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Androgen receptor (AR) is one of the key targets for the treatment of castration-resistant prostate cancer (CRPC). Current endocrine therapy can greatly improve patients with CRPC. However, with the change of pathogenic mechanism, acquired resistance often leads to the failure of treatment. Studies have shown that tanshinone IIA (TS-IIA) and its derivatives have significant antitumor activity, and have certain AR-targeting effects, but the mechanism is unknown. In this study, the TS-IIA analog TB3 was found to significantly inhibit the growth of CRPC in vitro and in vivo. Molecular docking, cellular thermal shift assay, and cycloheximide experiments confirmed that AR was the target of TB3 and promoted the degradation of AR. Furthermore, TB3 can significantly inhibit glycolysis metabolism by targeting the AR/PKM2 axis. The addition of pyruvic acid could significantly alleviate the inhibitory effect of TB3 on CRPC cells. Besides, the knockdown of AR or PKM2 also could reverse the effect of TB3 on CRPC cells. Taken together, our study suggests that TS-IIA derivative TB3 inhibits glycolysis to prevent the CRPC process by targeting the AR/PKM2 axis.
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Abietanos , Glicólise , Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Proteínas de Ligação a Hormônio da Tireoide , Animais , Humanos , Masculino , Camundongos , Abietanos/farmacologia , Proteínas de Transporte/metabolismo , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos Nus , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genética , Hormônios Tireóideos/metabolismoRESUMO
In this study, we present the design and synthesis of novel fully synthetic L-shaped ortho-quinone analogs with tanshinone IIA as the lead compoud, which is a molecule with numerous pharmacological benefits and potential to treat life-threatening diseases, such as cancer and viral infections. 24 L-shaped ortho-quinone analogs were designed and synthesized via click chemistry and introduced 1,2,3-triazole at the C-2 terminal of the furan ring. The cytotoxicity of these analogs toward different cancer cell lines was investigated in vitro. The new TD compounds showed potent inhibitory activities toward prostate cancer (PC3), leukemia (K562), breast cancer (MDA-231), lung cancer (A549), and cervical cancer (Hela) cell lines. Among them, TD1, TD11, and TD17 showed excellent broad-spectrum cytotoxic effects on five cancer cell lines by inducing apoptosis and arresting the cell cycle phase. Besides, TD1, TD11, and TD17 could target-bind with NQO1 protein in the prostate cancer cells PC3 leukemia cells K562. The results showed that removing the methyl group at C-3 and introducing 1,2,3-triazoles at the C-2 terminal of the furan ring were effective strategies for improving the broad-spectrum anticancer activity of L-shaped ortho-quinone analogs.
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Antineoplásicos/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Quinonas/química , Quinonas/farmacologia , Abietanos/síntese química , Abietanos/química , Abietanos/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias/tratamento farmacológico , Quinonas/síntese química , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Drought is a major limiting factor seriously influencing worldwide soybean production and its impact on yield, morphological and physiological traits depend on the timing it occurs and the intensity of water shortage. Only limited research has however been conducted on identifying the drought-tolerant genotypes at different growth stages (vegetative growth phase, reproductive growth phase and the whole growth phase) as well as evaluate the effectiveness and reliability of multiple phenotypic and yield-related characteristics in soybean. RESULTS: Two pot experiments and a 2-year field experiment were conducted to evaluate soybean drought tolerance at different growth stages. The membership function value of drought tolerance (MFVD) was used to identify drought-resistant cultivars during vegetative growth phase and reproductive growth stage; the relative drought index (RDI) of yield was used to assess drought-resistant cultivars during the whole growing period. In this study, regression models built based on MFVD indicated that the variation of drought tolerant coefficient (DC) of R/S, TRL, LAI and RSR could explain 73.70% of the total variation at vegetative growth phase. However, higher heritability only found in LAI and RSR, indicating the two traits could serve as reliable criteria for drought evaluation. Similarly, the DC of SPP, YPP, PH, PB, MSNN and STB could explain 94.30% of the total variation in MFVD according to stepwise multiple linear regression analyses at reproductive growth phase. Thus, these six traits were identified as indicators for screening drought resistance genotypes in soybean. In addition, correlation analysis revealed that the MFVD was significantly positively correlated with the DCRB, DCR/S, DCRSA, DCRSR and DCRBR at vegetative growth phase and DCYPP, DCSPP, DCRB, and DCPB at reproductive growth phase. This indicated that these traits were closely related to the drought resistance of plants. CONCLUSIONS: LD24, JD36 and TF31 of vegetative growth phase, and TD37 and LD26 of reproductive growth phase were identified with drought tolerant and highly drought tolerant, respectively. Moreover, 30 accessions with drought tolerance were screened in the field trial and could be applied for the drought resistance of other genotypes by cross-breeding.
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Glycine max/genética , Estresse Fisiológico , Secas , Genótipo , Fenótipo , Melhoramento Vegetal , Pesquisa , Glycine max/crescimento & desenvolvimento , Glycine max/fisiologia , Água/fisiologiaRESUMO
Prostate cancer (PCa), an epithelial malignant tumor, is the second common cause of cancer death among males in western countries. Thus, the development of new strategies is urgently needed. Tanshinones isolated from Salvia miltiorrhiza and its synthetic analogs show various biological activities including anticancer effects. Among them, the tanshinone analog 2-((Glycine methyl ester)methyl)-naphtho (TC7) is the most effective, with better selectivity and lower toxicity. Therefore, in this work, the effect of TC7 against PCa was investigated through assessing the molecular mechanisms regulating the growth, metastasis, and invasion of PCa cells. Human PCa cells, PC3 and LNCAP, were used to evaluate TC7 mechanisms of action in vitro, while male BALB/c nude mice were used for in vivo experiments by subjecting each mouse to a subcutaneous injection of PC3 cells into the right flank to evaluate TC7 effects on tumor volume. Our in vitro results showed that TC7 inhibited cell proliferation by arresting the cell cycle at G2/M through the regulation of cyclin b1, p53, GADD45A, PLK1, and CDC2/cyclin b1. In addition, TC7 induced cell apoptosis by regulating apoptosis-associated genes such as p53, ERK1, BAX, p38, BCL-2, caspase-8, cleaved-caspase-8, PARP1, and the phosphorylation level of ERK1 and p38. Furthermore, it decreased DNA synthesis and inhibited the migration and invasion ability by regulating VEGF-1 and MMP-9 protein expression. Our in vivo evidence supports the conclusion that TC7 could be considered as a potential promising chemotherapeutic candidate in the treatment of PCa.
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Abietanos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Neoplasias da Próstata/prevenção & controle , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Abietanos/química , Animais , Antineoplásicos Fitogênicos/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Fitoterapia/métodos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Salvia miltiorrhiza/químicaRESUMO
Twenty-seven L-shaped ortho-quinone analogs were designed and synthesized using a one pot double-radical synthetic strategy followed by removing methyl at C-3 of the furan ring and introducing a diverse side chain at C-2 of the furan ring. The synthetic derivatives were investigated for their cytotoxicity activities against human leukemia cells K562, prostate cancer cells PC3, and melanoma cells WM9. Compounds TB1, TB3, TB4, TB6, TC1, TC3, TC5, TC9, TC11, TC12, TC14, TC15, TC16, and TC17 exhibited a better broad-spectrum cytotoxicity on three cancer cells. TB7 and TC7 selectively displayed potent inhibitory activities on leukemia cells K562 and prostate cancer cells PC3, respectively. Further studies indicated that TB3, TC1, TC3, TC7, and TC17 could significantly induce the apoptosis of PC3 cells. TC1 and TC17 significantly induced apoptosis of K562 cells. TC1, TC11, and TC14 induced significant apoptosis of WM9 cells. The structure-activity relationships evaluation showed that removing methyl at C-3 of the furan ring and introducing diverse side chains at C-2 of the furan ring is an effective strategy for improving the anticancer activity of L-shaped ortho-quinone analogs.
Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citotoxinas , Neoplasias , Quinonas , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Células PC-3 , Quinonas/síntese química , Quinonas/química , Quinonas/farmacologia , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: Our aim in this study was to systematically assess the association of sodium-glucose cotransporter-2 inhibitors (SGLT2i) vs dipeptidyl peptidase-4 inhibitors (DPP4i) with pneumonia, COVID-19, and adverse respiratory events in patients with type 2 diabetes mellitus (DM). METHODS: PubMed, Embase, and Cochrane Library databases were retrieved to include studies on DM patients receiving SGLT2i (exposure group) or DPP4i (control group). Stata version 15.0 statistical software was used for the meta-analysis. RESULTS: Ten studies were included, all 10 of which were used for the qualitative review and 7 for the meta-analysis. According to the meta-analysis, patients receiving SGLT2i had a lower incidence of pneumonia (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.51 to 0.74) and pneumonia risk (OR 0.63, 95% CI 0.60 to 0.68, p=0.000) compared with those receiving DPP4i. The same situation was seen for mortality for pneumonia (OR 0.49, 95% CI 0.39 to 0.60) and pneumonia mortality risk (OR 0.47, 95% CI 0.42 to 0.51). There was lower mortality due to COVID-19 (OR 0.31, 95% CI 0.28 to 0.34) and a lower hospitalization rate (OR 0.61, 95% CI 0.56 to 0.68, p=0.000) and incidence of mechanical ventilation (OR 0.69, 95% CI 0.58 to 0.83, p=0.000) due to COVID-19 in patients with type 2 DM receiving SGLT2i. Qualitative analysis results show that SGLT2i were associated with a lower incidence of COVID-19, lower risk of obstructive airway disease events, and lower hospitalization rate of health-care-associated pneumonia than DPP4i. CONCLUSION: In patients with type 2 DM, SGLT2i are associated with a lower risk of pneumonia, COVID-19, and mortality than DPP4i.
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COVID-19 , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Pneumonia , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , COVID-19/epidemiologia , COVID-19/complicações , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Pneumonia/epidemiologia , SARS-CoV-2 , IncidênciaRESUMO
To achieve a highly realistic robot, closely mimicking human skin in terms of materials and functionality is essential. This paper presents an all-protein silk fibroin bionic skin (SFBS) that emulates both fast-adapting (FA) and slow-adapting (SA) receptors. The mechanically different silk film and hydrogel, which exhibited skin-like properties, such as stretchability (>140%), elasticity, low modulus (<10 kPa), biocompatibility, and degradability, were prepared through mesoscopic reconstruction engineering to mimic the epidermis and dermis. Our SFBS, incorporating SA and FA sensors, demonstrated a highly sensitive (1.083 kPa-1) static pressure sensing performance (in vitro and in vivo), showed the ability to sense high-frequency vibrations (50-400 Hz), could discriminate materials and sliding, and could even identify the fine morphological differences between objects. As proof of concept, an SFBS-integrated rehabilitation glove was synthesized, which could help stroke patients regain sensory feedback. In conclusion, this work provides a practical approach for developing skin equivalents, prostheses, and smart robots.
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Biônica , Fibroínas , Succinimidas , Humanos , Seda , PeleRESUMO
A major impedance to neuronal regeneration after peripheral nerve injury (PNI) is the activation of various programmed cell death mechanisms in the dorsal root ganglion. Ferroptosis is a form of programmed cell death distinguished by imbalance in iron and thiol metabolism, leading to lethal lipid peroxidation. However, the molecular mechanisms of ferroptosis in the context of PNI and nerve regeneration remain unclear. Ferroportin (Fpn), the only known mammalian nonheme iron export protein, plays a pivotal part in inhibiting ferroptosis by maintaining intracellular iron homeostasis. Here, we explored in vitro and in vivo the involvement of Fpn in neuronal ferroptosis. We first delineated that reactive oxygen species at the injury site induces neuronal ferroptosis by increasing intracellular iron via accelerated UBA52-driven ubiquitination and degradation of Fpn, and stimulation of lipid peroxidation. Early administration of the potent arterial vasodilator, hydralazine (HYD), decreases the ubiquitination of Fpn after PNI by binding to UBA52, leading to suppression of neuronal cell death and significant acceleration of axon regeneration and motor function recovery. HYD targeting of ferroptosis is a promising strategy for clinical management of PNI.
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Extracellular vesicles (EVs) have inherent advantages over cell-based therapies in regenerative medicine because of their cargos of abundant bioactive cues. Several strategies are proposed to tune EVs production in vitro. However, it remains a challenge for manipulation of EVs production in vivo, which poses significant difficulties for EVs-based therapies that aim to promote tissue regeneration, particularly for long-term treatment of diseases like peripheral neuropathy. Herein, a superparamagnetic nanocomposite scaffold capable of controlling EVs production on-demand is constructed by incorporating polyethyleneglycol/polyethyleneimine modified superparamagnetic nanoparticles into a polyacrylamide/hyaluronic acid double-network hydrogel (Mag-gel). The Mag-gel is highly sensitive to a rotating magnetic field (RMF), and can act as mechano-stimulative platform to exert micro/nanoscale forces on encapsulated Schwann cells (SCs), an essential glial cell in supporting nerve regeneration. By switching the ON/OFF state of the RMF, the Mag-gel can scale up local production of SCs-derived EVs (SCs-EVs) both in vitro and in vivo. Further transcriptome sequencing indicates an enrichment of transcripts favorable in axon growth, angiogenesis, and inflammatory regulation of SCs-EVs in the Mag-gel with RMF, which ultimately results in optimized nerve repair in vivo. Overall, this research provides a noninvasive and remotely time-scheduled method for fine-tuning EVs-based therapies to accelerate tissue regeneration, including that of peripheral nerves.
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Vesículas Extracelulares , Nervos Periféricos , Células de Schwann/fisiologia , Regeneração Nervosa/fisiologia , Nanopartículas Magnéticas de Óxido de FerroRESUMO
Soybean (Glycine max) productivity is significantly reduced by drought stress. Breeders are aiming to improve soybean grain yields both under well-watered (WW) and drought-stressed (DS) conditions, however, little is known about the genetic architecture of yield-related traits. Here, a panel of 188 soybean germplasm was used in a genome wide association study (GWAS) to identify single nucleotide polymorphism (SNP) markers linked to yield-related traits including pod number per plant (PN), biomass per plant (BM) and seed weight per plant (SW). The SLAF-seq genotyping was conducted on the population and three phenotype traits were examined in WW and DS conditions in four environments. Based on best linear unbiased prediction (BLUP) data and individual environmental analyses, 39 SNPs were significantly associated with three soybean traits under two conditions, which were tagged to 26 genomic regions by linkage disequilibrium (LD) analysis. Of these, six QTLs qPN-WW19.1, qPN-DS8.8, qBM-WW1, qBM-DS17.4, qSW-WW4 and qSW-DS8 were identified controlling PN, BM and SW of soybean. There were larger proportions of favorable haplotypes for locus qPN-WW19.1 and qSW-WW4 rather than qBM-WW1, qBM-DS17.4, qPN-DS8.8 and qSW-DS8 in both landraces and improved cultivars. In addition, several putative candidate genes such as Glyma.19G211300, Glyma.17G057100 and Glyma.04G124800, encoding E3 ubiquitin-protein ligase BAH1, WRKY transcription factor 11 and protein zinc induced facilitator-like 1, respectively, were predicted. We propose that the further exploration of these locus will facilitate accelerating breeding for high-yield soybean cultivars.
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The repair of annulus fibrosus (AF) defect after discectomy in the intervertebral disc (IVD) has presented a challenge over the past decade. Hostile microenvironments in the IVD, including, compression and hypoxia, are critical issues that require special attention. Till date, little information is available on potential strategies to cope with the hypoxia dilemma in AF defect sites. In this study, perfluorotributylamine (PFTBA) core-shell fibers were fabricated by coaxial electrospinning to construct oxygen-releasing scaffold for promoting endogenous repair in the AF after discectomy. We demonstrated that PFTBA fibers (10% chitosan, chitosan: PCL, 1:6) could release oxygen for up to 144 âh. The oxygen released from PFTBA fibers was found to protect annulus fibrosus stem cells (AFSCs) from hypoxia-induced apoptosis. In addition, the PFTBA fibers were able to promote proliferation, migration and extracellular matrix (ECM) production in AFSCs under hypoxia, highlighting their therapeutic potential in AF defect repair. Subsequent in vivo studies demonstrated that oxygen-supplying fibers were capable of ameliorating disc degeneration after discectomy, which was evidenced by improved disc height and morphological integrity in rats with the oxygen-releasing scaffolds. Further transcriptome analysis indicated that differential expression genes (DEGs) were enriched in "oxygen transport" and "angiogenesis", which likely contributed to their beneficial effect on endogenous AF regeneration. In summary, the oxygen-releasing scaffold provides novel insights into the oxygen regulation by bioactive materials and raises the therapeutic possibility of oxygen supply strategies for defect repair in AF, as well as other aerobic tissues.
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The annual regrowth of deer antlers provides a valuable model for studying organ regeneration in mammals. We describe a single-cell atlas of antler regrowth. The earliest-stage antler initiators were mesenchymal cells that express the paired related homeobox 1 gene (PRRX1+ mesenchymal cells). We also identified a population of "antler blastema progenitor cells" (ABPCs) that developed from the PRRX1+ mesenchymal cells and directed the antler regeneration process. Cross-species comparisons identified ABPCs in several mammalian blastema. In vivo and in vitro ABPCs displayed strong self-renewal ability and could generate osteochondral lineage cells. Last, we observed a spatially well-structured pattern of cellular and gene expression in antler growth center during the peak growth stage, revealing the cellular mechanisms involved in rapid antler elongation.
Assuntos
Chifres de Veado , Cervos , Células-Tronco Mesenquimais , Regeneração , Animais , Chifres de Veado/citologia , Chifres de Veado/fisiologia , Cervos/fisiologia , Células-Tronco Mesenquimais/fisiologia , Análise de Célula Única , Proteínas de Homeodomínio/metabolismoRESUMO
Addressing the challenge of promoting directional axonal regeneration in a hostile astrocytic scar, which often impedes recovery following spinal cord injury (SCI), remains a daunting task. Cell transplantation is a promising strategy to facilitate nerve restoration in SCI. In this research, a pro-regeneration system is developed, namely miR-26a@SPIONs-OECs, for olfactory ensheathing cells (OECs), a preferred choice for promoting nerve regeneration in SCI patients. These entities show high responsiveness to external magnetic fields (MF), leading to synergistic multimodal cues to enhance nerve regeneration. First, an MF stimulates miR-26a@SPIONs-OECs to release extracellular vesicles (EVs) rich in miR-26a. This encourages axon growth by inhibiting PTEN and GSK-3ß signaling pathways in neurons. Second, miR-26a@SPIONs-OECs exhibit a tendency to migrate and orientate along the direction of the MF, thereby potentially facilitating neuronal reconnection through directional neurite elongation. Third, miR-26a-enriched EVs from miR-26a@SPIONs-OECs can interact with host astrocytes, thereby diminishing inhibitory cues for neurite growth. In a rat model of SCI, the miR-26a@SPIONs-OECs system led to significantly improved morphological and motor function recovery. In summary, the miR-26a@SPIONS-OECs pro-regeneration system offers innovative insights into engineering exogenous cells with multiple additional cues, augmenting their efficacy for stimulating and guiding nerve regeneration within a hostile astrocytic scar in SCI.
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MicroRNAs , Traumatismos da Medula Espinal , Ratos , Humanos , Animais , Astrócitos/metabolismo , Cicatriz/patologia , Orientação de Axônios , Glicogênio Sintase Quinase 3 beta/metabolismo , Regeneração Nervosa/fisiologia , Traumatismos da Medula Espinal/terapia , Traumatismos da Medula Espinal/metabolismo , Fenômenos Magnéticos , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Local hypoxia in cellular grafts remains a challenge during the repair of peripheral nerve injury. Oxygen carriers (perfluorotributylamine, PFTBA) have been shown to provide oxygen to Schwann cells (SCs) for a short period. However, the limited oxygen supply from oxygen-carrying materials hinders the ability of such systems to counteract hypoxia over an extended period and limits their therapeutic potential. In this study, PFTBA/VEGF core-shell fibers were fabricated through coaxial electrospinning to construct an oxygen supply system that can sequentially provide oxygen, first via the oxygen carrier and subsequently by promoting angiogenesis via VEGF. Then, the oxygen release and proangiogenic effects of the PFTBA/VEGF core-shell fibers were examined in vitro. Furthermore, sequential oxygen supply conduits prepared using the fibers and filled with SCs were used to bridge 15-mm-long sciatic nerve defects in rats. The PFTBA-VEGF system was confirmed to protect SCs from hypoxia and promote angiogenesis in vitro. Subsequent in vivo studies showed that after the oxygen carried by PFTBA was exhausted, the VEGF could induce neovascularization, and the nascent blood vessels acted as sequential oxygen suppliers for SCs during nerve regeneration. In addition, rats transplanted with the sequential oxygen supply system showed significant morphological and functional improvements in axonal regeneration, the sciatic function index, and the muscle wet weight ratio. The final functional outcomes were similar after treatment with the sequential oxygen supply conduits and autografts. Western blots revealed that the VEGF in the system could upregulate p-AMPK, contributing to axon regeneration after sciatic nerve injury. The sequential oxygen supply system offers essential insights into the oxygen regulation of biomaterials and highlights the potential of oxygen supply strategies as therapeutic approaches for repairing defects in peripheral nerves and other aerobic tissues.
Assuntos
Regeneração Nervosa , Traumatismos dos Nervos Periféricos , Proteínas Quinases Ativadas por AMP/farmacologia , Animais , Axônios , Materiais Biocompatíveis/farmacologia , Hipóxia , Oxigênio/farmacologia , Ratos , Ratos Sprague-Dawley , Células de Schwann/transplante , Nervo Isquiático/fisiologia , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
Inflammation following nerve injury and surgery often causes peripheral nerve adhesion (PNA) to the surrounding tissue. Numerous investigations independently examined the prevention or inhibition of PNA, however, an intervention targeting macrophages has not been fully elucidated. Basement membrane (BM) genes are known to modulate central nervous system (CNS) inflammation, however, their activities in the peripheral nervous system (PNS) remains undiscovered. In this report, we carried out weighted correlation network analysis (WCNA) to screen for principal sciatic nerve injury (SNI) module genes. Once an association between the module and BM genes was established, the protein-protein interaction (PPI) and immune infiltration analyses were employed to screen for relevant BM-related immune genes (Itgam, SDC1, Egflam, and CD44) in SNI. Subsequently, using the Drug SIGnatures (DSigDB) database and molecular docking, we demonstrated that Trichostatin A (TSA) interacted with key immune genes. TSA is known to enhance M2 macrophage expression and attenuate fibrosis. Nevertheless, the significance of the epigenetic modulation of macrophage phenotypes in dorsal root ganglion (DRG) is undetermined after SNI. In this article, we examined the TSA role in fibrogenesis and macrophage plasticity associated with DRG. We revealed that TSA enhanced M2 macrophage aggregation, inhibited fibroblast activation, and improved sciatic nerve regeneration (SNR) and sensory functional recovery (FR) after SNI. In addition, TSA suppressed M1 macrophages and enhanced M2 macrophage invasion within the DRG tissue. Furthermore, TSA dramatically reduced IL-1ß and TNFα levels, while upregulating IL-10 level. In summary, this research revealed for the first time that TSA alleviates fibrosis in DRG by promoting an M1 to M2 macrophage transition, which, in turn, accelerates SNR.
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Circadian rhythm (CR) imparts significant benefits in treating multiple diseases, such as heart diseases and arthritis. But the CR effect on intervertebral disc degeneration (IVDD) therapy remains unclear. Recent studies revealed that pulsed electromagnetic fields (PEMF) are capable of alleviating IVDD. In this study, we evaluated the CR-mediated regulation of PEMF therapeutic effect on IVDD induced by rat tail disc needle puncture. Our results demonstrated that the daytime PEMF stimulation (DPEMF) is more effective than the nighttime PEMF (NPEMF) in delaying IVDD. Moreover, the rats treated with DPEMF maintained better disc stability and histology after 8 weeks, relative to NPEMF. CR and PEMF cotherapies were also examined in cellular models, whereby serum shock was used to induce different levels of clock gene expression in the nucleus pulposus (NP), thus imitating CR in vitro. PEMF at ZT8 (higher level of clock gene expression) correlated with a higher extracellular matrix (ECM) component expression, compared to ZT20 (lower level of clock gene expression). Taken together, these data suggest a strong role of CR in regulating the beneficial effect of PEMF on IVDD. Our findings provide a potential clinical significance of CR in optimizing PEMF positive effects on IVDD.
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Degeneração do Disco Intervertebral , Núcleo Pulposo , Animais , Ritmo Circadiano , Campos Eletromagnéticos , Degeneração do Disco Intervertebral/patologia , Núcleo Pulposo/patologia , RatosRESUMO
Intervertebral disc (IVD) degeneration is regarded as a major contributor to low back pain (LBP), causing serious economic burden on individuals and society. Unfortunately, there are limited effective treatment for IVD degeneration. Pulsed electromagnetic field (PEMF) is an economical and effective physical therapy method, with reduced side-effects. It offers certain protection to a number of degenerative diseases. Therefore, understanding the underlying mechanism of PEMF on IVD is important for improving the PEMF therapeutic efficiency. In this study, PEMF up-regulated extracellular matrix (ECM) related genes in degenerated nucleus pulposus (NP) cells. It also increased SIRT1 expression and promoted autophagy in degenerated NP cells. In contrast, the autophagy suppressor 3-methyladenine (3-MA) reversed the beneficial effect of PEMF on ECM production. Similarly, the SIRT1 enzyme activity suppressor EX 527 also inhibited the effect of PEMF on autophagy and ECM production in NP cells, thereby suggesting that PEMF regulated ECM related genes expression through SIRT1-autophagy signaling pathway. Lastly, PEMF significantly reduced IVD degeneration in a rat model of IVD degeneration in vivo. In summary, our study uncovers a critical role of SIRT1-dependent autophagy signaling pathway in ECM protection and thus in the establishment of therapeutic effect of PEMF on IVD degeneration.
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In this paper, three configurations of LC (inductor-capacitor) pressure sensors are developed, namely series LC pressure sensors, compact LC pressure sensors, and far-field LC pressure sensor tags. The modified silk protein films have been chosen as substrates due to their good biocompatibility and air/water permeability, which is suitable for continuously pasting such substrates on skin. For series LC pressure sensors, conducting wire is used to connect the flexible capacitor and spiral inductor. It exhibits good cycling stability and high sensitivities, suitable for electronic skin. For compact LC pressure sensors, the spiral coil functions as inductor, antenna, and capacitor electrode simultaneously, minimizing the space cost and is suitable for array integration, while the sensitivities remain the same. By tailoring the turn of the spiral coil, the resonate frequency can be regulated continuously. An annular array of compact LC sensors with ten distinct resonate frequencies ranged from 400 to 1000 MHz is developed to remotely monitor the press of number 0-9. Finally, far-field LC pressure sensor tags with elongated detection distances are developed in which each compact LC sensor acts as a filter. A wireless in-shoe plantar to detect the sole pressure distribution using the far-field LC sensor configuration is developed.
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Dispositivos Eletrônicos Vestíveis , Tecnologia sem Fio , Monitorização Fisiológica , Seda , PeleRESUMO
The preparation of multifunctional materials with low cost and simple synthesis processes is still challenging. Herein, by employing various sizes (50-500 nm) of polystyrene (PS) spheres as templates, different free-standing carbon@MXene films with three-dimensional (3D) mesoporous structures were fabricated through a simple multistep route. The microstructure, composition, mechanical property, conductivity, electrochemical activity, and sensing characteristics of these carbon@MXene films were investigated in detail. The intercalation of the PS spheres can effectively reduce the self-accumulation of MXene nanosheets and construct 3D cross-linked mesoporous structures, therefore broadening the ion transport channels and exposing more active sites of carbon@MXene films. When applied in a symmetrical supercapacitor, the optimized carbon@MXene electrode has a satisfactory specific capacitance of 447.67 F g-1 at a current density of 1 A g-1. Moreover, the 3D mesoporous structures of carbon@MXene films can significantly improve the sensitivity of the resultant pressure sensors with excellent stability (10,000 cycles). Thus, such mesoporous carbon@MXene films prepared by a facile yet robust route will be a versatile material for many applications.
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The search for drugs that can facilitate axonal regeneration and elongation following peripheral nerve injury has been an area of increasing interest in recent years. Epothilone B (EpoB) is an FDA-approved antineoplastic agent, which shows the capacity to induce α-tubulin polymerization and to improve the stability of microtubules. Recently, it has been increasingly recognized that EpoB has a regenerative effect in the central nervous system. However, the information currently available regarding the potential therapeutic effect of EpoB on peripheral nerve regeneration is limited. Here, we used a rat sciatic crush injury model system to determine that EpoB strikingly improved axonal regeneration and recovery of function. Also, EpoB (1 nM) did not result in significant apoptosis in Schwann cells (SCs) and showed little effect on their viability either. Interestingly, EpoB (1 nM) significantly enhanced migration in SCs, which was inhibited by autophagy inhibitors 3-methyladenine (3-MA). Since PI3K/Akt signaling has been implicated in regulating autophagy, we further examined the involvement of PI3K/Akt in the process of EpoB-induced SC migration. We found that EpoB (1 nM) significantly inhibited phosphorylation of PI3K and Akt in SCs. Further studies showed that both EpoB-enhanced migration and autophagy were increased/inhibited by inhibition/activation of PI3K/Akt signaling with LY294002 or IGF-1. In conclusion, EpoB can promote axonal regeneration following peripheral nerve injury by enhancing the migration of SCs, with this activity being controlled by PI3K/Akt signaling-mediated autophagy in SCs. This underscores the potential therapeutic value of EpoB in enhancing regeneration and functional recovery in cases of peripheral nerve injury.