined with NPWT technology can significantly enhance clinical repair effectiveness and accelerate wound healing, with a high healing rate, and is worth further promotion and practice.


Assuntos
Tratamento de Ferimentos com Pressão Negativa , Plasma Rico em Plaquetas , Humanos , Cicatrização , Bandagens , China
2.
Cell Mol Life Sci ; 81(1): 185, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38630271

RESUMO

When cells proliferate, stress on DNA replication or exposure to endogenous or external insults frequently results in DNA damage. DNA-Damage Response (DDR) networks are complex signaling pathways used by multicellular organisms to prevent DNA damage. Depending on the type of broken DNA, the various pathways, Base-Excision Repair (BER), Nucleotide Excision Repair (NER), Mismatch Repair (MMR), Homologous Recombination (HR), Non-Homologous End-Joining (NHEJ), Interstrand Crosslink (ICL) repair, and other direct repair pathways, can be activated separately or in combination to repair DNA damage. To preserve homeostasis, innate and adaptive immune responses are effective defenses against endogenous mutation or invasion by external pathogens. It is interesting to note that new research keeps showing how closely DDR components and the immune system are related. DDR and immunological response are linked by immune effectors such as the cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway. These effectors act as sensors of DNA damage-caused immune response. Furthermore, DDR components themselves function in immune responses to trigger the generation of inflammatory cytokines in a cascade or even trigger programmed cell death. Defective DDR components are known to disrupt genomic stability and compromise immunological responses, aggravating immune imbalance and leading to serious diseases such as cancer and autoimmune disorders. This study examines the most recent developments in the interaction between DDR elements and immunological responses. The DDR network's immune modulators' dual roles may offer new perspectives on treating infectious disorders linked to DNA damage, including cancer, and on the development of target immunotherapy.


Assuntos
Doenças Autoimunes , Neoplasias , Humanos , Imunidade Adaptativa , Citocinas , Apoptose , Neoplasias/genética
3.
Nat Commun ; 15(1): 1429, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38365899

RESUMO

Senescence of vascular smooth muscle cells (VSMCs) contributes to aging-related cardiovascular diseases by promoting arterial remodelling and stiffness. Ferroptosis is a novel type of regulated cell death associated with lipid oxidation. Here, we show that pro-ferroptosis signaling drives VSMCs senescence to accelerate vascular NAD+ loss, remodelling and aging. Pro-ferroptotic signaling is triggered in senescent VSMCs and arteries of aged mice. Furthermore, the activation of pro-ferroptotic signaling in VSMCs not only induces NAD+ loss and senescence but also promotes the release of a pro-senescent secretome. Pharmacological or genetic inhibition of pro-ferroptosis signaling, ameliorates VSMCs senescence, reduces vascular stiffness and retards the progression of abdominal aortic aneurysm in mice. Mechanistically, we revealed that inhibition of pro-ferroptotic signaling facilitates the nuclear-cytoplasmic shuttling of proliferator-activated receptor-γ and, thereby impeding nuclear receptor coactivator 4-ferrtin complex-centric ferritinophagy. Finally, the activated pro-ferroptotic signaling correlates with arterial stiffness in a human proof-of-concept study. These findings have significant implications for future therapeutic strategies aiming to eliminate vascular ferroptosis in senescence- or aging-associated cardiovascular diseases.


Assuntos
Doenças Cardiovasculares , Músculo Liso Vascular , Humanos , Animais , Camundongos , Senescência Celular/genética , Doenças Cardiovasculares/metabolismo , NAD/metabolismo , Células Cultivadas , Envelhecimento/fisiologia , Artérias , Miócitos de Músculo Liso/metabolismo
4.
Adv Sci (Weinh) ; : e2305715, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38417117

RESUMO

Drug-induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non-canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP-DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP-DILI. Mice with hepatocyte-specific rescue of GSDME reproduced APAP-induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP-induced DILI, such as the replacement of TIM4+ resident Kupffer cells (KCs) by monocyte-derived KCs, Ly6C+ monocyte infiltration, MerTk+ macrophages depletion, and neutrophil increase, reappeared in mice with hepatocyte-specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon-stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase-1 (CPS1), promoted its degradation via K48-linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl-fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP-DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP-DILI.

5.
Sci Total Environ ; 912: 169002, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38040347

RESUMO

Lake ice, as a crucial component of the cryosphere, serves as a sensitive indicator of climate change. Fine-scale monitoring of spatiotemporal patterns in lake ice phenology holds significant importance in scientific research and environmental management. However, the rapid and dynamic nature of the freeze-thaw process of lake ice poses challenges to existing methods, resulting in their limited application in small lakes. In this study, we propose a novel approach of investigating ice phenology of lakes in various sizes. We conducted a case study in Hoh Xil, known for its vulnerability to climate change and a wide distribution of small lakes, to analyze the ice phenology of 372 lakes (>1 km2) during 2017-2021. Firstly, ensemble machine-learning model was developed for lake ice identification from Landsat-8/9 and Sentinel-2 A/B imagery. The accuracy evaluation reveals the overall good performance for ice extraction results based on Landsat-8/9 (97.03 %) and Sentinel-2 A/B (96.89 %). Next, the XGBoost models were employed to reconstruct ice coverages on unobserved dates for the freezeup and breakup periods, respectively. Totally, 744 XGBoost models were constructed for the study lakes, and the majority of them perform well. Based on the reconstructed daily ice coverage, phenology parameters could be extracted for examining the spatiotemporal characteristics of ice cover and possible relationships with lake sizes and terrains. From early-October to early-November, the Hoh Xil lakes freeze from the northwest to the southeast, while the breakup period starts in late-March and lasts until late-June. Moreover, the results indicate relatively small variability in freezeup-end dates among lakes, but significant differences in breakup dates, showing a greater sensitivity to temperature variations. Furthermore, ice phenology in small lakes exhibit stronger consistency with subtle climatic fluctuations. The results highlight the significant role of ice phenology in small lakes, as they dominate the overall tendency of ice phenology in Hoh Xil.

6.
Redox Biol ; 67: 102930, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37847980

RESUMO

Benzo[α]pyrene (Bap) is recognized as a ubiquitous environmental pollutant among the polycyclic aromatic hydrocarbons (PAHs) class. Previous studies have shown that the hepatotoxicity of Bap is mainly caused by its metabolites, although it remains unclear whether Bap itself induces such damage. This study integrated metabolomics and chemical proteomics approaches to comprehensively identify the potential target proteins affected by Bap in liver cells. The results from the metabolomics showed that the significant changed metabolites were related with cellular redox homeostasis. CEllular Thermal Shift Assay (CETSA) showed that Bap induced protein thermal displacement of superoxide dismutase 3 (SOD3) and glutathione peroxidase 4 (GPX4), which are closely related to oxidative homeostasis. Further validation through in vitro CETSA and drug affinity response target stability (DARTS) revealed that Bap directly affected the stability of SOD3 and GPX4 proteins. The binding affinities of Bap to the potential target proteins were further evaluated using molecular docking, while the isothermal titration calorimetry (ITC) interaction measurements indicated nanomolar-level Kd values. Importantly, we found that Bap weakened the antioxidant capacity by destroying the activities of SOD3 and GPX4, which provided a new understanding of the mechanism of hepatotoxicity induced by Bap. Moreover, our provided workflow integrating metabolomics and label-free chemical proteomics, can be regarded as a practical way to identify the targets and inter-mechanisms for the various environmental compounds.


Assuntos
Benzo(a)pireno , Doença Hepática Induzida por Substâncias e Drogas , Humanos , Benzo(a)pireno/toxicidade , Proteômica/métodos , Simulação de Acoplamento Molecular , Superóxido Dismutase , Proteínas , Doença Hepática Induzida por Substâncias e Drogas/etiologia
7.
Psychol Res Behav Manag ; 16: 3413-3425, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37664140

RESUMO

Background: To promote the balanced development with the population, China has phased out a one-child policy in 2016, and a two-child policy was launched, which has led to dramatic changes in family structure. The transition could be a huge challenge for adolescents who are in a period of psychological vulnerability. Purpose: This study explored the differences and predictors of family dynamics and functioning between two-child and one-child families in the context of China's two-child policy. Methods: We used the Self-rating scale of Systemic Family Dynamics (SSFD) and Family Assessment Device-General Functioning (FAD-GF) to investigate the family dynamics, family functioning, and family structure and status of 3289 adolescents under the background of China's two-child policy. Results: Results revealed that the mean scores for family atmosphere, personalization, disease concept, overall family dynamics, and family functioning health rate of the one-child families were higher than those of the two-child families. Parental marital status, mother's education, annual household income, and family economic satisfaction in two-child and one-child families was positively correlated with family dynamics and functioning, but not significantly associated with living style, parental age and employment. Family financial satisfaction, parental marital status, and distress in the family were predictors of family dynamics and functioning, and parental preference was also an important factor in two-child families. Conclusion: The findings suggest family atmosphere, personality, disease concept, family dynamics, and family functioning of the one-child families were better than those of the two-child families. Unlike one-child families, parental preference is an important predictor of family dynamics and functioning in two child families. This study increases our understanding of adolescents psychological problems during family structure transitions under the background of fertility policy, providing psychologists with more evidence-based evidence and intervention directions.

8.
Int J Biol Macromol ; 253(Pt 3): 126934, 2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-37722640

RESUMO

N6-methyladenosine (m6A) is the most prevalent chemical modifications of intracellular RNA, which recently emerging as a multifaceted effector of viral genomic RNA. As a dynamic process, three groups of biological proteins control the levels of m6A modification in eukaryocyte, designed as m6A writers, erasers, and readers. The m6A writers comprising of methyltransferases complex initiate the modification process. On the contrary, the m6A erasers ALKBH5 or FTO abolish the modification through three-step demethylation: m6A to N6-hydroxymethyl adenosine (hm6A), then hm6A to N6-methyladenosine (f6A), and finally f6A to adenosine. The known m6A readers include the YTH family and the hnRNP family. As m6A modification regulates RNA nuclear exportation, stability, and translation, m6A proteins commonly participate in virus infection by regulating viral genomic RNA synthesis. Moreover, m6A proteins establish molecular linkages between virus genome/viral encode proteins and host cells proteins via their multifunctional roles in cellular RNA metabolism. The m6A writers and erasers directly impact interferon expression and macrophage innate immune responses, facilitating them to act as anti-/pro-viral factors. The m6A readers enable to alter cell metabolism and stress granules (SGs) production to regulate virus-host interactions. Here, the latest progress of m6A proteins in regulating viral infection is reviewed. Demonstrating the roles of m6A proteins will enhance the understanding of epigenetic regulation of virus infection and stimulate the development of novel antiviral strategies.


Assuntos
Epigênese Genética , Viroses , Humanos , RNA Viral , Adenosina/metabolismo , Viroses/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética
9.
bioRxiv ; 2023 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-37745514

RESUMO

Sympathetic nerves co-develop with their target organs and release neurotransmitters to stimulate their functions after maturation. Here, we provide the molecular mechanism that during sweat gland morphogenesis, neurotransmitters released from sympathetic nerves act first to promote sweat duct elongation via norepinephrine and followed by acetylcholine to specify sweat gland stem cell fate, which matches the sequence of neurotransmitter switch. Without neuronal signals during development, the basal cells switch to exhibit suprabasal (luminal) cell features. Sarcolipin (SLN), a key regulator of sarcoendoplasmic reticulum (SR) Ca 2+ -ATPase (SERCA), expression is significantly down-regulated in the sweat gland myoepithelial cells upon denervation. Loss of SLN in sweat gland myoepithelial cells leads to decreased intracellular Ca 2+ over time in response to ACh stimulation, as well as upregulation of luminal cell features. In cell culture experiments, we showed that contrary to the paradigm that elevation of Ca 2+ promote epidermal differentiation, specification of the glandular myoepithelial (basal) cells requires high Ca 2+ while lowering Ca 2+ level promotes luminal (suprabasal) cell fate. Our work highlights that neuronal signals not only act transiently for mature sweat glands to function, but also exert long-term impact on glandular stem cell specification through regulating intracellular Ca 2+ dynamics.

10.
ACS Chem Neurosci ; 14(17): 2995-3012, 2023 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-37579022

RESUMO

Ferroptosis is increasingly being recognized as a key element in the pathogenesis of diverse diseases. Recent studies have highlighted the intricate links between iron metabolism and neurodegenerative disorders. Emerging evidence suggests that iron homeostasis, oxidative stress, and neuroinflammation all contribute to the regulation of both ferroptosis and neuronal health. However, the precise molecular mechanisms underlying the involvement of ferroptosis in the pathological processes of neurodegeneration and its impact on neuronal dysfunction remain incompletely understood. In our Review, we provide a comprehensive analysis and summary of the potential molecular mechanisms underlying ferroptosis in neurodegenerative diseases, aiming to elucidate the disease progression of neurodegeneration. Additionally, we discuss potential therapeutic agents that modulate ferroptosis with the goal of identifying novel drug molecules for the treatment of neurodegenerative disorders.


Assuntos
Ferroptose , Doenças Neurodegenerativas , Morte Celular Regulada , Humanos , Progressão da Doença , Ferro
11.
Front Microbiol ; 14: 1190939, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37455722

RESUMO

Since the pandemic started, the coronavirus disease 2019 (COVID-19) has spread worldwide. In patients with COVID-19, the gut microbiome (GM) has been supposed to be closely related to the progress of the disease. The gut microbiota composition and human genetic variation are also connected in COVID-19 patients, assuming a triangular relationship between the genome, GM, and COVID-19. Here, we reviewed the recent developments in the study of the relationship between gut microbiota and COVID-19. The keywords "COVID-19," "microbiome," and "genome" were used to search the literature in the PubMed database. We first found that the composition of the GM in COVID-19 patients varies according to the severity of the illness. Most obviously, Candida albicans abnormally increased while the probiotic Bifidobacterium decreased in severe cases of COVID-19. Interestingly, clinical studies have consistently emphasized that the family Lachnospiraceae plays a critical role in patients with COVID-19. Additionally, we have demonstrated the impact of microbiome-related genes on COVID-19. Specially, we focused on angiotensin-converting enzyme 2's dual functions in SARS-CoV-2 infection and gut microbiota alternation. In summary, these studies showed that the diversity of GMs is closely connected to COVID-19. A triangular relationship exists between COVID-19, the human genome, and the gut flora, suggesting that human genetic variations may offer a chance for a precise diagnosis of COVID-19, and the important relationships between genetic makeup and microbiome regulation may affect the therapy of COVID-19.

12.
Mol Omics ; 19(10): 769-786, 2023 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-37498608

RESUMO

Chinese herbal medicine (CHM) exhibits a broad spectrum of clinical applications and demonstrates favorable therapeutic efficacy. Nonetheless, elucidating the underlying mechanism of action (MOA) of CHM in disease treatment remains a formidable task due to its inherent characteristics of multi-level, multi-linked, and multi-dimensional non-linear synergistic actions. In recent years, the concept of a Quality marker (Q-marker) proposed by Liu et al. has significantly contributed to the monitoring and evaluation of CHM products, thereby fostering the advancement of CHM research. Within this study, a Q-marker screening strategy for CHM formulas has been introduced, particularly emphasising efficacy and biological activities, integrating absorption, distribution, metabolism, and excretion (ADME) studies, systems biology, and experimental verification. As an illustrative case, the Q-marker screening of Qianghuo Shengshi decoction (QHSSD) for treating rheumatoid arthritis (RA) has been conducted. Consequently, from a pool of 159 compounds within QHSSD, five Q-markers exhibiting significant in vitro anti-inflammatory effects have been identified. These Q-markers encompass notopterol, isoliquiritin, imperatorin, cimifugin, and glycyrrhizic acid. Furthermore, by employing an integrated analysis of network pharmacology and metabolomics, several instructive insights into pharmacological mechanisms have been gleaned. This includes the identification of key targets and pathways through which QHSSD exerts its crucial roles in the treatment of RA. Notably, the inhibitory effect of QHSSD on AKT1 and MAPK3 activation has been validated through western blot analysis, underscoring its potential to mitigate RA-related inflammatory responses. In summary, this research demonstrates the proposed strategy's feasibility and provides a practical reference model for the systematic investigation of CHM formulas.


Assuntos
Artrite Reumatoide , Medicamentos de Ervas Chinesas , Humanos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Biologia de Sistemas , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Metabolômica
13.
Res Sq ; 2023 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-37131801

RESUMO

Chimeric antigen receptor (CAR) T cell immunotherapy is promising for treatment of blood cancers; however, clinical benefits remain unpredictable, necessitating development of optimal CAR T cell products. Unfortunately, current preclinical evaluation platforms are inadequate due to their limited physiological relevance to humans. We herein engineered an organotypic immunocompetent chip that recapitulates microarchitectural and pathophysiological characteristics of human leukemia bone marrow stromal and immune niches for CAR T cell therapy modeling. This leukemia chip empowered real-time spatiotemporal monitoring of CAR T cell functionality, including T cell extravasation, recognition of leukemia, immune activation, cytotoxicity, and killing. We next on-chip modelled and mapped different responses post CAR T cell therapy, i.e., remission, resistance, and relapse as observed clinically and identify factors that potentially drive therapeutic failure. Finally, we developed a matrix-based analytical and integrative index to demarcate functional performance of CAR T cells with different CAR designs and generations produced from healthy donors and patients. Together, our chip introduces an enabling '(pre-)clinical-trial-on-chip' tool for CAR T cell development, which may translate to personalized therapies and improved clinical decision-making.

14.
BMC Psychiatry ; 23(1): 348, 2023 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-37208711

RESUMO

BACKGROUND: Patients diagnosed withmajor depressive disorder (MDD) usually experience impaired cognitive functioning, which might negatively impact their clinical and functional outcomes. This study aimed to investigate the association of specific clinical factors with cognitive dysfunction in a group of MDD patients. METHODS: A total of 75 subjects diagnosed with recurrent MDD were evaluated during the acute stage. Their cognitive functions were assessed using the THINC-integrated tool (THINC-it) for attention/alertness, processing speed, executive function, and working memory. Clinical psychiatric evaluations, such as the Hamilton Anxiety Scale (HAM-A), the Young Mania Rating Scale (YMRS), the Hamilton Depression Scale (HAM-D), and the Pittsburgh Sleep Quality Index(PSQI), were used to assess patients' levels of anxiety, depression and sleeping problems. The investigated clinical variables were age, years of education, age at onset, number of depressive episodes, disease duration, presence of depressive and anxiety symptoms, sleep problems, and number of hospitalizations. RESULTS: The results revealed that significant differences were observed between the two groups in the THINC-it total scores, Spotter, Codebreaker, Trails, and PDQ-5-D scores (P < 0.001). The THINC-it total scores, Spotter, Codebreaker, Trails, and Symbol Check were significantly associated with age and age at onset(P < 0.01). In addition, regression analysis found that years of education was positively associated with the Codebreaker total scores (P < 0.05). the THINC-it total scores, Symbol Check, Trails, and Codebreaker were correlated with the HAM-D total scores(P < 0.05). Additionally, the THINC-it total scores, Symbol Check, PDQ-5-D and Codebreaker significantly correlated with the PSQI total scores (P < 0.05). CONCLUSION: We found a significant statistical association between almost all cognitive domains and different clinical aspects in depressive disorder, such asage, age at onset, severity of depression, years of education, and sleep problems. Additionally, education was shown to be a protective factor against processing speed impairments. Special considerations of these factors might help outline better management strategies to improve cognitive functions in MDD patients.


Assuntos
Disfunção Cognitiva , Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/psicologia , Depressão , População do Leste Asiático , Disfunção Cognitiva/complicações , Disfunção Cognitiva/diagnóstico , Cognição
15.
Front Neurosci ; 17: 1143476, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37090790

RESUMO

Purpose: To study the independent risk factors for development of different degrees of diabetic retinopathy (DR) as well as non-DR (NDR) among type 2 diabetic patients. Methods: This cross-sectional study included 218 patients with type 2 diabetes between January 2022 and June 2022. All the patients were divided into two groups: the DR group and the NDR group. The DR group was subdivided into the mild, moderate and severe non-proliferative DR (NPDR) group and the proliferative DR (PDR) group. Data recorded for all patients included age, gender, duration of diabetes, blood pressure, glycated hemoglobin (HbA1c), fasting blood glucose (FBG), blood lipids, best corrected visual acuity (BCVA), intraocular pressure (IOP), axial length (AL), anterior chamber depth (ACD), and renal function. Logistic regression methods were used to analyze the risk factors for DR. Results: The prevalence of DR in type 2 diabetes was 28.44%. The duration of diabetes, age, mean arterial pressure (MAP), HbA1c, FBG, urinary albumin/creatinine ratio (UACR), BCVA, AL, and ACD were significantly different between the DR and the NDR groups (p < 0.05). Multivariate logistic regression analysis identified age, FBG, UACR, and AL as the independent risk factors for DR (OR = 0.843, 2.376, 1.049, 0.005; p = 0.034, 0.014, 0.016, p < 0.001). Conclusion: Young age, short AL, higher levels of FBG and UACR were the independent risk factors for the progression of DR in type 2 diabetes.

16.
Eur J Nucl Med Mol Imaging ; 50(7): 2081-2099, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36849748

RESUMO

PURPOSE: Currently, there are multiple active clinical trials involving poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of glioblastoma. The noninvasive quantification of baseline PARP expression using positron emission tomography (PET) may provide prognostic information and lead to more precise treatment. Due to the lack of brain-penetrant PARP imaging agents, the reliable and accurate in vivo quantification of PARP in the brain remains elusive. Herein, we report the synthesis of a brain-penetrant PARP PET tracer, (R)-2-(2-methyl-1-(methyl-11C)pyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide ([11C]PyBic), and its preclinical evaluations in a syngeneic RG2 rat glioblastoma model and healthy nonhuman primates. METHODS: We synthesized [11C]PyBic using veliparib as the labeling precursor, performed dynamic PET scans on RG2 tumor-bearing rats and calculated the distribution volume ratio (DVR) using simplified reference region method 2 (SRTM2) with the contralateral nontumor brain region as the reference region. We performed biodistribution studies, western blot, and immunostaining studies to validate the in vivo PET quantification results. We characterized the brain kinetics and binding specificity of [11C]PyBic in nonhuman primates on FOCUS220 scanner and calculated the volume of distribution (VT), nondisplaceable volume of distribution (VND), and nondisplaceable binding potential (BPND) in selected brain regions. RESULTS: [11C]PyBic was synthesized efficiently in one step, with greater than 97% radiochemical and chemical purity and molar activity of 148 ± 85 MBq/nmol (n = 6). [11C]PyBic demonstrated PARP-specific binding in RG2 tumors, with 74% of tracer binding in tumors blocked by preinjected veliparib (i.v., 5 mg/kg). The in vivo PET imaging results were corroborated by ex vivo biodistribution, PARP1 immunohistochemistry and immunoblotting data. Furthermore, brain penetration of [11C]PyBic was confirmed by quantitative monkey brain PET, which showed high specific uptake (BPND > 3) and low nonspecific uptake (VND < 3 mL/cm3) in the monkey brain. CONCLUSION: [11C]PyBic is the first brain-penetrant PARP PET tracer validated in a rat glioblastoma model and healthy nonhuman primates. The brain kinetics of [11C]PyBic are suitable for noninvasive quantification of available PARP binding in the brain, which posits [11C]PyBic to have broad applications in oncology and neuroimaging.


Assuntos
Glioblastoma , Ratos , Animais , Glioblastoma/diagnóstico por imagem , Glioblastoma/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/metabolismo , Distribuição Tecidual , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Primatas
17.
Psychiatry Res ; 320: 115033, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36603383

RESUMO

BACKGROUND: Social cognitive and negative symptoms impairment may increase the risk of mental disability in individuals with schizophrenia. However, randomized controlled studies on the effectiveness of accelerated intermittent theta burst stimulation (iTBS) for social cognition and negative symptoms in individuals with schizophrenia are very limited. METHODS: A total of 125 individuals with schizophrenia were recruited, 66 of whom were randomly divided into an active iTBS group (n=34) and sham iTBS group (n=32) by stratified sampling. Participants received either active iTBS or sham iTBS targeting the left dorsolateral prefrontal cortex (DLPFC) 20 sessions for 4 weeks under navigation. The Facial Emotion Recognition Test (FERT), Hinting Task (HT), and Positive and Negative Syndrome Scale (PANSS) were measured at baseline, 2 weeks, and 4 weeks. The trial protocol was registered with the Chinese Clinical Trial Registry (ChiCTR2100051984). RESULTS: Sixty patients (90.90%) completed the intervention and the 4-week follow-up, including 29 women (43.94%) and 37 men (56.06%) with a mean (SD) age of 47.53 (10.17) years. The primary outcomes showed FERT scores (week 2; 0.27 [95% CI, 0.09 to 0.45]; P< .01; ES 0.14) (week 4; 0.63 [95% CI, 0.45 to 0.80]; P< .001; ES 0.47) and HT scores (week 2; 1.00 [95% CI, -0.02 to 1.98]; P< .05; ES 0.67) (week 4; 2.13 [95% CI, 1.21 to 3.06]; P< .001; ES 0.27) in the active iTBS group were significantly different from those in the sham iTBS group at 2 and 4 weeks of follow-up. The secondary outcome showed that the negative symptom score (-3.43 [95% CI, -4.85 to -2.01]; P< .001; ES 0.29) of the active iTBS group was significantly different from that of the sham iTBS group at the 4th week of follow-up. CONCLUSIONS: Accelerated iTBS can effectively ameliorate the social cognition and negative symptoms of individuals with schizophrenia. These results suggest that accelerated iTBS may be a safe and effective neuromodulation technique to improve the overall functional recovery of individuals with schizophrenia, and has a good clinical application prospect.


Assuntos
Esquizofrenia , Estimulação Magnética Transcraniana , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Emoções , Córtex Pré-Frontal , Esquizofrenia/complicações , Esquizofrenia/terapia , Cognição Social , Ritmo Teta/fisiologia , Estimulação Magnética Transcraniana/métodos
18.
Med Res Rev ; 43(3): 683-712, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36658745

RESUMO

Cardio-metabolic-diseases (cardio-metabolic-diseases) are leading causes of death and disability worldwide and impose a tremendous burden on whole society as well as individuals. As a new type of regulated cell death (RCD), ferroptosis is distinct from several classical types of RCDs such as apoptosis and necroptosis in cell morphology, biochemistry, and genetics. The main molecular mechanisms of ferroptosis involve iron metabolism dysregulation, mitochondrial malfunction, impaired antioxidant capacity, accumulation of lipid-related peroxides and membrane disruption. Within the past few years, mounting evidence has shown that ferroptosis contributes to the pathophysiological process in cardio-metabolic-diseases. However, the exact roles and underlying molecular mechanisms have not been fully elucidated. This review comprehensively summarizes the mechanism of ferroptosis in the development and progression of cardio-metabolic-diseases, so as to provide new insights for cardio-metabolic-diseases pathophysiology. Moreover, we highlight potential druggable molecules in ferroptosis signaling pathway, and discuss recent advances in management strategies by targeting ferroptosis for prevention and treatment of cardio-metabolic-diseases.


Assuntos
Ferroptose , Doenças Metabólicas , Humanos , Apoptose , Doenças Metabólicas/tratamento farmacológico , Antioxidantes , Peróxidos Lipídicos
19.
Huan Jing Ke Xue ; 44(1): 20-29, 2023 Jan 08.
Artigo em Chinês | MEDLINE | ID: mdl-36635791

RESUMO

In this study, we report observations of various chemical species in PM2.5 samples that were collected between November 25, 2019 and March 31, 2020 in the northern, urban, and southern areas of Langfang, among which the concentrations of PM2.5 followed the order of southern>urban>northern. The abundance and chemical compositions of the particles in this study were temporally and spatially variable, with major contributions from organic matter (25.4%), nitrate (21.5%), sulfate (11.0%), ammonium (13.5%), and crustal matter (13.7%). The contributions of nitrate, sulfate, and ammonium were higher in the urban site compared with that in the southern and northern sites. On the contrary, organic matter and crustal matter exhibited much higher values in the southern and northern sites. In addition, the contributions of organic matter to the particle mass decreased from 27.3% to 23.0%, and the total contributions of sulfate, nitrate, and ammonium ions increased from 38.7% to 51.3% between clean and haze days, respectively. Source apportionment using positive matrix factorization showed five PM2.5 sources: secondary inorganic aerosol (41.9%), traffic emissions (19.9%), coal combustion (12.7%), industrial pollution (9.1%), and mineral dust (9.3%). The contributions of the first two factors followed the order of urban>northern>southern, whereas the contributions of the last three factors followed the order of southern>northern>urban. Further, the contributions of secondary inorganic aerosol, traffic emissions, and coal combustion were higher on haze days, whereas the contributions of industrial pollution and mineral dust were higher on clean days.


Assuntos
Poluentes Atmosféricos , Poluentes Atmosféricos/análise , Material Particulado/análise , Emissões de Veículos/análise , Nitratos , Monitoramento Ambiental , Poeira/análise , Estações do Ano , Compostos Orgânicos , Carvão Mineral/análise , Aerossóis/análise , China
20.
Cell Death Differ ; 30(2): 457-474, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36477078

RESUMO

Smooth muscle cell (SMC) phenotypic switch from a quiescent 'contractile' phenotype to a dedifferentiated and proliferative state underlies the development of cardiovascular diseases (CVDs); however, our understanding of the mechanism is still incomplete. In the present study, we explored the potential role of ferroptosis, a novel nonapoptotic form of cell death, in SMC phenotypic switch and related neointimal formation. We found that ferroptotic stress was triggered in cultured dedifferentiated SMCs and arterial neointimal tissue of wire-injured mice. Moreover, pro-ferroptosis stress was activated in arterial neointimal tissue of clinical patients who underwent carotid endarterectomy. Blockade of ferroptotic stress via administration of a pharmacological inhibitor or by global genetic overexpression of glutathione peroxidase-4 (GPX4), a well-established anti-ferroptosis molecule, delayed SMC phenotype switch and arterial remodelling. Conditional SMC-specific gene delivery of GPX4 using adreno-associated virus in the carotid artery inhibited ferroptosis and prevented neointimal formation. Conversely, ferroptosis stress directly triggered dedifferentiation of SMCs. Transcriptomics analysis demonstrated that inhibition of ferroptotic stress mainly targets the mitochondrial respiratory chain and oxidative phosphorylation. Mechanistically, ferroptosis inhibition corrected the disrupted mitochondrial homeostasis in dedifferentiated SMCs, including enhanced mitochondrial ROS production, dysregulated mitochondrial dynamics, and mitochondrial hyperpolarization, and ultimately inhibited SMC phenotypic switch and growth. Copper-diacetyl-bisN4-methylthiosemicarbazone (CuATSM), an agent used for clinical molecular imaging and that potently inhibits ferroptosis, prevented SMC phenotypic switch, neointimal formation and arterial inflammation in mice. These results indicate that pro-ferroptosis stress is likely to promote SMC phenotypic switch during neointimal formation and imply that inhibition of ferroptotic stress may be a promising translational approach to treat CVDs with SMC phenotype switch.


Assuntos
Desdiferenciação Celular , Miócitos de Músculo Liso , Camundongos , Animais , Células Cultivadas , Homeostase , Miócitos de Músculo Liso/metabolismo , Músculo Liso , Proliferação de Células
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