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1.
Front Aging Neurosci ; 14: 883503, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35663575

RESUMO

Cerebral small-vessel disease (CSVD) is the main cause of vascular cognitive impairment (VCI), and the accumulation of amyloid ß-protein (Aß) may be significantly involved in CSVD-induced VCI. The imbalance between Aß production and clearance is believed to be an important pathological mechanism of Aß deposition in Alzheimer disease. In this study, we aimed to disclose the roles of aquaporin 4 (AQP4) and neuroinflammation in CSVD, which were the key factors for Aß clearance and production, respectively, and the effect of mesenchymal stem cells (MSCs) on Aß deposition and these two factors. The stroke-prone renovascular hypertensive (RHRSP) rats were grouped and received MSC and MSC + AS1517499 (an inhibitor of pSTAT6). The latter was used to explore the underlying mechanism. The cognitive function, white matter lesions, Aß expression, expression, and polarity of AQP4, neuroinflammation and the STAT6 pathway were investigated. Compared with sham-operated rats, RHRSP rats showed spatial cognitive impairment, white matter lesions and Aß deposition. Moreover, AQP4 polarity disorder and neuroinflammatory activation were found, which were linked to Aß deposition. Treatment with MSCs markedly improved cognitive tasks and reduced Aß deposition but failed to reduce white-matter lesions. Furthermore, MSCs not only promoted AQP4 polarity but also alleviated neuroinflammation probably through the STAT6 pathway. The present study demonstrated that Aß deposition, AQP4 polarity disorder and neuroinflammation might be involved in CSVD and the regulatory effects of MSCs on them suggested potential therapeutic value for CSVD.

2.
Circ Res ; : 101161CIRCRESAHA121319582, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35642564

RESUMO

BACKGROUND: Insulin resistance (IR) can increase atherosclerotic and cardiovascular risk by inducing endothelial dysfunction, decreasing nitric oxide (NO) production, and accelerating arterial inflammation. The aim is to determine the mechanism by which insulin action and NO production in endothelial cells can improve systemic bioenergetics and decrease atherosclerosis via differentiation of perivascular progenitor cells (PPCs) into brown adipocytes (BAT). METHODS: Studies used various endothelial transgenic and deletion mutant ApoE-/- mice of insulin receptors, eNOS (endothelial NO synthase) and ETB (endothelin receptor type B) receptors for assessments of atherosclerosis. Cells were isolated from perivascular fat and micro-vessels for studies on differentiation and signaling mechanisms in responses to NO, insulin, and lipokines from BAT. RESULTS: Enhancing insulin's actions on endothelial cells and NO production in ECIRS1 transgenic mice reduced body weight and increased systemic energy expenditure and BAT mass and activity by inducing differentiation of PPCs into beige/BAT even with high-fat diet. However, positive changes in bioenergetics, BAT differentiation from PPCs and weight loss were inhibited by N(gamma)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of eNOS, in ECIRS1 mice and eNOSKO mice. The mechanism mediating NO's action on PPC differentiation into BAT was identified as the activation of solubilized guanylate cyclase/cGMP protein-dependent kinase Iα/GSK3ß (glycogen synthase kinase 3ß) pathways. Plasma lipidomics from ECIRS1 mice with NO-induced increased BAT mass revealed elevated 12,13-diHOME production. Infusion of 12,13-diHOME improved endothelial dysfunction and decreased atherosclerosis, whereas its reduction had opposite effects in ApoE-/-mice. CONCLUSIONS: Activation of eNOS and endothelial cells by insulin enhanced the differentiation of PPC to BAT and its lipokines and improved systemic bioenergetics and atherosclerosis, suggesting that endothelial dysfunction is a major contributor of energy disequilibrium in obesity.

3.
Scott Med J ; : 369330221107099, 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35686317

RESUMO

BACKGROUND AND AIMS: This updated meta-analysis aimed to further quantify the risk of endometrial, ovarian, and breast cancer in patients with polycystic ovary syndrome (PCOS), thus providing updated and more reliable estimates. METHODS AND RESULTS: We identified relevant articles by searching electronic databases of PubMed, Embase, Web of Science, and Chinese Biological Medical Literature (CBM) published up to March 20, 2021. The pooled effect estimates and their 95% confidence intervals (CIs) were calculated using the random-effect model or the fixed-effect model. A total of 26 eligible studies were included. We found that PCOS was significantly associated with endometrial cancer (odds ratios [OR]: 3.66, 95%CI: 2.05-6.54, P < 0.001), but not with ovarian or breast cancer (OR: 1.23, 95%CI: 0.99-1.53, P = 0.059; OR: 0.94, 95%CI: 0.78-1.14, P = 0.551, respectively). However, in subgroups of high-quality studies, cohort studies, younger women (54 years or less or premenopausal), and studies with unadjusted body mass index (BMI), PCOS patients had a significantly higher risk of ovarian cancer. CONCLUSION: These results indicated that PCOS is a significant risk factor for endometrial cancer independent of BMI, but not for breast cancer. PCOS may increase the risk of ovarian cancer in younger women.

4.
Cell Rep ; 39(9): 110870, 2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35649368

RESUMO

Overcoming resistance to chemotherapies remains a major unmet need for cancers, such as triple-negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid ß-oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclear. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-coenzyme A (CoA). Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.


Assuntos
Membranas Mitocondriais , Neoplasias de Mama Triplo Negativas , Acetilcoenzima A/metabolismo , Apoptose , Ácidos Graxos/metabolismo , Humanos , Lipídeos de Membrana/metabolismo , Membranas Mitocondriais/metabolismo , Oxirredução , Fosfolipídeos/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo
5.
Front Mol Biosci ; 9: 875324, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35655758

RESUMO

Nuclear Factor I B (NFIB) has been reported to promote tumor growth, metastasis, and liver regeneration, but its mechanism in liver cancer is not fully elucidated. The present study aims to reveal the role of NFIB in hepatocellular carcinogenesis. In our study, we constructed hepatocyte-specific NFIB gene knockout mice with CRISPR/Cas9 technology (Nfib-/-; Alb-cre), and induced liver cancer mouse model by intraperitoneal injection of DEN/CCl4. First, we found that Nfib-/- mice developed more tumor nodules and had heavier livers than wild-type mice. H&E staining indicated that the liver histological severity of Nfib-/- group was more serious than that of WT group. Then we found that the differentially expressed genes in the tumor tissue between Nfib-/- mice and wild type mice were enriched in urea cycle. Furthermore, ASS1 and CPS1, the core enzymes of the urea cycle, were significantly upregulated in Nfib-/- tumors. Subsequently, we validated that the expression of ASS1 and CPS1 increased after knockdown of NFIB by lentivirus in normal hepatocytes and also promoted cell proliferation in vitro. In addition, ChIP assay confirmed that NFIB can bind with promoter region of both ASS1 and CPS1 gene. Our study reveals for the first time that hepatocyte-specific knock-out of Nfib aggravates hepatocellular tumor development by enhancing the urea cycle.

6.
JAMA Netw Open ; 5(6): e2215217, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35657627

RESUMO

Importance: Delayed graft function (DGF) is a risk factor for acute rejection and graft failure after kidney transplant. Previous studies have suggested that dexmedetomidine may be renoprotective, but whether the use of dexmedetomidine would improve kidney allograft function is unknown. Objective: To investigate the effects of perioperative dexmedetomidine on DGF following a donation-after-cardiac-death (DCD) kidney transplant. Design, Setting, and Participants: This single-center, double-blind, placebo-controlled randomized clinical trial was conducted at The First Affiliated Hospital of Soochow University in Suzhou, China. Adults (18 years or older) who were scheduled for DCD kidney transplant were enrolled between September 1, 2019, and January 28, 2021, and then randomized to receive either dexmedetomidine or normal saline (placebo). One-year postoperative outcomes were recorded. All analyses were based on the modified intention-to-treat population. Interventions: Patients who were randomized to the dexmedetomidine group received a 24-hour perioperative dexmedetomidine intravenous infusion (0.4 µg/kg/h intraoperatively and 0.1 µg/kg/h postoperatively). Patients who were randomized to the normal saline group received an intravenous infusion of the placebo with the same dose regimen as the dexmedetomidine. Main Outcomes and Measures: The primary outcome was the incidence of DGF, defined as the need for dialysis in the first posttransplant week. The prespecified secondary outcomes were in-hospital repeated dialysis in the first posttransplant week, in-hospital acute rejection, and serum creatinine, serum cystatin C, estimated glomerular filtration rate, need for dialysis, and patient survival on posttransplant day 30. Results: Of the 114 patients enrolled, 111 completed the study (mean [SD] age, 43.4 [10.8] years; 64 male patients [57.7%]), of whom 56 were randomized to the dexmedetomidine group and 55 to the normal saline group. Dexmedetomidine infusion compared with normal saline reduced the incidence of DGF (17.9% vs 34.5%; odds ratio [OR], 0.41; 95% CI, 0.17-0.98; P = .04) and repeated dialysis (12.5% vs 30.9%; OR, 0.32; 95% CI, 0.13-0.88; P = .02, which was not statistically significant after multiple testing corrections), without significant effect on other secondary outcomes. Dexmedetomidine vs normal saline infusion led to a higher median (IQR) creatinine clearance rate on postoperative days 1 (9.9 [4.9-21.2] mL/min vs 7.9 [2.0-10.4] mL/min) and 2 (29.6 [9.7-67.4] mL/min vs 14.6 [3.8-45.1] mL/min) as well as increased median (IQR) urine output on postoperative days 2 (106.5 [66.3-175.6] mL/h vs 82.9 [27.1-141.9] mL/h) and 7 (126.1 [98.0-151.3] mL/h vs 107.0 [82.5-137.5] mL/h) and at hospital discharge discharge (110.4 [92.8-121.9] mL/h vs 97.1 [77.5-113.8] mL/h). Three patients (5.5%) from the normal saline group developed allograft failure by the post hoc 1-year follow-up visit. Conclusions and Relevance: This randomized clinical trial found that 24-hour perioperative dexmedetomidine decreased the incidence of DGF after DCD kidney transplant. The findings support the use of dexmedetomidine in kidney transplants. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1900025493.


Assuntos
Dexmedetomidina , Transplante de Rim , Adulto , Morte , Função Retardada do Enxerto/epidemiologia , Função Retardada do Enxerto/etiologia , Função Retardada do Enxerto/prevenção & controle , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Humanos , Transplante de Rim/efeitos adversos , Masculino , Diálise Renal/efeitos adversos , Solução Salina
7.
Chin Med ; 17(1): 75, 2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35718787

RESUMO

BACKGROUND: Investigation on protective effects of Panax notoginseng against obesity and its related mechanisms is incomplete. Present study aimed to investigate the potential anti-obesity effect of the total saponins (PNS) and ethanolic extract of P. notoginseng (PNE). METHODS: Six-week-old male C57BL/6J mice received 45% kcal fat diet for 12 weeks to induce obesity. Oral administration of PNS and PNE at 20 mg/kg/day was applied for the last 4 weeks in the obese mice. Lipid profile was determined by ELISA. Histological examination was performed in liver and fat tissues. Protein levels were measured by Western blot. RESULTS: PNS and PNE did not cause weight loss. PNE but not PNS decreased the mass of epididymal and retroperitoneal white adipose tissue, accompanied by a reduction in adipocyte hypertrophy. PNS and PNE improved lipid profile by reducing the concentrations of triglyceride, total cholesterol and low-density lipoprotein cholesterol in plasma or liver samples. PNS and PNE also relieved fatty liver in obese mice. PNS and PNE inhibited expression and phosphorylation of endoplasmic reticulum (ER) stress-responsive proteins in hypertrophic adipose tissue. CONCLUSIONS: PNS and PNE can regulate ER stress-mediated apoptosis and inflammation to alleviate obesity.

8.
9.
Artigo em Inglês | MEDLINE | ID: mdl-35708947

RESUMO

Delay discounting (DD), the decrease of the subjective value of a reward as the delay to its receipt increases, is a crucial aspect of decision-making processes. As evidence continues to mount, additional attention needs to be given to nonsystematic DD, a response pattern that has been reported in the literature but rarely investigated. We noticed in our recent online research an increase in the proportion of nonsystematic DD responses across samples, consistent with the so-called Amazon Mechanical Turk (MTurk) data quality crisis. The significant proportion of nonsystematic responses created an opportunity to investigate its association with data quality in the present study. In a sample of smokers recruited from MTurk (n = 210), three independent quality check indexes evaluated participants' response quality. The degree of nonsystematic DD was quantified by the algorithms developed by Johnson and Bickel (2008). The area under the receiver operating characteristic curve (AUC) predicting response quality by nonsystematic DD was obtained. The observed AUC values were at the extreme of the null distributions (ps < .001) in a permutation test. Furthermore, the nonsystematic DD cutoffs provided in Johnson and Bickel (2008) showed good sensitivity (0.77-0.93), albeit low-moderate specificity (0.42-0.74), in detecting low-quality responses. The findings showed that nonsystematic DD was associated with low-quality responses, although other factors contributing to the nonsystematic responses remain to be identified. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

10.
Bioengineered ; 13(5): 13872-13881, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35707830

RESUMO

Atherosclerosis is an inflammatory disease with a high level of cholesterol in the blood. Apremilast is a new anti-inflammatory drug that possesses a potential anti-atherosclerosis effect. RT-qPCR and western blot were undertaken to assay the levels of Sirtuin 1 (SIRT1), oxidized low density lipoprotein receptor 1 (LOX-1), and CD36 molecule (CD36). Reactive oxygen species (ROS) levels were evaluated by 2', 7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining, and Oil Red O staining was performed to show lipid accumulation. The result showed that apremilast treatment reduced the expression levels of pro-inflammatory factors and p-p65, as well as lipid accumulation. Meanwhile, triglyceride (TG), total cholesterol (TC) and free cholesterol (FC) levels declined in oxidized low density lipoprotein (ox-LDL)-treated macrophages. Mechanistically, apremilast targets SIRT1 and increases SIRT1 expression. The efficacy of apremilast on inflammatory response and lipid formation required the involvement of SIRT1. Additionally, apremilast treatment reduced scavenger receptors, LOX-1, and CD36 levels. These findings suggest the protective effects of apremilast via SIRT1 in atherogenesis and highlight the need for translational research from bench to bedside.


Assuntos
Aterosclerose , Sirtuína 1 , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/metabolismo , Colesterol/metabolismo , Colesterol/uso terapêutico , Humanos , Receptores Depuradores Classe E/genética , Receptores Depuradores Classe E/metabolismo , Receptores Depuradores Classe E/uso terapêutico , Sirtuína 1/genética , Sirtuína 1/metabolismo , Talidomida/análogos & derivados
11.
Front Bioeng Biotechnol ; 10: 884601, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35646839

RESUMO

Objective: Increasing the mass and/or activity of brown adipose tissue (BAT) is one promising avenue for treating obesity and related metabolic conditions, given that BAT has a high potential for energy expenditure and is capable of improving glucose and lipid homeostasis. BAT occurs either in discrete "classical" depots, or interspersed in white adipose tissue (WAT), termed "inducible/recruitable" BAT, or 'beige/brite' adipocytes. We and others have demonstrated that bone morphogenetic protein 7 (BMP7) induces brown adipogenesis in committed and uncommitted progenitor cells, resulting in increased energy expenditure and reduced weight gain in mice. BMP7 is therefore a reliable growth factor to induce browning of WAT. Methods: In this study, we sought to deliver BMP7 specifically to subcutaneous (sc)WAT in order to induce tissue-resident progenitor cells to differentiate into energy-expending recruitable brown adipocytes, without off-target effects like bone formation, which can occur when BMPs are in the presence of bone progenitor cells (outside of WAT). BMP7 delivery directly to WAT may also promote tissue innervation, or directly activate mitochondrial activity in brown adipocytes, as we have demonstrated previously. We utilized silk protein in the form of an injectable hydrogel carrying BMP7. Silk scaffolds are useful for in vivo delivery of substances due to favorable material properties, including controlled release of therapeutic proteins in an active form, biocompatibility with minimal immunogenic response, and prior FDA approval for some medical materials. For this study, the silk was engineered to meet desirable release kinetics for BMP7 in order to mimic our prior in vitro brown adipocyte differentiation studies. Fluorescently-labeled silk hydrogel loaded with BMP7 was directly injected into WAT through the skin and monitored by non-invasive in vivo whole body imaging, including in UCP1-luciferase reporter mice, thereby enabling an approach that is translatable to humans. Results: Injection of the BMP7-loaded silk hydrogels into the subcutaneous WAT of mice resulted in "browning", including the development of multilocular, uncoupling protein 1 (UCP1)-positive brown adipocytes, and an increase in whole-body energy expenditure and skin temperature. In diet-induced obese mice, BMP7-loaded silk delivery to subcutaneous WAT resulted in less weight gain, reduced circulating glucose and lower respiratory exchange ratio (RER). Conclusions: In summary, BMP7 delivery via silk scaffolds directly into scWAT is a novel translational approach to increase browning and energy expenditure, and represents a potential therapeutic avenue for delivering substances directly to adipose depots in pursuit of metabolic treatments.

12.
Inorg Chem ; 61(23): 8685-8693, 2022 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-35639458

RESUMO

Titanium oxo clusters (TOCs) with accurate molecular structures have potential applications in photocatalysis, such as photocatalytic degradation, hydrogen production, and water oxidation. The hydrolytic stability and light absorption ability of TOCs have important impacts on photocatalysis, where the selection of peripheral organic ligands plays a significant role. In this regard, salicylhydroxamic acid (abbreviated as H3L) attracts our attention, acting as a ligand for its multidentate and dye-functional features, which can increase the hydrolytic stability and broaden light absorption for TOCs. Herein, two TOCs were solvothermally synthesized and structurally characterized using H3L, formulated as [Ti8(µ2-O)2(µ3-O)2(OiPr)12(L)4]·2CH3CN (1) and [Ti16(µ2-O)10(µ3-O)4(PhCOO)14(L)6(HL)2]·4CH3CN·2iPrOH (2). Complex 2 was obtained by adding excessive benzoic acid over the reaction system of 1, resulting in enhanced hydrolytic stability via the replacement of all alkoxy ligands by multidentate ligands for protection. Interestingly, for the first time, the "three-in-one" structural building mode with {Ti6} + {Ti4} + {Ti6} by the common subunits in 2 was observed among all reported TOCs. Moreover, complex 2 can strongly absorb visible light reaching up to 700 nm and exhibit obvious activity for the photodegradation of methyl orange.


Assuntos
Benzoatos , Titânio , Ligantes , Salicilamidas , Titânio/química
13.
Parasitology ; : 1-7, 2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35570693

RESUMO

The parasite Fasciola hepatica is an important zoonotic parasite. The development of an animal model of F. hepatica's life cycle is critical for studying the biological characteristics of the parasite in snails and mammals. Eggs of F. hepatica of bovine origin were cultured, and metacercariae were obtained after infection of Galba pervia snails. The life cycle system of F. hepatica was initiated in 2 different animals by orally infecting rabbits, SD rats and Kunming mice with the metacercariae. The animals' survival after infection, parasite migration in the animals and pathological damage to the liver were observed. We discovered that rabbits died due to acute suppurative hepatitis 60­69 days after infection, and eggs were found in the feces on day 63 of infection. The liver of SD rats showed punctate lesions on day 3 of infection, and further changes occurred as the infection progressed. However, liver repair was observed at week 9. SD rats survived for more than a year after infection and continued the F. hepatica life cycle. The liver lesions in Kunming mice after infection were similar but more severe than those in SD rats. Death was observed on the 31st post-infection day. We discovered that while rabbits, SD rats and Kunming mice can all be used as animal models of F. hepatica, SD rats are more suitable experimental animals in terms of tolerance and pathological response.

14.
Structure ; 30(6): 886-899.e4, 2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35504278

RESUMO

Unlike most kinases, phosphatidylinositol 5-phosphate 4-kinase ß (PI5P4Kß) utilizes GTP as a physiological phosphate donor and regulates cell growth under stress (i.e., GTP-dependent stress resilience). However, the genesis and evolution of its GTP responsiveness remain unknown. Here, we reveal that PI5P4Kß has acquired GTP preference by generating a short dual-nucleotide-recognizing motif called the guanine efficient association (GEA) motif. Comparison of nucleobase recognition with 660 kinases and 128 G proteins has uncovered that most kinases and PI5P4Kß use their main-chain atoms for adenine recognition, while the side-chain atoms are required for guanine recognition. Mutational analysis of the GEA motif revealed that the acquisition of GTP reactivity is accompanied by an extended activity toward inosine triphosphate (ITP) and xanthosine triphosphate (XTP). Along with the evolutionary analysis data that point to strong negative selection of the GEA motif, these results suggest that the GTP responsiveness of PI5P4Kß has evolved from a compromised trade-off between activity and specificity, underpinning the development of the GTP-dependent stress resilience.


Assuntos
Proteínas de Ligação ao GTP , Inosina Trifosfato , Proteínas de Ligação ao GTP/metabolismo , Guanina , Guanosina Trifosfato/metabolismo , Inosina Trifosfato/metabolismo
15.
Nat Commun ; 13(1): 2835, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35595767

RESUMO

Cyclin-dependent kinase 2 (CDK2) complex is significantly over-activated in many cancers. While it makes CDK2 an attractive target for cancer therapy, most inhibitors against CDK2 are ATP competitors that are either nonspecific or highly toxic, and typically fail clinical trials. One alternative approach is to develop non-ATP competitive inhibitors; they disrupt interactions between CDK2 and either its partners or substrates, resulting in specific inhibition of CDK2 activities. In this report, we identify two potential druggable pockets located in the protein-protein interaction interface (PPI) between CDK2 and Cyclin A. To target the potential druggable pockets, we perform a LIVS in silico screening of a library containing 1925 FDA approved drugs. Using this approach, homoharringtonine (HHT) shows high affinity to the PPI and strongly disrupts the interaction between CDK2 and cyclins. Further, we demonstrate that HHT induces autophagic degradation of the CDK2 protein via tripartite motif 21 (Trim21) in cancer cells, which is confirmed in a leukemia mouse model and in human primary leukemia cells. These results thus identify an autophagic degradation mechanism of CDK2 protein and provide a potential avenue towards treating CDK2-dependent cancers.


Assuntos
Autofagia , Quinases relacionadas a CDC2 e CDC28 , Ciclina A , Quinase 2 Dependente de Ciclina , Leucemia , Animais , Linhagem Celular Tumoral/metabolismo , Ciclina A/antagonistas & inibidores , Ciclina A/metabolismo , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Mepesuccinato de Omacetaxina/metabolismo , Mepesuccinato de Omacetaxina/farmacologia , Humanos , Camundongos , Ribonucleoproteínas
16.
Int J Mol Sci ; 23(10)2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35628107

RESUMO

Excess inflammatory processes play a key detrimental role in the pathophysiology of acute lung injury (ALI). Mesenchymal stem cells (MSCs) were reported to be beneficial to ALI, but the underlying mechanisms have not been completely understood. The present study aimed to examine the involvement of MyD88-NFκB signaling in the immunomodulation of MSCs in mice with lipopolysaccharides (LPS)-induced ALI. We found that serum concentrations of IL-6, TNF-α, MCP-1, IL-1ß, and IL-8 were significantly decreased at 6 h after LPS-induced ALI in the MSC group (p < 0.05). For each of the five cytokines, the serum concentration of each individual mouse in either group declined to a similar level at 48 h. The intensity of lung injury lessened in the MSC group, as shown by histopathology and lung injury scores (p < 0.001). The expressions of MyD88 and phospho-NFκB in the lung tissue were significantly decreased in mice receiving MSCs as measured by Western blotting and immunohistochemistry. Our data demonstrated that human umbilical cord-derived MSCs could effectively alleviate the cytokine storm in mice after LPS-induced ALI and attenuated lung injury. Firstly, we documented the correlation between the down-regulation of MyD88-NFκB signaling and immunomodulatory effects of MSCs in the situation of ALI.


Assuntos
Lesão Pulmonar Aguda , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , NF-kappa B , Cordão Umbilical , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/terapia , Animais , Modelos Animais de Doenças , Humanos , Imunomodulação , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Cordão Umbilical/citologia , Cordão Umbilical/metabolismo
17.
Drug Deliv ; 29(1): 1743-1753, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35635315

RESUMO

It is a decade-long controversy that transarterial chemoembolization (TACE) has definite priority over transarterial embolization (TAE) in treating patients with hepatocellular carcinoma (HCC), since HCC cells are regularly resistant to chemotherapy by enhanced expression of proteins that confer drug resistance, and ABC transporters pump the intracellular drug out of the cell. We addressed this issue by modulating the chemo-environment. In an animal model, sevelamer, a polymeric phosphate binder, was introduced as an embolic agent to induce intratumoral inorganic phosphate (Pi) starvation, and trans-arterially co-delivered with doxorubicin (DOX). The new type of TACE was named as DOX-TASE. This Pi-starved environment enhanced DOX tumoral accumulation and retention, and DOX-TASE thereby induced more severe tumor necrosis than that induced by conventional TACE (C-TACE) and drug-eluting bead TACE (D-TACE) at the same dose. In vitro tests showed that Pi starvation increased the cellular accumulation of DOX in an irreversible manner and enhanced cytotoxicity and cell apoptosis by suppressing the expression of ABC transporters (P-glycoprotein (P-gp), BCRP, and MRP1) and the production of intracellular ATP. Our results are indicative of an alternative interventional therapy combining chemotherapy with embolization more effectively.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Quimioembolização Terapêutica/métodos , Doxorrubicina , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Proteínas de Neoplasias
18.
Small ; 18(24): e2201737, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35585680

RESUMO

The utilization of azobenzene-based photoisomerization cannot only control the morphology of supramolecular assemblies, but can also regulate many biological processes. However, the design of azobenzene-involved nanoconstructs with switchable photoluminescence remains challenging because of the light-quenching ability of azobenzene. Herein, an azobenzene-derived multicomponent nanosystem is reported and its function as a supramolecular lanthanide photoswitch is explored. The metal chelation between lanthanide ions (Ln3+  = Eu3+ and Tb3+ ) and 2,6-pyridinedicarboxylic acid is utilized as the light-emitting center but its inherent fluorescence emission is completely suppressed via the disordered motion of the adjoining azophenyl unit. Interestingly, the hydrophobic cavity of α-cyclodextrin can provide a confined microenvironment to immobilize the molecular conformation of trans-azobenzene, thus leading to the recovery of characteristic lanthanide luminescence both in aqueous solution and the hydrogel state. Also, the luminescence can be reversibly turned off when the cis-azobenzene is expelled from the cavity of α-cyclodextrin upon alternating light irradiation. This mutual cooperation arising from host-guest complexation and metal-ligand coordination confers the desired photoswitchable luminescence abilities on the commonly used azobenzenes, which may hold great promise in the creation of more advanced light-responsive smart materials.


Assuntos
Ciclodextrinas , Elementos da Série dos Lantanídeos , alfa-Ciclodextrinas , Ciclodextrinas/química , Elementos da Série dos Lantanídeos/química , Luminescência , Conformação Molecular
19.
Eur J Pharm Sci ; 175: 106208, 2022 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-35577181

RESUMO

The onset of variant angina (VA) shows circadian rhythmicity that its attacks occur most often from midnight to early morning. Thus, chronotherapeutic treatments should be tailored accordingly to its occurrence frequency. Tanshinol (TS), the bioactive component of Salvia miltiorrhiza was used as the model drug. The pharmacokinetics, pharmacodynamics and PK-PD relationship of TS was investigated in angina model rabbits. The therapeutic effect of TS was evaluated from different aspects including cardiac injury, oxidative stress and vascular endothelium by measuring the serum levels of cTn-I, CK-MB, SOD and NO. In addition, the change of cTn-I levels from baseline as the pharmacodynamic endpoint was used for establishing the pharmacodynamic model. To synchronize the therapeutic effect profile of TS to the occurrence frequency of VA, ideal time courses of therapeutic effect, plasma concentration and drug release were simulated and calculated based on pharmacodynamic/deconvolution integrated model method. Then, sustained release pellets of TS (TS-SRPs) were developed according to the above calculated results and evaluated in vitro-in vivo. The established pharmacodynamic model of TS could precisely quantify the relationship between its effect and concentration. Then, ideal time courses of therapeutic effect, plasma concentration and release of TS were simulated and calculated successfully. After formulation optimization, the prepared TS-SRPs exhibited similar in vitro and in vivo behaviors to the corresponding ideal ones. Meanwhile, the effect curves of TS were synchronous with the occurrence frequency of VA, implying that appropriate therapeutic effect could be provided according to the needs of patients. In conclusion, the tailor of therapeutic effect based on integrated model method is efficient, feasible and reliable.

20.
Front Nutr ; 9: 889901, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35571903

RESUMO

This study focused on the formation of Maillard hazards in air fried fries, highlighting the correlation between the resultant physical properties of the fries and the formation of Maillard hazards. In the meantime, the effects of air frying on the in vitro starch digestibility of fries were explored. Potato strips were fried at various temperatures (180-200°C) and time (12-24 min). Results indicated that the extent of browning, hardness, and the contents of Maillard hazards (acrylamide, 5-hydroxymethylfurfural, methylglyoxal, and glyoxal) all increased steadily with air frying temperature and time. Moisture content were negatively correlated (p < 0.001) with Maillard hazards content and physicochemical properties except for L* with the correlation coefficients range from -0.53 to 0.94, and positively correlated with L* value with correlation coefficient was 0.91, hence, reducing the Maillard hazard exposure while maintaining the desired product quality can be achieved by controlling the moisture content of the air fried French fries. Compared with deep frying (180°C-6 min), air frying decreased acrylamide and 5-hydroxymethylfurfural content with the maximum reduction rate were 47.31 and 57.04%, respectively. In addition, the in vitro digestion results suggested that air frying resulted in higher levels of slowly digestible starch (48.54-58.42%) and lower levels of resistant starch (20.08-29.34%) as compared to those from deep frying (45.59 ± 4.89 and 35.22 ± 0.65%, respectively), which might contribute to more balanced blood sugar levels after consumption. Based on the above results, it was concluded that air frying can reduce the formation of food hazards and was relatively healthier.

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