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1.
Adv Mater ; : e2105351, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34647345

RESUMO

Fast and effective thrombolysis using tissue plasminogen activator (tPA) is limited by the poor delivery efficiency of thrombolytic drugs, which is induced by an interrupted bloodstream and delayed recanalization. Existing magnetic micro/nanodrug-loaded robots used for targeted thrombotic therapy are limited by the complexity of the clinical verification of nanodrugs and the limited space of magnetic actuation systems. Herein, a general drug delivery strategy based on mass transportation theory for thrombolysis is presented, and an open space C-shaped magnetic actuation system with laser location and ultrasound imaging navigation for in vivo evaluation is developed. tPA can be guided through an interrupted bloodstream to the thrombi by the locomotion of magnetic nanoparticle swarms (MNSs), thereby improving the thrombolysis efficacy. Notably, this strategy is able to quickly establish a life channel to achieve time-critical recanalization, which is typically inaccessible using native tPA. Both in vitro and in vivo thrombolysis experiments demonstrate that the thrombus lysis efficacy significantly increases after the application of the MNS under a rotating magnetic field. This study provides an anticipated C-shaped magnetic actuation system for in vivo validation and also presents a clinically feasible drug delivery strategy for targeted thrombolytic therapy with minimal systemic tPA exposure.

2.
J Anim Sci ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34634123

RESUMO

The current study was undertaken to determine the effect of myostatin (MSTN) on lipid accumulation in porcine subcutaneous preadipocytes (PSPAs) and to further explore the potential molecular mechanisms. PSPAs isolated from Meishan weaned piglets were added with various concentrations of MSTN recombinant protein during the entire period of adipogenic differentiation process. Results showed that MSTN treatment significantly reduced the lipid accumulation, intracellular triglyceride (TG) content, glucose consumption and glycerol phosphate dehydrogenase activity, while increased glycerol and free fatty acid release. Consistent with above results, the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway was obviously activated and thus key adipogenic transcription factors peroxisome proliferator-activated receptor-gamma (PPAR-γ), CCAAT/enhancer-binding protein-alpha (C/EBP-α) and their downstream engymes fatty acid synthase and acetyl-CoA carboxylase were all inhibited. However, chemical inhibition of ERK1/2 signaling pathway by PD98059 markedly reversed the decreased TG content by increasing PPAR-γ expression. In addition, MSTN activated the cyclic AMP/protein kinase A (cAMP/PKA) pathway and stimulated lipolysis by reducing the expression of antilipolytic gene perilipin, thus elevated key lipolytic enzymes adipose triglyceride lipase and hormone-sensitive lipase expression and enzyme activity. On the contrary, pretreatment with PKA inhibitor H89 significantly reversed TG accumulation by increasing PPAR-γ expression and thus inhibiting ERK1/2, perilipin and HSL phosphorylation, supporting the crosstalk between PKA and ERK1/2 pathways in both the anti-adipogenic and pro-lipolytic effects. In summary, our results suggested that MSTN suppressed adipogenesis and stimulated lipolysis, which was mainly mediated by activating crosstalk of ERK1/2 and PKA signaling pathways, and consequently decreased lipid accumulation in PSPAs, our findings may provide novel insights for further exploring MSTN as a potent inhibitor of porcine subcutaneous lipid accumulation.

3.
Adv Mater ; : e2106265, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34613627

RESUMO

Autoimmune diseases are the third most common disease influencing the quality of life of many patients. Here, we develop a PD-L1+ mesenchymal stem cell (MSC) derived extracellular vesicles (MSC-sEVs-PD-L1) using lentivirus-mediated gene transfection technology for reconfiguration of the local immune microenvironment of affected tissue in autoimmune diseases. MSC-sEVs-PD-L1 exhibits an impressive ability to regulate various activated immune cells to an immunosuppressed state in vitro. More importantly, in dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) and imiquimod-induced psoriasis mouse models, we observe a significantly high accumulation of MSC-sEVs-PD-L1 in the inflamed tissues compared to the PD-L1+ MSCs. Therapeutic efficiency in both UC and psoriasis mouse disease models is demonstrated using MSC-sEVs-PD-L1 to reshape the inflammatory ecosystem in the local immune context. We develop a technology using MSC-sEVs-PD-L1 as a natural delivery platform for autoimmune diseases treatment with high clinical potential. This article is protected by copyright. All rights reserved.

4.
BMC Psychiatry ; 21(1): 498, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34641795

RESUMO

OBJECTIVE: The novel coronavirus disease 2019 (COVID-19) is a global public health emergency that has caused worldwide concern. The mental health of medical students under the COVID-19 epidemic has attracted much attention. This study aims to identify subgroups of medical students based on depression and anxiety and explore the influencing factors during the COVID-19 epidemic in China. METHODS: A total of 29,663 medical students were recruited during the epidemic of COVID-19 in China. Depression and anxiety symptoms were assessed using Patient Health Questionnaire 9 (PHQ9) and Generalized Anxiety Disorder 7 (GAD7) respectively. Latent class analysis was performed based on depression and anxiety symptoms in medical students. The latent class subtypes were compared using the chi-square test. Multinomial logistic regression was used to examine associations between identified classes and related factors. RESULTS: In this study, three distinct subgroups were identified, namely, the poor mental health group, the mild mental health group and the low symptoms group. The number of medical students in each class is 4325, 9321 and 16,017 respectively. The multinomial logistic regression results showed that compared with the low symptoms group, the factors influencing depression and anxiety in the poor mental health group and mild mental health group were sex, educational level, drinking, individual psychiatric disorders, family psychiatric disorders, knowledge of COVID-19, fear of being infected, and participate in mental health education on COVID-19. CONCLUSIONS: Our findings suggested that latent class analysis can be used to categorize different medical students according to their depression and anxiety symptoms during the outbreak of COVID-19. The main factors influencing the poor mental health group and the mild mental health group are basic demographic characteristics, disease history, COVID-19 related factors and behavioural lifestyle. School administrative departments can carry out targeted psychological counseling according to different subgroups to promote the physical and mental health of medical students.

5.
J Psychiatry Neurosci ; 46(5): E506-E515, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34467747

RESUMO

Background: Schizophrenia, bipolar disorder and major depressive disorder are increasingly being conceptualized as a transdiagnostic continuum. Disruption of white matter is a common alteration in these psychiatric disorders, but the molecular mechanisms underlying the disruption remain unclear. Neuregulin 1 (NRG1) is genetically linked with susceptibility to schizophrenia, bipolar disorder and major depressive disorder, and it is also related to white matter. Methods: Using a transdiagnostic approach, we aimed to identify white matter differences associated with NRG1 and their relationship to transdiagnostic symptoms and cognitive function. We examined the white matter of 1051 participants (318 healthy controls and 733 patients with major psychiatric disorders: 254 with schizophrenia, 212 with bipolar disorder and 267 with major depressive disorder) who underwent diffusion tensor imaging. We measured the plasma NRG1-ß1 levels of 331 participants. We also evaluated clinical symptoms and cognitive function. Results: In the patient group, abnormal white matter was negatively associated with NRG1-ß1 levels in the genu of the corpus callosum, right uncinate fasciculus, bilateral inferior fronto-occipital fasciculus, right external capsule, fornix, right optic tract, left straight gyrus white matter and left olfactory radiation. These NRG1-associated white matter abnormalities were also associated with depression and anxiety symptoms and executive function in patients with a major psychiatric disorder. Furthermore, across the 3 disorders we observed analogous alterations in white matter, NRG1-ß1 levels and clinical manifestations. Limitations: Medication status, the wide age range and our cross-sectional findings were limitations of this study. Conclusion: This study is the first to provide evidence for an association between NRG1, white matter abnormalities, clinical symptoms and cognition in a transdiagnostic psychiatric cohort. These findings provide further support for an understanding of the molecular mechanisms that underlie the neuroimaging substrates of major psychiatric disorders and their clinical implications.

6.
Biomaterials ; 277: 121106, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34492581

RESUMO

Sepsis, a syndrome of acute organ dysfunction induced by various infections, could lead to a very high mortality in hospitals despite the development of advanced medical technologies. Herein, a type of two-phase releasing immune-stimulating composite is developed by mixing alginate (ALG) with muramyl dipeptide (MDP) and the nanoparticle formulation of monophosphoryl lipid A (MPLA), the latter two are immunomodulatory agents with different release rates from the formed ALG hydrogel. The obtained two phase-releasing composite could provide instantaneous sepsis protection by the rapid release of MDP to enhance the phagocytic and bactericidal function of macrophages. Later on, such composite could further offer long-term sepsis protection by the sustained release of MPLA to continuously activate the immune system, via up-regulating the production of various pro-inflammatory cytokines, promoting the polarization of macrophages, and increasing the percent of natural killer (NK) cells in the lesion after sepsis challenge. Mice survived from sepsis challenge after such treatment could resist a second infection. Notably, treatment with our composite could increase the mouse survival rate in a cecal ligation and puncture (CLP) induced polymicrobial sepsis model. This work provides an easy-translatable immune-stimulating formulation for effective protection against sepsis under various triggering causes. Our strategy may be promising for long-term broad prevention against various infections, and could potentially be used to protect medical workers under a new pandemic before a reliable vaccine is available.

7.
Biomaterials ; 277: 121125, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34534859

RESUMO

Gallium indium (GaIn) alloy as a kind of liquid metal (LM) with unique chemical and physical properties has attracted increasing attention for its potential biomedical applications. Herein, a series of core-shell GaIn@Metal (Metal: Pt, Au, Ag, and Cu) heterogeneous nanoparticles (NPs) are obtained by a simple in-situ reduction method. Take core-shell GaIn@Pt NPs for example, the synthesized GaIn@Pt NPs after Pt growth on their surface showed significantly improved photothermal conversion efficiency (PCE) and thermal stability under near-infrared (NIR) II light irradiation. Moreover, the core-shell GaIn@Pt NPs also exhibited good Fenton-like catalytic effect due to the presence of Pt on their surface, and could convert tumor endogenous H2O2 to generate reactive oxygen species (ROS) for cancer cell killing. With biocompatible polyethylene glycol (PEG) modification, such GaIn@Pt-PEG NPs showed efficient tumor homing after intravenous injection, and could lead to effective NIR II triggered photothermal-chemodynamic synergistic therapy of tumors as evidenced in a mouse tumor model. Our work highlights the ingenious use of the chemical properties of metals, providing a rather simple route for the surface engineering of LM-based multifunctional nanoplatforms to achieve a variety of functionalities.

8.
J Invest Dermatol ; 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34536485

RESUMO

Pressure ulcer (PU) is a chronic wound often seen in patients with spinal cord injury and other bed-bound individuals, particularly in the elderly population. Despite its association with high mortality, the pathophysiology of PU remains poorly understood. In this study, we compared single-cell transcriptomic profiles of human epidermal cells from PU wound edges with those from uninjured skin and acute wounds in healthy donors. We identified significant shifts in the cell composition and gene expression patterns in PU. In particular, we found that major histocompatibility complex class II‒expressing keratinocytes were enriched in patients with worse healing outcomes. Furthermore, we showed that the IFN-γ in PU-derived wound fluid could induce major histocompatibility complex II expression in keratinocytes and that these wound fluid‒treated keratinocytes inhibited autologous T-cell activation. In line with this observation, we found that T cells from PUs enriched with major histocompatibility complex II+ keratinocytes produced fewer inflammatory cytokines. Overall, our study provides a high-resolution molecular map of human PU compared with that of acute wounds and intact skin, providing insights into PU pathology and the future development of tailored wound therapy.

9.
J Hazard Mater ; 421: 126801, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34388916

RESUMO

A novel chemosensor is developed for the sensitive and facile detection of trace strontium ions (Sr2+) based on the ion-imprinted hydrogels. With Sr2+ as the templates, the ion-imprinted hydrogels are synthesized by copolymerizing the ion-responsive units 5'-O-acryloyl-2',3'-O-isopropylidene guanosine (APG) and the thermo-responsive units N-isopropylacrylamide (NIPAM). In the presence of Sr2+, APG units can self-assemble to form planar G-quartets via the complexation with Sr2+, which are introduced into the gel network during polymerization. Then Sr2+ templates can be removed by multiple repeated washing. When re-exposed to Sr2+, the relaxed G-quartets can recognize Sr2+, leading to the weakening of electrostatic repulsion between the four oxygen atoms in the G-quartets and inducing the shrinkage of the hydrogels. In this work, the Sr2+-imprinted chemosensors are designed as the grating systems for detecting trace Sr2+. Based on the array of hydrogel strings synthesized on a nano-scale, the smart grating systems thus constructed can convert and amplify the Sr2+ concentration signals to the easily-measurable optical signals. With the Sr2+-imprinted hydrogel gratings, trace Sr2+ (10-11 M) in an aqueous solution can be detected sensitively. Moreover, the proposed Sr2+-imprinted chemosensors can be integrated with other smart systems for developing various detectors with high performance.

10.
Int J Med Robot ; 17(5): e2304, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34197045

RESUMO

BACKGROUND: This paper describes a case of a patient with situs inversus totalis (SIT) and dextrocardia in which robotic atrial septal defect (ASD) repair was successfully performed in a beating heart. METHODS AND RESULTS: A 45-year-old female patient who had SIT and dextrocardia was diagnosed with secundum ASD 5 years ago. Because of progressive dyspnoea, fatigue, and obvious cough, she came to our hospital for surgical treatment. Transthoracic echocardiography showed the defect located in the middle and lower segments of the atrial septum with a maximum diameter of 27 mm, with a left-to-right shunt. Transcatheter ASD closure could not be performed because there was not enough tissue surrounding the defect. After communicating with the patient, we performed robotic ASD repair in a beating heart using the da Vinci surgical system. The operation was successful, and the patient recovered quickly. CONCLUSION: As a minimally invasive approach, robotic cardiac surgery has many advantages and is feasible and safe in suitable patients.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Dextrocardia , Comunicação Interatrial , Procedimentos Cirúrgicos Robóticos , Robótica , Dextrocardia/complicações , Dextrocardia/cirurgia , Feminino , Comunicação Interatrial/complicações , Comunicação Interatrial/cirurgia , Humanos , Pessoa de Meia-Idade
11.
J Mater Chem B ; 9(32): 6364-6376, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34296735

RESUMO

Elevated levels of low-density lipoproteins (LDL) are recognized as a crucial indicator of hyperlipidemia (HLP) and lowering of LDL levels represents an effective clinical treatment strategy. Inspired by the conjugation of phospholipid monolayers and the lipid content of the LDL particle, the current study describes the preparation of an innovative hemoperfusion adsorbent. The adsorbent was prepared by attachment of phosphatidyl ethanolamine to poly(acrylic acid) modified poly(vinyl alcohol-co-triallyl isocyanurate) beads (PVA@PAA-PE). The interaction between LDL and adsorbent mimics the lipoprotein microemulsion present in the blood and thus promotes efficient binding with high affinity. In vitro adsorption using serum from patients with HLP revealed that the LDL adsorption of PVA@PAA-PE was 4.44 times higher than that of controls and the removal rate of LDL using PVA@PAA-PE was about twice as high as that of the anti-atherogenic high-density lipoprotein (HDL). In vivo whole blood perfusion demonstrated the superior affinity of PVA@PAA-PE for LDL since LDL concentration was significantly reduced from 10.71 ± 2.36 mmol L-1 to 6.21 ± 1.45 mmol L-1, while the HDL level was not severely reduced (from 0.98 ± 0.12 mmol L-1 to 0.56 ± 0.15 mmol L-1). Additionally, PVA@PAA-PE exhibited excellent hemocompatibility and low cytotoxicity. Therefore, PVA@PAA-PE is a potential adsorbent for whole blood perfusion to treat hyperlipidemia.

12.
Proc Natl Acad Sci U S A ; 118(29)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34292870

RESUMO

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2), presents an urgent health crisis. More recently, an increasing number of mutated strains of SARS-CoV-2 have been identified globally. Such mutations, especially those on the spike glycoprotein to render its higher binding affinity to human angiotensin-converting enzyme II (hACE2) receptors, not only resulted in higher transmission of SARS-CoV-2 but also raised serious concerns regarding the efficacies of vaccines against mutated viruses. Since ACE2 is the virus-binding protein on human cells regardless of viral mutations, we design hACE2-containing nanocatchers (NCs) as the competitor with host cells for virus binding to protect cells from SARS-CoV-2 infection. The hACE2-containing NCs, derived from the cellular membrane of genetically engineered cells stably expressing hACE2, exhibited excellent neutralization ability against pseudoviruses of both wild-type SARS-CoV-2 and the D614G variant. To prevent SARS-CoV-2 infections in the lung, the most vulnerable organ for COVID-19, we develop an inhalable formulation by mixing hACE2-containing NCs with mucoadhesive excipient hyaluronic acid, the latter of which could significantly prolong the retention of NCs in the lung after inhalation. Excitingly, inhalation of our formulation could lead to potent pseudovirus inhibition ability in hACE2-expressing mouse model, without imposing any appreciable side effects. Importantly, our inhalable hACE2-containing NCs in the lyophilized formulation would allow long-term storage, facilitating their future clinical use. Thus, this work may provide an alternative tactic to inhibit SARS-CoV-2 infections even with different mutations, exhibiting great potential for treatment of the ongoing COVID-19 epidemic.


Assuntos
COVID-19/prevenção & controle , Nanoestruturas/administração & dosagem , SARS-CoV-2/efeitos dos fármacos , Adesivos/administração & dosagem , Adesivos/química , Adesivos/farmacocinética , Administração por Inalação , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Crioprotetores/química , Armazenamento de Medicamentos , Células Epiteliais/metabolismo , Excipientes/administração & dosagem , Excipientes/química , Excipientes/farmacocinética , Células HEK293 , Humanos , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/química , Ácido Hialurônico/farmacocinética , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/virologia , Camundongos , Camundongos Transgênicos , Nanoestruturas/química , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Ligação Viral/efeitos dos fármacos
13.
Artigo em Inglês | MEDLINE | ID: mdl-34196110

RESUMO

PURPOSE: To evaluate the prognosis of estrogen receptor-positive breast cancer patients with CYP2D6*10 mutant genotypes under tamoxifen or toremifen therapy. METHODS: Estrogen receptor-positive breast cancer patients were selected and CYP2D6*10 genotypes (C/C, C/T, and T/T) were determined by Sanger sequencing. Patients were divided into tamoxifen, toremifene, or tamoxifen + toremifene groups according to prior therapy. The correlation between CYP2D6*10 genotype and disease-free survival was analyzed. RESULTS: In total, 293 estrogen receptor-positive breast cancer patients treated with tamoxifen or toremifene between 2008 and 2017 were studied. Median follow-up was 39 months (10-141). Of these, 107 (36.52%), 112 (38.23%), and 74 (25.26%) patients had C/C, C/T, and T/T genotypes, respectively. Genotype was significantly associated with disease-free survival in tamoxifen patients. Patients with C/T and T/T genotypes showed worse disease-free survival than patients with a C/C genotype. Genotype and disease-free survival in toremifene and tamoxifen+toremifene patients were not correlated. Of patients with a C/T genotype, toremifene or tamoxifen+toremifene groups showed better disease-free survival than tamoxifen patients. Although disease-free survival of patients with a T/T genotype in the three groups was not statistically different, tamoxifen patients showed worse disease-free survival. There was no correlation between different treatments and disease-free survival in patients with a C/C genotype. Cox proportional hazard analysis revealed toremifene patients had a better prognosis than tamoxifen patients; toremifene was an independent protective factoremifene for disease-free survival. CONCLUSIONS: Tamoxifen was less effective in patients with CYP2D6*10 C/T and T/T genotypes. Estrogen receptor-positive breast cancer patients with a CYP2D6*10 mutation genotype have a better prognosis with toremifen than tamoxifen.

14.
Nat Commun ; 12(1): 4299, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262038

RESUMO

Radiofrequency ablation (RFA) is clinically adopted to destruct solid tumors, but is often incapable of completely ablating large tumors and those with multiple metastatic sites. Here we develop a CaCO3-assisted double emulsion method to encapsulate lipoxidase and hemin with poly(lactic-co-glycolic acid) (PLGA) to enhance RFA. We show the HLCaP nanoreactors (NRs) with pH-dependent catalytic capacity can continuously produce cytotoxic lipid radicals via the lipid peroxidation chain reaction using cancer cell debris as the fuel. Upon being fixed inside the residual tumors post RFA, HLCaP NRs exhibit a suppression effect on residual tumors in mice and rabbits by triggering ferroptosis. Moreover, treatment with HLCaP NRs post RFA can prime antitumor immunity to effectively suppress the growth of both residual and metastatic tumors, also in combination with immune checkpoint blockade. This work highlights that tumor-debris-fueled nanoreactors can benefit RFA by inhibiting tumor recurrence and preventing tumor metastasis.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Nanomedicina/métodos , Neoplasias/terapia , Ablação por Radiofrequência , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Animais , Carbonato de Cálcio/química , Carbonato de Cálcio/uso terapêutico , Catálise , Linhagem Celular Tumoral , Terapia Combinada , Ferroptose/efeitos dos fármacos , Hemina/química , Hemina/uso terapêutico , Humanos , Concentração de Íons de Hidrogênio , Inibidores de Checkpoint Imunológico/uso terapêutico , Morte Celular Imunogênica/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoxigenase/química , Lipoxigenase/uso terapêutico , Camundongos , Metástase Neoplásica , Neoplasia Residual , Neoplasias/imunologia , Neoplasias/patologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/uso terapêutico , Coelhos
15.
J Ethnopharmacol ; 277: 114254, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34062246

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Yixin-Fumai granules (YXFMs)-composed of Ginseng quinquefolium (L.) Alph. Wood, Ophiopogon japonicus (Thunb.) Ker Gawl, Schisandra arisanensis Hayata, Astragalus aaronsohnianus Eig, Salvia cryptantha Montbret & Aucher ex Benth, and Ligusticum striatum DC-are compound granules used in traditional Chinese medicine to increase heart rate and thus treat bradyarrhythmia. It may be effective in treating sick sinus syndrome (SSS). AIM: To observe the effect of YXFMs on aging-induced SSS in mice and explore whether this effect is related to the Nrf-2/HO-1 signaling pathway. MATERIALS AND METHODS: Mice with a significant decrease in the heart rate due to natural aging were selected to construct an SSS model. After the mice were administered YXFMs, the damage to their sinoartrial node (SAN) was assessed through electrocardiography, Masson's trichrome staining, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Dihydroethidium staining and immunofluorescence staining were used to assay reactive oxygen species (ROS) content and HCN4, respectively. Moreover, to observe the effects of YXFMs in vitro, the HL-1 cell line, derived from mouse atrial myocytes, was used to simulate SAN pacemaker cells, with H2O2 used as the cellular oxidative stress (OS) inducer. 2,7-Dichlorodihydrofluorescein diacetate staining was used to assay ROS content, whereas immunofluorescence staining and Western blotting were used to elucidate the related protein expression. Finally, mice were injected the Nrf-2 inhibitor ML385 to reversely verify the effects of YXFMs. RESULTS: In our in vivo experiments, YXFMs significantly inhibited aging-induced SSS, shortened the R-R interval, increased heart rate, alleviated fibrosis, reduced apoptosis rate and ROS content, and promote HCN4 expression in the SAN. In our in vitro experiments, YXFMs significantly inhibited H2O2-induced cell peroxidation damage, promoted Nrf-2 activation and nuclear metastasis, increased HO-1 expression- thereby inhibiting ROS accumulation-and finally, upregulated HCN4 expression through the inhibition of histone deacetylase 4 (HDAC4) expression and its nuclear metastasis. Finally, injection of the Nrf-2 inhibitor ML385 after YXFMs administration inhibited their protective effect in the mice. CONCLUSION: Here, we elaborated on the relationship between aging-induced SSS and the Nrf-2/HO-1 pathway for the first time and proposed that YXFMs improve SSS via the Nrf-2/HO-1 axis. Specifically, YXFMs promoted Nrf-2 activation and plasma-nuclear transfer to enhance HO-1 expression via the Nrf-2/HO-1 axis. This inhibited OS and reduced ROS accumulation in the SAN, and then, through the ROS/HDAC4 axis, reduced HDAC4 expression and plasma-nuclear transfer. Thereby, the OS-induced HCN4 loss in the SAN was inhibited-improving the function of If channel and thus producing SAN protection effect against SSS and improving the heart rate and R-R interval. In the future, we plan to use bioinformatics analysis technology to execute the next step of our research, namely to determine the effect of isolated, purified components of YXFMs in SSS, to increase its efficiency and reduce the toxicity of YXFMs.

17.
Adv Healthc Mater ; 10(19): e2100748, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34137207

RESUMO

Transcatheter arterial embolization (TAE) is an extensively applied treatment method for hepatocellular carcinoma (HCC). However, the worsened tumor microenvironment (TME, e.g., reduced pH post-TAE) may result in unsatisfactory therapeutic outcome. Herein, a new kind of embolic agent, calcium carbonate encapsulated alginate microspheres (CaCO3 -ALG MSs) are synthesized. Such CaCO3 -ALG MSs are able to neutralize the tumor pH owing to the reaction of CaCO3 with protons, which would not affect the overall morphology of microspheres after decomposition of CaCO3 . TAE treatment with CaCO3 -ALG MSs is then conducted in an orthotopic rat liver cancer model. 18 F-Fluorodeoxyglucose micropositron emission tomography/computed tomography imaging is conducted post-TAE and discovered that intra-arterial injection of CaCO3 -ALG MSs shows obvious enhanced therapeutic outcome compared to the same treatment with bare ALG MSs or the clinically used lipiodol. Further studies including analysis of immune cells in tumors, cytokine assays, and bioinformatics analysis all verify the reverse of immunosuppressive TME toward a more immunosupportive one after TAE with CaCO3 -ALG MSs. The research not only presents a new CaCO3 -containing embolic agent for enhanced TAE treatment of HCC but also highlights a clinically meaningful approach to improve cancer treatment via tumor pH neutralization.


Assuntos
Carcinoma Hepatocelular , Embolização Terapêutica , Neoplasias Hepáticas , Animais , Carbonato de Cálcio , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , Microesferas , Ratos , Microambiente Tumoral
18.
Chem Soc Rev ; 50(15): 8669-8742, 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34156040

RESUMO

Inorganic nanomaterials that have inherently exceptional physicochemical properties (e.g., catalytic, optical, thermal, electrical, or magnetic performance) that can provide desirable functionality (e.g., drug delivery, diagnostics, imaging, or therapy) have considerable potential for application in the field of biomedicine. However, toxicity can be caused by the long-term, non-specific accumulation of these inorganic nanomaterials in healthy tissues, preventing their large-scale clinical utilization. Over the past several decades, the emergence of biodegradable and clearable inorganic nanomaterials has offered the potential to prevent such long-term toxicity. In addition, a comprehensive understanding of the design of such nanomaterials and their metabolic pathways within the body is essential for enabling the expansion of theranostic applications for various diseases and advancing clinical trials. Thus, it is of critical importance to develop biodegradable and clearable inorganic nanomaterials for biomedical applications. This review systematically summarizes the recent progress of biodegradable and clearable inorganic nanomaterials, particularly for application in cancer theranostics and other disease therapies. The future prospects and opportunities in this rapidly growing biomedical field are also discussed. We believe that this timely and comprehensive review will stimulate and guide additional in-depth studies in the area of inorganic nanomedicine, as rapid in vivo clearance and degradation is likely to be a prerequisite for the future clinical translation of inorganic nanomaterials with unique properties and functionality.

19.
J Affect Disord ; 292: 89-94, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34107425

RESUMO

BACKGROUND: The purpose of this study was to explore the association between perceived stress and depression among medical students and the mediating role of insomnia in this relationship during the COVID-19 pandemic in China. METHODS: A cross-sectional survey was conducted from March to April 2020 in medical university. Levels of perceived stress, insomnia and depression were measured using Perceived Stress Scale (PSS), Insomnia Severity Index (ISI) and Patient Health Questionnaire 9 (PHQ-9). The descriptive analyses of the demographic characteristics and correlation analyses of the three variables were calculated. The significance of the mediation effect was obtained using a bootstrap approach with SPSS PROCESS macro. RESULTS: The mean age of medical students was 21.46 years (SD=2.50). Of these medical students, 10,185 (34.3%) were male and 19,478 (65.7%) were female. Perceived stress was significantly associated with depression (ß=0.513, P < 0.001). Insomnia mediated the association between perceived stress and depression (ß=0.513, P < 0.001). The results of the non-parametric bootstrapping method confirmed the significance of the indirect effect of perceived stress through insomnia (95% bootstrap CI =0.137, 0.149). The indirect effect of insomnia accounted for 44.13% of the total variance in depression. CONCLUSIONS: These findings contribute to a better understanding of the interactive mechanisms underlying perceived stress and depression, and elucidating the mediating effects of insomnia on the association. This research provides a useful theoretical and methodological approach for prevention of depression in medical students. Findings from this study indicated that it may be effective to reduce depression among medical students by improving sleep quality and easing perceived stress.


Assuntos
COVID-19 , Distúrbios do Início e da Manutenção do Sono , Estudantes de Medicina , Adulto , Ansiedade , China/epidemiologia , Estudos Transversais , Depressão/epidemiologia , Surtos de Doenças , Feminino , Humanos , Masculino , Pandemias , SARS-CoV-2 , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Estresse Psicológico/epidemiologia , Adulto Jovem
20.
ACS Appl Mater Interfaces ; 13(24): 28802-28817, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34109788

RESUMO

In this study, a novel class of multifunctional responsive nanoparticles is designed and fabricated as drug nanocarriers for synergetic chemo-photothermal therapy of tumors. The proposed nanoparticles are composed of a thermo-/pH-responsive poly(N-isopropylacrylamide-co-acrylic acid) (PNA) nanogel core, a polydopamine (PDA) layer for photothermal conversion, and an outer folic acid (FA) layer as a targeting agent for the folate receptors on tumor cells. The fabricated nanoparticles show good biocompatibility and outstanding photothermal conversion efficiency. The proposed nanoparticles loaded with doxorubicin (DOX) drug molecules are stable under physiological conditions with low leakage of drugs, while rapidly release drugs in environments with low pH conditions and at high temperature. The experimental results show that the drug release process is mainly governed by Fickian diffusion. In vitro cell experimental results demonstrate that the PNA-DOX@PDA-FA nanoparticles can be phagocytized by 4T1 tumor cells and release drugs in tumor cell acidic environments, and confirm that the combined chemo and photothermal therapeutic efficacy of PNA-DOX@PDA-FA nanoparticles is higher than the photothermal therapeutic efficacy or the chemotherapeutic efficacy alone. The proposed multifunctional responsive nanoparticles in this study provide a novel class of drug nanocarriers as a promising tool for synergetic chemo-photothermal therapy of tumors.


Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Nanopartículas Multifuncionais/química , Acrilamidas/química , Acrilamidas/metabolismo , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Doxorrubicina/química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/efeitos da radiação , Liberação Controlada de Fármacos , Endocitose/fisiologia , Ácido Fólico/análogos & derivados , Ácido Fólico/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Indóis/química , Indóis/metabolismo , Indóis/efeitos da radiação , Raios Infravermelhos , Camundongos , Nanopartículas Multifuncionais/metabolismo , Terapia Fototérmica , Polímeros/química , Polímeros/metabolismo , Polímeros/efeitos da radiação , Temperatura
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