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1.
J Neurointerv Surg ; 2024 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-39168621

RESUMEN

BACKGROUND: Intracranial hemorrhage is the major safety concern of standard-dose ticagrelor (90 mg twice daily) based dual antiplatelet therapy (DAPT). The bleeding avoidance strategy through dose de-escalation has been investigated in interventional cardiology. However, the preserved antithrombotic efficacy and better safety of half-dose (45 mg twice daily) ticagrelor remains unverified in patients undergoing stent-assist coiling (SAC) or flow diversion (FD) treating unruptured intracranial aneurysms (UIA). METHODS: A single-center, prospective, cohort study was conducted to compare DAPT with aspirin 100 mg daily plus half-dose ticagrelor vs standard-dose clopidogrel (75 mg daily) in UIA patients. The adenosine diphosphate inhibition (ADPi) rate was utilized to quantify the antagonization of adenosine diphosphate (ADP)-induced platelet aggregation. The patients were followed-up at 6 month after discharge. The primary efficacy outcome was the major adverse cardiovascular and cerebrovascular events (MACCE), and the primary safety outcome was major bleeding. The secondary outcome was minor hemorrhage. RESULTS: Our study included 322 UIA patients, of which 254 patients were eventually enrolled after propensity score matching. The ADPi of half-dose ticagrelor (51.56%±31.46%) was comparable (P=0.089) to that of clopidogrel (57.44%±22.76%). The outcomes were also comparable. Five (3.94%) patients in the ticagrelor group and eight (6.30%) patients in the clopidogrel group reported MACCE (P=0.393). One patient in the ticagrelor group was diagnosed with asymptomatic intracranial hemorrhage 1 month after stenting. There were 36 (28.35%) minor hemorrhagic events in the ticagrelor group and 35 (27.56%) in the clopidogrel group, (P=0.889). CONCLUSION: Half-dose ticagrelor was effective and safe as a potential alternative to clopidogrel in the DAPT regimen for patients undergoing SAC/FD for UIA.

3.
World J Clin Cases ; 12(19): 3936-3941, 2024 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-38994295

RESUMEN

BACKGROUND: Pancreatic cancer presents a challenge with its low early diagnosis and treatment rates, leading to high metastasis and mortality rates. The median survival time for advanced pancreatic cancer is a mere 3 months. However, there's hope: small pancreatic cancers diagnosed at an early stage (T1) or those less than or equal to 1 cm in diameter boast an impressive 5-year survival rate of nearly 100%. This underscores the critical importance of early pancreatic cancer detection for significantly improving prognosis. CASE SUMMARY: Pancreatic cancer, a malignant tumor of the digestive tract, poses challenges in both diagnosis and treatment due to its occult and atypical clinical symptoms. Clinically, patients with recurrent pancreatitis should be vigilant, as it may be indicative of pancreatic cancer, particularly in middle-aged and elderly patients. Here, we presented the case of a patient who experienced recurrent acute pancreatitis within a span of 2 months. During the initial episode of pancreatitis, routine imaging failed to identify the cause of pancreatic cancer. However, upon recurrence of acute pancreatitis, endoscopic ultrasonography (EUS) revealed a space-occupying lesion approximately 1 cm in size in the pancreatic body. Subsequent EUS coupled with fine-needle aspiration examination demonstrated atypical pancreatic gland epithelium. Ultimately, the patient underwent surgery and was diagnosed with an intraductal papillary mucinous tumor of the pancreas (severe epithelial dysplasia, focal cancer). CONCLUSION: We recommend EUS for patients with recurrent pancreatitis of unknown etiology to exclude early pancreatic cancer.

5.
Mater Horiz ; 11(4): 876-902, 2024 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-38175543

RESUMEN

An MXene is a novel two-dimensional transition metal carbide or nitride, with a typical formula of Mn+1XnTx (M = transition metals, X = carbon or nitrogen, and T = functional groups). MXenes have found wide application in biomedicine and biosensing, owing to their high biocompatibility, abundant reactive surface groups, good conductivity, and photothermal properties. Applications include photo- and electrochemical sensors, energy storage, and electronics. This review will highlight recent applications of MXene and MXene-derived materials in drug delivery, tissue engineering, antimicrobial activity, and biosensors (optical and electrochemical). We further elaborate on recent developments in utilizing MXenes for photothermal cancer therapy, and we explore multimodal treatments, including the integration of chemotherapeutic agents or magnetic nanoparticles for enhanced therapeutic efficacy. The high surface area and reactivity of MXenes provide an interface to respond to the changes in the environment, allowing MXene-based drug carriers to respond to changes in pH, reactive oxygen species (ROS), and electrical signals for controlled release applications. Furthermore, the conductivity of MXene enables it to provide electrical stimulation for cultured cells and endows it with photocatalytic capabilities that can be used in antibiotic applications. Wearable and in situ sensors incorporating MXenes are also included. Major challenges and future development directions of MXenes in biomedical applications are also discussed. The remarkable properties of MXenes will undoubtedly lead to their increasing use in the applications discussed here, as well as many others.


Asunto(s)
Antibacterianos , Carbono , Nitritos , Elementos de Transición , Terapia Combinada , Portadores de Fármacos
6.
Cell Transplant ; 32: 9636897231190178, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37592717

RESUMEN

This study tested whether human umbilical cord-derived mesenchymal stem cells (HUCDMSCs) treatment effectively protected the rat lung against acute respiratory distress syndrome (ARDS) injury, and benefits of early and dose-dependent treatment. Rat pulmonary epithelial cell line L2 (PECL2) were categorized into G1 (PECL2), G2 (PECL2 + healthy rat lung-derived extraction/50 mg/ml co-cultured for 24 h), G3 (PECL2 + ARDS rat lung-derived extraction/50 mg/ml co-cultured for 24 h), and G4 (condition as G3 + HUCDMSCs/1 × 105/co-cultured for 24 h). The result showed that the protein expressions of inflammatory (HMGB-1/TLR-2/TLR-4/MAL/TRAM/MyD88/TRIF/TRAF6/IkB/NF-κB/IL-1ß/TNF-α), oxidative-stress/mitochondrial-damaged (NOX-1/NOX-2/ASK1/p-MKK4/p-MKK7/JNKs/JUN/cytosolic-cytochrome-C/cyclophilin-D/DRP1), and cell-apoptotic/fibrotic (cleaved-caspase 3/cleaved-PARP/TGF-ß/p-Smad3) biomarkers were significantly increased in G3 than in G1/G2 and were significantly reversed in G4 (all P < 0.001), but they were similar between G1/G2. Adult male rats (n = 42) were equally categorized into group 1 (normal control), group 2 (ARDS only), group 3 [ARDS + HUCDMSCs/1.2 × 106 cells intravenous administration at 3 h after 48 h ARDS induction (i.e., early treatment)], group 4 [ARDS + HUCDMSCs/1.2 × 106 cells intravenous administration at 24 h after 48 h ARDS induction (late treatment)], and group 5 [ARDS + HUCDMSCs/1.2 × 106 cells intravenous administration at 3 h/24 h after-48 h ARDS induction (dose-dependent treatment)]. By day 5 after ARDS induction, the SaO2%/immune regulatory T cells were highest in group 1, lowest in group 2, significantly lower in group 4 than in groups 3/5, and significantly lower in group 3 than in group 5, whereas the circulatory/bronchioalveolar lavage fluid inflammatory cells (CD11b-c+/LyG6+/MPO+)/circulatory immune cells (CD3-C4+/CD3-CD8+)/lung-leakage-albumin level/lung injury score/lung protein expressions of inflammatory (HMGB-1/TLR-2/TLR-4/MAL/TRAM/MyD88/TRIF/TRAF6/IκB-ß/p-NF-κB/IL-1ß/TNF-α)/fibrotic (p-SMad3/TGF-ß), apoptosis (mitochondrial-Bax/cleaved-caspase-3)/oxidative-cell-stress (NOX-1/NOX-2/ASK1/p-MKK4/p-MKK7/p-JNKs/p-cJUN)/mitochondrial damaged (cyclophilin-D/DRP1/cytosolic-cytochrome-C) biomarkers displayed an opposite pattern of SaO2% among the groups (all P < 0.0001). Early administration was superior to and two-dose counterpart was even more superior to late HUCDMSCs treatment for protecting the lung against ARDS injury.


Asunto(s)
Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Síndrome de Dificultad Respiratoria , Ratas , Masculino , Humanos , Animales , Ratas Sprague-Dawley , Roedores/metabolismo , Ciclofilinas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , FN-kappa B/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Inflamación/terapia , Inflamación/metabolismo , Síndrome de Dificultad Respiratoria/terapia , Células Madre Mesenquimatosas/metabolismo , Estrés Oxidativo , Factor de Crecimiento Transformador beta/metabolismo , Biomarcadores/metabolismo , Citocromos/metabolismo , Proteínas HMGB/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/metabolismo
7.
Stem Cell Rev Rep ; 19(8): 2852-2868, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37632641

RESUMEN

BACKGROUND: This study tested the hypothesis that inflammatory and interleukin (IL)-17 signalings were essential for acute liver ischemia (1 h)-reperfusion (72 h) injury (IRI) that was effectively ameliorated by adipose-derived mesenchymal stem cells (ADMSCs) and tacrolimus. METHODS: Adult-male SD rats (n = 50) were equally categorized into groups 1 (sham-operated-control), 2 (IRI), 3 [IRI + IL-17-monoclonic antibody (Ab)], 4 (IRI + tacrolimus), 5 (IRI + ADMSCs) and 6 (IRI + tacrolimus-ADMSCs) and liver was harvested at 72 h. RESULTS: The main findings included: (1) circulatory levels: inflammatory cells, immune cells, and proinflammatory cytokines as well as liver-damage enzyme at the time point of 72 h were highest in group 2, lowest in group 1 and significantly lower in group 6 than in groups 3 to 5 (all p < 0.0001), but they did not differ among these three latter groups; (2) histopathology: the liver injury score, fibrosis, inflammatory and immune cell infiltration in liver immunity displayed an identical pattern of inflammatory cells among the groups (all p < 0.0001); and (3) protein levels: upstream and downstream inflammatory signalings, oxidative-stress, apoptotic and mitochondrial-damaged biomarkers exhibited an identical pattern of inflammatory cells among the groups (all p < 0.0001). CONCLUSION: Our results obtained from circulatory, pathology and molecular-cellular levels delineated that acute IRI was an intricate syndrome that elicited complex upstream and downstream inflammatory and immune signalings to damage liver parenchyma that greatly suppressed by combined tacrolimus and ADMSCs therapy.


Asunto(s)
Hepatopatías , Células Madre Mesenquimatosas , Daño por Reperfusión , Ratas , Masculino , Animales , Interleucina-17 , Tacrolimus/farmacología , Ratas Sprague-Dawley , Daño por Reperfusión/terapia , Daño por Reperfusión/patología , Células Madre Mesenquimatosas/patología
8.
Front Cardiovasc Med ; 10: 1153428, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37063964

RESUMEN

Background: This study tested whether early left intracoronary arterial (LAD) administration of human bone marrow-derived mesenchymal stem cells (hBMMSCs, called OmniMSCs) in acute ST-segment elevation myocardial infarction (STEMI) of Lee-Sung pigs induced by 90 min balloon-occluded LAD was safe and effective. Methods and results: Young male Lee-Sung pigs were categorized into SC (sham-operated control, n = 3), AMI-B (STEMI + buffer/21 cc/administered at 90 min after STEMI, n = 6), and AMI-M [acute myocardial infarction (AMI) + hBMMSCs/1.5 × 107/administered at 90 min after STEMI, n = 6] groups. By 2 and 5 months after STEMI, the cardiac magnetic resonance imaging demonstrated that the muscle scar score (MSS) and abnormal cardiac muscle exercise score in the infarct region were significantly increased in the AMI-B than in the SC group that were significantly reversed in the AMI-M group, whereas the left ventricular ejection function by each month (from 1 to 5) displayed an opposite pattern of MSS among the groups (all p < 0.001). By 5 months, histopathological findings of infarct and fibrosis areas and isolectin-B4 exhibited an identical pattern, whereas the cellular expressions of troponin-I/troponin-T/von Willebrand factor exhibited an opposite pattern of MSS among the groups (all p < 0.001). The ST-segment resolution (>80%) was significantly earlier (estimated after 6-h AMI) in the AMI-M group than in the AMI-B group (p < 0.001). The protein expressions of inflammation (IL-1ß/TNF-α/NF-κB)/oxidative stress (NOX-1/NOX-2/oxidized protein)/apoptosis (cleaved caspase-3/cleaved PARP)/DNA damage (γ-H2AX) displayed an identical pattern to MSS among the groups, whereas the protein expressions of angiogenesis factors (SDF-1α/VEGF) were significantly and progressively increased from SC, AMI-B, to AMI-M groups (all p < 0.001). Conclusion: Early intra-LAD transfusion of OmniMSC treatment effectively reduced the infarct size and preserved LV function in porcine STEMI.

9.
J Mater Chem B ; 11(9): 1866-1870, 2023 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-36789698

RESUMEN

Insulin may help to control blood glucose levels in diabetes; however, the long-term release of insulin is important for therapy. In this work, four guide RNAs (gRNA) for factors that promote specification and maturation of insulin-producing cells were synthesized: pancreatic and duodenal homeobox 1 (PDX1), protoendocrine factor (neurogenin 3, NGN3), NK6 homeobox 1 (NKX6.1), and musculoaponeurotic fibrosarcoma oncogene family A (MAFA). These gRNAs were used to form ribonucleoproteins (RNPs) with tracRNA and dCas9-VPR, and were then immobilized on magnetic peptide-imprinted chitosan nanoparticles, which enhanced transfection. The production and release of insulin from transfected cells were then measured using ELISA and staining with anti-insulin antibodies. The expression of the genes was evaluated using qRT-PCR; this was also used to investigate the cascade of additional transcriptional regulators. The magnitude and duration of insulin production were evaluated for single and repeated transfections (using different transfection schedules) to identify the most promising protocol.


Asunto(s)
Células Secretoras de Insulina , Factores de Transcripción , Factores de Transcripción/genética , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Transactivadores/genética , Transactivadores/metabolismo , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo
10.
J Cell Mol Med ; 27(4): 482-495, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36660907

RESUMEN

Traumatic spinal cord injury (SCI) is a highly destructive disease in human neurological functions. Adipose-derived mesenchymal stem cells (ADMSCs) have tissue regenerations and anti-inflammations, especially with prion protein overexpression (PrPcOE ). Therefore, this study tested whether PrPcOE -ADMSCs therapy offered benefits in improving outcomes via regulating nod-like-receptor-protein-3 (NLRP3) inflammasome/DAMP signalling after acute SCI in rats. Compared with ADMSCs only, the capabilities of PrPcOE -ADMSCs were significantly enhanced in cellular viability, anti-oxidative stress and migration against H2 O2 and lipopolysaccharide damages. Similarly, PrPcOE -ADMSCs significantly inhibited the inflammatory patterns of Raw264.7 cells. The SD rats (n = 32) were categorized into group 1 (Sham-operated-control), group 2 (SCI), group 3 (SCI + ADMSCs) and group 4 (SCI + PrPcOE -ADMSCs). Compared with SCI group 2, both ADMSCs and PrPcOE -ADMSCs significantly improved neurological functions. Additionally, the circulatory inflammatory cytokines levels (TNF-α/IL-6) and inflammatory cells (CD11b/c+/MPO+/Ly6G+) were highest in group 2, lowest in group 1, and significantly higher in group 3 than in group 4. By Day 3 after SCI induction, the protein expressions of inflammasome signalling (HGMB1/TLR4/MyD88/TRIF/c-caspase8/FADD/p-NF-κB/NEK7/NRLP3/ASC/c-caspase1/IL-ß) and by Day 42 the protein expressions of DAMP-inflammatory signalling (HGMB1/TLR-4/MyD88/TRIF/TRAF6/p-NF-κB/TNF-α/IL-1ß) in spinal cord tissues displayed an identical pattern as the inflammatory patterns. In conclusion, PrPcOE -ADMSCs significantly attenuated SCI in rodents that could be through suppressing the inflammatory signalling.


Asunto(s)
Células Madre Mesenquimatosas , Priones , Traumatismos de la Médula Espinal , Ratas , Humanos , Animales , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , FN-kappa B/metabolismo , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/metabolismo , Priones/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/metabolismo , Médula Espinal/metabolismo , Células Madre Mesenquimatosas/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/metabolismo
11.
World Neurosurg ; 170: e755-e765, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36442786

RESUMEN

BACKGROUND: Dual antiplatelet therapy (DAPT) of aspirin plus clopidogrel is commonly used in patients with unruptured intracranial aneurysms treated with stent-assisted coil (SAC) embolization. However, the unpredictable clopidogrel efficacy of the 5%-55% nonresponders limits its use. Ticagrelor, as a potential alternative of clopidogrel, is an antiplatelet agent with low resistance rates but uncertain efficacy and safety in these patients. METHODS: A single-center cohort study was performed to compare the efficacy and safety of ticagrelor with clopidogrel in the DAPT regimen in patients with unruptured intracranial aneurysms and treated with SAC. The patients with clopidogrel resistance identified as inadequate adenosine diphosphate inhibition rate determined by thromboelastography were treated with ticagrelor instead, and both drugs achieved adequate suppression of platelet aggregation when stents were implanted. The occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) and bleeding events was recorded through 6 months follow-up. RESULTS: Data from 86 patients with 99 unruptured intracranial aneurysms and treated by SAC with clopidogrel were compared with those from 108 patients with 111 aneurysms and treated with ticagrelor. Neither the baseline characteristics nor the incidence of the MACCE or bleeding events differed between the groups. Ticagrelor exerted significantly higher adenosine diphosphate inhibition rate than that of the clopidogrel. Multivariable logistic regression analysis showed that the incidence of MACCE was related to hematocrit and fibrinogen levels. CONCLUSIONS: Ticagrelor seemed to be as effective and safe as clopidogrel for SAC in unruptured intracranial aneurysms. Hematocrit and fibrinogen levels were independent risk factors for the incidence of MACCE.


Asunto(s)
Embolización Terapéutica , Aneurisma Intracraneal , Humanos , Clopidogrel/uso terapéutico , Ticagrelor/uso terapéutico , Estudios de Cohortes , Aneurisma Intracraneal/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Stents , Adenosina Difosfato , Fibrinógeno/uso terapéutico , Resultado del Tratamiento
12.
Polymers (Basel) ; 16(1)2023 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-38201691

RESUMEN

The features or actuation behaviors of nature's creatures provide concepts for the development of biomimetic soft bioactuators/robots with stimuli-responsive capabilities, design convenience, and environmental adaptivity in various fields. Mimosa pudica is a mechanically responsive plant that can convert pressure to the motion of leaves. When the leaves receive pressure, the occurrence of asymmetric turgor in the extensor and flexor sides of the pulvinus from redistributing the water in the pulvinus causes the bending of the pulvinus. Inspired by the actuation of Mimosa pudica, designing soft bioactuators can convert external stimulations to driving forces for the actuation of constructs which has been receiving increased attention and has potential applications in many fields. 4D printing technology has emerged as a new strategy for creating versatile soft bioactuators/robots by integrating printing technologies with stimuli-responsive materials. In this study, we developed a hybrid ink by combining gelatin methacryloyl (GelMA) polymers with iron oxide nanoparticles (IONs). This hybrid ION-GelMA ink exhibits tunable rheology, controllable mechanical properties, magnetic-responsive behaviors, and printability by integrating the internal metal ion-polymeric chain interactions and photo-crosslinking chemistries. This design offers the inks a dual crosslink mechanism combining the advantages of photocrosslinking and ionic crosslinking to rapidly form the construct within 60 s of UV exposure time. In addition, the magnetic-responsive actuation of ION-GelMA constructs can be regulated by different ION concentrations (0-10%). Furthermore, we used the ION-GelMA inks to fabricate a Mimosa pudica-like soft bioactuator through a mold casting method and a direct-ink-writing (DIW) printing technology. Obviously, the pinnule leaf structure of printed constructs presents a continuous reversible shape transformation in an air phase without any liquid as a medium, which can mimic the motion characteristics of natural creatures. At the same time, compared to the model casting process, the DIW printed bioactuators show a more refined and biomimetic transformation shape that closely resembles the movement of the pinnule leaf of Mimosa pudica in response to stimulation. Overall, this study indicates the proof of concept and the potential prospect of magnetic-responsive ION-GelMA inks for the rapid prototyping of biomimetic soft bioactuators/robots with untethered non-contact magneto-actuations.

13.
Cell Transplant ; 31: 9636897221133821, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36317711

RESUMEN

This study tested whether combined hyperbaric oxygen (HBO) and allogenic adipose-derived mesenchymal stem cells (ADMSCs) would be superior to either one for improving the locomotor recovery in rat after acute traumatic spinal cord injury (TSCI) in rat. Adult-male Sprague-Dawley rats were equally categorized into group 1 (sham-operated control), group 2 (TSCI), group 3 (TSCI + HBO for 1.5 h/day for 14 consecutive days after TSCI), group 4 (TSCI + ADMSCs/1.2 × 106 cells by intravenous injection at 3 h and days 1/2 after TSCI), and group 5 (TSCI + HBO + ADMSCs), euthanized, and spinal cord tissue was harvested by day 49 after TSCI. The protein expressions of oxidative-stress (NOX-1/NOX-2), inflammatory-signaling (TLR-4/MyD88/IL-1ß/TNF-α/substance-p), cell-stress signaling (PI3K/p-AKT/p-mTOR), and the voltage-gated sodium channel (Nav1.3/1.8/1.9) biomarkers were highest in group 2, lowest in group 1, and significantly lower in group 5 than in groups 3/4 (all P <0.0001), but they did not differ between groups 3 and 4. The spinal cord damaged area, the cellular levels of inflammatory/DNA-damaged biomarkers (CD68+/GFAP+/γ-H2AX+ cells), mitogen-activated protein kinase family biomarkers (p-P38/p-JNK/p-ERK1/2), and cellular expressions of voltage-gated sodium channel (Nav.1.3, Nav.1.8, and Nav.1.9 in NF200+ cells) as well as the pain-facilitated cellular expressions (p-P38+/peripherin+ cells, p-JNK+/peripherin+ cells, p-ERK/NF200+ cells) exhibited an identical pattern of inflammation, whereas the locomotor recovery displayed an opposite pattern of inflammation among the groups (all P < 0.0001). Combined HBO-ADMSCs therapy offered additional benefits for preserving the neurological architecture and facilitated the locomotor recovery against acute TSCI.


Asunto(s)
Oxigenoterapia Hiperbárica , Células Madre Mesenquimatosas , Traumatismos de la Médula Espinal , Animales , Ratas , Masculino , Ratas Sprague-Dawley , Periferinas/metabolismo , Células Madre Mesenquimatosas/metabolismo , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/metabolismo , Inflamación/terapia , Inflamación/metabolismo , Biomarcadores/metabolismo
14.
Int J Mol Sci ; 23(19)2022 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-36233275

RESUMEN

This study investigated the hypothesis that probiotics enhanced the therapeutic effect of adipose-derived mesenchymal stem cells (ADMSCs) on alleviating neuropathic pain (NP) due to chronic constriction injury (CCI) mainly through regulating the microbiota in rats. SD rats (n = 50) were categorized into group 1 (sham-control), group 2 (NP), group 3 (NP + probiotics (i.e., 1.5 billion C.F.U./day/rat, orally 3 h after NP procedure, followed by QOD 30 times)), group 4 (NP + ADMSCs (3.0 × 105 cells) 3 h after CCI procedure, followed by QOD six times (i.e., seven times in total, i.e., mimic a clinical setting of drug use) and group 5 (NP + probiotics + ADMSCs (3.0 × 105 cells)) and euthanized by day 60 after NP induction. By day 28 after NP induction, flow-cytometric analysis showed circulating levels of early (AN-V+/PI−) and late (AN-V+/PI+) apoptotic, and three inflammatory (CD11b-c+, Ly6G+ and MPO+) cells were lowest in group 1 and significantly progressively reduced in groups 2 to 5 (all p < 0.0001). By days 7, 14, 21, 28, and 60 after CCI, the thresholds of thermal paw withdrawal latency (PWL) and mechanical paw withdrawal threshold (PWT) were highest in group 1 and significantly progressively increased in groups 2 to 5 (all p < 0.0001). Numbers of pain-connived cells (Nav1.8+/peripherin+, p-ERK+/peripherin+, p-p38+/peripherin+ and p-p38+/NF200+) and protein expressions of inflammatory (p-NF-κB, IL-1ß, TNF-α and MMP-9), apoptotic (cleaved-caspase-3, cleaved-PARP), oxidative-stress (NOX-1, NOX-2), DNA-damaged (γ-H2AX) and MAPK-family (p-P38, p-JNK, p-ERK1/2) biomarkers as well as the protein levels of Nav.1.3, Nav.1.8, and Nav.1.9 in L4-L5 in dorsal root ganglia displayed an opposite pattern of mechanical PWT among the groups (all p < 0.0001). In conclusion, combined probiotic and ADMSC therapy was superior to merely one for alleviating CCI-induced NP mainly through suppressing inflammation and oxidative stress.


Asunto(s)
Células Madre Mesenquimatosas , Neuralgia , Probióticos , Animales , Biomarcadores/metabolismo , Caspasa 3/metabolismo , ADN/metabolismo , Inflamación/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Células Madre Mesenquimatosas/metabolismo , FN-kappa B/metabolismo , Neuralgia/tratamiento farmacológico , Neuralgia/terapia , Periferinas/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Probióticos/farmacología , Probióticos/uso terapéutico , Ratas , Ratas Sprague-Dawley , Roedores/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
15.
Front Oncol ; 12: 855807, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35795053

RESUMEN

The human programmed cell death 4 (PDCD4) gene was mapped at chromosome 10q24 and encodes the PDCD4 protein comprised of 469 amino acids. PDCD4 inhibits protein translation PDCD4 inhibits protein translation to suppress tumor progression, and its expression is frequently decreased in breast cancer. PDCD4 blocks translation initiation complex by binding eIF4A via MA-3 domains or by directly binding 5' mRNA internal ribosome entry sites with an RNA binding domain to suppress breast cancer progression and proliferation. Numerous regulators and biological processes including non-coding RNAs, proteasomes, estrogen, natural compounds and inflammation control PDCD4 expression in breast cancer. Loss of PDCD4 expression is also responsible for drug resistance in breast cancer. HER2 activation downregulates PDCD4 expression by activating MAPK, AKT, and miR-21 in aromatase inhibitor-resistant breast cancer cells. Moreover, modulating the microRNA/PDCD4 axis maybe an effective strategy for overcoming chemoresistance in breast cancer. Down-regulation of PDCD4 is significantly associated with short overall survival of patients, which suggests that PDCD4 may be an independent prognostic marker for breast cancer.

16.
Molecules ; 27(9)2022 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-35565995

RESUMEN

Diabetes-induced chronic kidney disease leads to mortality and morbidity and thus poses a great health burden worldwide. Krüppel-like factor 10 (KLF10), a zinc finger-containing transcription factor, regulates numerous cellular functions, such as proliferation, differentiation, and apoptosis. In this study, we explored the effects of KLF10 on diabetes-induced renal disease by using a KLF10 knockout mice model. Knockout of KLF10 obviously diminished diabetes-induced tumor growth factor-ß (TGF-ß), fibronectin, and type IV collagen expression, as evidenced by immunohistochemical staining. KLF10 knockout also repressed the expression of Dickkopf-1 (DKK-1) and phosphorylated ß-catenin in diabetic mice, as evidenced by immunohistochemical staining and Western blot analysis. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) revealed that significantly decreased type IV collagen, fibronectin, and DKK-1 existed in KLF10 knockout diabetic mice compared with control diabetic mice. Moreover, knockout of KLF10 reduced the renal fibrosis, as shown by Masson's Trichrome analysis. Overall, the results indicate that depletion of KLF10 ameliorated diabetic renal fibrosis via the downregulation of DKK-1 expression and inhibited TGF-ß1 and phosphorylated ß-catenin expression. Our findings suggest that KLF10 may be a promising therapeutic choice for the treatment of diabetes-induced renal fibrosis.


Asunto(s)
Diabetes Mellitus Experimental , Nefropatías Diabéticas , Factores de Transcripción de Tipo Kruppel , Animales , Colágeno Tipo IV/metabolismo , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/metabolismo , Regulación hacia Abajo , Factores de Transcripción de la Respuesta de Crecimiento Precoz/genética , Factores de Transcripción de la Respuesta de Crecimiento Precoz/metabolismo , Femenino , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrosis , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Masculino , Ratones , Ratones Noqueados , Factor de Crecimiento Transformador beta1/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
18.
BMC Anesthesiol ; 22(1): 34, 2022 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-35086470

RESUMEN

BACKGROUND: Agitation is common in subarachnoid hemorrhage (SAH), and sedation with midazolam, propofol and dexmedetomidine is essential in agitation management. Previous research shows the tendency of dexmedetomidine and propofol in improving long-term outcome of SAH patients, whereas midazolam might be detrimental. Brain metabolism derangement after SAH might be interfered by sedatives. However, how sedatives work and whether the drugs interfere with patient outcome by altering cerebral metabolism is unclear, and the comprehensive view of how sedatives regulate brain metabolism remains to be elucidated. METHODS: For cerebrospinal fluid (CSF) and extracellular space of the brain exchange instantly, we performed a cohort study, applying CSF of SAH patients utilizing different sedatives or no sedation to metabolomics. Baseline CSF metabolome was corrected by selecting patients of the same SAH and agitation severity. CSF components were analyzed to identify the most affected metabolic pathways and sensitive biomarkers of each sedative. Markers might represent the outcome of the patients were also investigated. RESULTS: Pentose phosphate pathway was the most significantly interfered (upregulated) pathway in midazolam (p = 0.0000107, impact = 0.35348) and propofol (p = 0.00000000000746, impact = 0.41604) groups. On the contrary, dexmedetomidine decreased levels of sedoheptulose 7-phosphate (p = 0.002) and NADP (p = 0.024), and NADP is the key metabolite and regulator in pentose phosphate pathway. Midazolam additionally augmented purine synthesis (p = 0.00175, impact = 0.13481) and propofol enhanced pyrimidine synthesis (p = 0.000203, impact = 0.20046), whereas dexmedetomidine weakened pyrimidine synthesis (p = 0.000000000594, impact = 0.24922). Reduced guanosine diphosphate (AUC of ROC 0.857, 95%CI 0.617-1, p = 0.00506) was the significant CSF biomarker for midazolam, and uridine diphosphate glucose (AUC of ROC 0.877, 95%CI 0.631-1, p = 0.00980) for propofol, and succinyl-CoA (AUC of ROC 0.923, 95%CI 0.785-1, p = 0.000810) plus adenosine triphosphate (AUC of ROC 0.908, 95%CI 0.6921, p = 0.00315) for dexmedetomidine. Down-regulated CSF succinyl-CoA was also associated with favorable outcome (AUC of ROC 0.708, 95% CI: 0.524-0.865, p = 0.029333). CONCLUSION: Pentose phosphate pathway was a crucial target for sedatives which alter brain metabolism. Midazolam and propofol enhanced the pentose phosphate pathway and nucleotide synthesis in poor-grade SAH patients, as presented in the CSF. The situation of dexmedetomidine was the opposite. The divergent modulation of cerebral metabolism might further explain sedative pharmacology and how sedatives affect the outcome of SAH patients.


Asunto(s)
Dexmedetomidina/farmacología , Midazolam/farmacología , Vía de Pentosa Fosfato/efectos de los fármacos , Propofol/farmacología , Agitación Psicomotora/prevención & control , Hemorragia Subaracnoidea/complicaciones , Anciano , Estudios de Cohortes , Femenino , Humanos , Hipnóticos y Sedantes/farmacología , Masculino , Persona de Mediana Edad , Agitación Psicomotora/etiología
19.
Int J Biol Sci ; 17(14): 3728-3744, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34671196

RESUMEN

Colorectal cancer (CRC) is the third most common cancer worldwide. Colorectal carcinogenesis is frequently induced by hypoxia to trigger the reprogramming of cellular metabolism and gain of malignant phenotypes. Previously, hyperbaric oxygen (HBO) therapy and melatonin have been reported to alter the hypoxic microenvironment, resulting in inhibiting cancer cell survival. Accordingly, this study tested the hypothesis whether HBO and melatonin effectively inhibited CRC carcinogenesis. In vitro results indicated that melatonin therapy significantly suppressed the malignant phenotypes, including colony formation, growth, invasion, migration and cancer stemness with dose-dependent manners in CRC cell lines through multifaceted mechanisms. Similar to in vitro study, in vivo findings further demonstrated the melatonin, HBO and combined treatments effectively promoted apoptosis (cleaved-caspase 3/ cleaved-PARP) and arrested tumor proliferation, followed by inhibiting colorectal tumorigenesis in CRC xenograft tumor model. Moreover, melatonin, HBO and combined treatments modulated multifaceted mechanisms, including decreasing HIF-1α expression, alleviating AKT activation, repressing glycolytic metabolism (HK-2/PFK1/PKM2/LDH), restraining cancer stemness pathway (TGF-ß/p-Smad3/Oct4/Nanog), reducing inflammation (p-NFκB/ COX-2), diminishing immune escape (PD-L1), and reversing expression of epithelial mesenchymal transition (E-cadherin/N-cadherin/MMP9). In conclusion, melatonin and HBO therapies suppressed colorectal carcinogenesis through the pleiotropic effects and multifaceted mechanisms, suggesting melatonin and HBO treatments could be novel therapeutic strategies for CRC treatment.


Asunto(s)
Neoplasias Colorrectales/terapia , Oxigenoterapia Hiperbárica , Melatonina/uso terapéutico , Animales , Apoptosis , Carcinogénesis , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/patología , Terapia Combinada , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta/metabolismo
20.
J Cell Mol Med ; 25(16): 7675-7689, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34161651

RESUMEN

This study tested the hypothesis that therapy with double overexpression of miR-19a-3p and miR-20a-5p (miRDOE ) to human inducible pluripotent stem cell-derived mesenchymal stem cells (iPS-MSCs) was superior to iPS-MSCs alone for preserving renal function in rat with pre-existing chronic kidney disease (CKD), followed by ischaemia-reperfusion (IR) injury. In vitro study demonstrated that the protein expressions of oxidative stress (NOX-1/NOX-2/NOX4/oxidized protein/p22phox), inflammatory downstream signalling (TLR2&4/MyD88/TRAF6/IKK-ß/p-NFκB/IL-1ß/IL-6/MMP-9) and cell apoptosis/death signalling (cleaved caspase-3/mitochondrial Bax/p-ERKs/p-JNK/p-p38) at time-points of 24-hour/48-hour cell cultures were significantly increased in p-Cresol-treated NRK-52E cells than in the control that was significantly reversed by miR-19a-3p-transfected iPS-MSC (all P < .001). Animals were categorized into group 1 (sham-operated control), group 2 (CKD-IR), group 3 (CKD-IR + oligo-miRDOE of iPS-MSCs/6.0 ×105 /intra-renal artery transfusion/3 hours after IR procedure), group 4 (CKD-IR + iPS-MSCs) and group 5 (CKD-IR + miRDOE of iPS-MSCs/6.0 ×105/ intra-renal artery transfusion/3 hour after IR procedure). By day 35, the creatinine/BUN levels were lowest in group 1, highest in group 2 and significantly lower in group 5 than in groups 3 and 4 (all P < .0001) but they showed no difference between the latter two groups. The protein expressions of oxidative stress, inflammatory downstream signalling and cell apoptosis/death signalling exhibited an identical pattern of creatinine level among the five groups (all P < .00001). Also, the microscopic findings demonstrated that the kidney injury score/fibrotic area/number of inflammatory cells (CD14+/CD68+) exhibited an identical pattern of creatine level (all P < .0001). The miRDOE of iPS-MSCs was superior to iPS-MSCs for preserving the residual kidney function and architecture in CKD-IR rat.


Asunto(s)
Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Mesenquimatosas/metabolismo , MicroARNs/farmacología , Estrés Oxidativo , Insuficiencia Renal Crónica/tratamiento farmacológico , Daño por Reperfusión/complicaciones , Animales , Apoptosis , Línea Celular , Modelos Animales de Enfermedad , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Masculino , MicroARNs/genética , Ratas , Ratas Sprague-Dawley , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Transducción de Señal
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