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1.
Nature ; 613(7945): 656-661, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36653455

RESUMO

Domain-wall nanoelectronics is considered to be a new paradigm for non-volatile memory and logic technologies in which domain walls, rather than domains, serve as an active element. Especially interesting are charged domain walls in ferroelectric structures, which have subnanometre thicknesses and exhibit non-trivial electronic and transport properties that are useful for various nanoelectronics applications1-3. The ability to deterministically create and manipulate charged domain walls is essential to realize their functional properties in electronic devices. Here we report a strategy for the controllable creation and manipulation of in-plane charged domain walls in BiFeO3 ferroelectric films a few nanometres thick. By using an in situ biasing technique within a scanning transmission electron microscope, an unconventional layer-by-layer switching mechanism is detected in which ferroelectric domain growth occurs in the direction parallel to an applied electric field. Based on atomically resolved electron energy-loss spectroscopy, in situ charge mapping by in-line electron holography and theoretical calculations, we show that oxygen vacancies accumulating at the charged domain walls are responsible for the domain-wall stability and motion. Voltage control of the in-plane domain-wall position within a BiFeO3 film gives rise to multiple non-volatile resistance states, thus demonstrating the key functional property of being a memristor a few unit cells thick. These results promote a better understanding of ferroelectric switching behaviour and provide a new strategy for creating unit-cell-scale devices.


Assuntos
Eletricidade , Filmes Cinematográficos , Eletrônica , Elétrons , Honorários e Preços
2.
Bioresour Technol ; 372: 128662, 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36693505

RESUMO

Effects of limited dissolved oxygen (DO) on hydrogenotrophic denitrification at biocathode was investigated using bioelectrochemical system. It was found that total nitrogen removal increased by 5.9%, as DO reached about 0.24 mg/L with the cathodic chamber unplugged (group R_Exposure). With the presence of limited DO, not only the nitrogen metabolic pathway was influenced, but the composition of microbial communities of ammonia-oxidizing bacteria and nitrite-oxidizing bacteria were enriched accordingly. After metagenomic analysis, enriched genes in R_Exposure were found to be associated with nearly each of nitrogen removal steps as denitrification, nitrification, DNRA, nitrate assimilation and even nitrogen fixation. Moreover, genes encoding both Complexes III and IV constituted the electron transfer chain were significantly enriched, indicating that more electrons would be orientated to the reduction of NO2--N, NO-N and oxygen. Therefore, enhanced nitrogen removal could be attained through the co-respiration of nitrate and oxygen by means of NH4+-N oxidation.

3.
Artigo em Inglês | MEDLINE | ID: mdl-36701096

RESUMO

Aquacultural shrimps suffer economic lost due to the white spot syndrome virus (WSSV) that is the most notorious virus for its fatality and contagion, leading to a 100% death rate on infected shrimps within 7 days. However, the infection of mechanism remains a mystery and crucial problem. To elucidate the pathogenesis of WSSV, a high abundance of protein is required to identify and characterize its functions. Therefore, the optimal WSSV355 overexpression was explored in engineered Escherichia coli strains, in particular C43(DE3) as a toxic tolerance strain remedied 40% of cell growth from BL21(DE3). Meanwhile, a trace amount of WSSV355 was observed in both strains. To optimize the codon of WSSV355 using codon adaption index (CAI), an overexpression was observed with 1.32 mg/mL in C43(DE3), while the biomass was decreased by 35%. Subsequently, the co-expression with pRARE boosted the target protein up to 1.93 mg/mL. Finally, by scaling up production of WSSV355 in the fermenter with sufficient oxygen supplied, the biomass and total and soluble protein were enhanced 67.6%, 44.9%, and 7.8% compared with that in flask condition. Herein, the current approach provides efficacious solutions to produce toxic proteins via codon usage, strain selection, and processing optimization by alleviating the burden and boosting protein production in E. coli.

4.
ACS Med Chem Lett ; 14(1): 92-102, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36655129

RESUMO

The RAF/MEK/ERK pathway is a crucial signal path which is closely associated with the proliferation, differentiation, and apoptosis of tumors. MEK1/2 is a key kinase target in the pathway, with ERK1/2 acting as the main substrate of it. Despite the rapid development of MEK1/2 inhibitors, acquired resistance still happens and remains a significant problem. Most of the inhibitors possess a similar diarylamine scaffold. Here we designed and synthesized a series of MEK1/2 degraders based on a coumarin derivative which was a potent non-diarylamine allosteric MEK1/2 inhibitor. P6b among them showed the most potent degradation effect, with DC50 values of 0.3 µM and 0.2 µM in MEK1 and MEK2 degradation, respectively. An antiproliferation assay showed that it more significantly inhibits the growth of A375 cells (IC50= 2.8 µM) compared to A549 cells (IC50 = 27.3 µM). To sum up, we discovered P6b with a non-diarylamine scaffold for the first time as a potent MEK PROTAC effective in human cancer cells.

5.
Cell Rep Med ; : 100911, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36657446

RESUMO

Predicting the clinical response to chemotherapeutic or targeted treatment in patients with locally advanced or metastatic lung cancer requires an accurate and affordable tool. Tumor organoids are a potential approach in precision medicine for predicting the clinical response to treatment. However, their clinical application in lung cancer has rarely been reported because of the difficulty in generating pure tumor organoids. In this study, we have generated 214 cancer organoids from 107 patients, of which 212 are lung cancer organoids (LCOs), primarily derived from malignant serous effusions. LCO-based drug sensitivity tests (LCO-DSTs) for chemotherapy and targeted therapy have been performed in a real-world study to predict the clinical response to the respective treatment. LCO-DSTs accurately predict the clinical response to treatment in this cohort of patients with advanced lung cancer. In conclusion, LCO-DST is a promising precision medicine tool in treating of advanced lung cancer.

6.
Food Chem ; 411: 135378, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36669338

RESUMO

Foxtail millet prolamin has been demonstrated to have anti-diabetic effects. In this study, we compared the generation of anti-α-glucosidase peptides derived from prolamins of raw and cooked foxtail millet (PRFM and PCFM). PRFM and PCFM hydrolysates (PRFMH and PCFMH) both exhibited α-glucosidase inhibitory activity. After ultrafiltration according to molecular weight (Mw), the fraction with Mw < 3 kDa in PCFMH (PCFMH<3) showed higher α-glucosidase inhibitory activity than that in PRFMH (PRFMH<3). The composition of α-glucosidase inhibitory peptides identified by de novo sequencing in PCFMH<3 and PRFMH<3 was compared by virtual screening, combining biological activity, net charge, grand average of hydropathicity (GRAVY), and key hydrophobic amino acids (Met, Pro, Phe, and Leu). We found that the proportion of peptides with excellent α-glucosidase binding force in PCFMH<3 was higher than in PRFMH<3. Overall, cooking may positively affect the generation of peptides that perform well in inhibiting α-glucosidase derived from foxtail millet prolamin.

7.
Antioxidants (Basel) ; 12(1)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36671071

RESUMO

This study examined whether diets with high dietary methionine levels could alleviate chronic heat stress in Chinese mitten crab Eriocheir sinensis. Crabs were fed three dietary methionine levels of 0.49%, 1.29% and 2.09% for six weeks. The analyzed methionine concentration of diets was 0.48%, 1.05% and 1.72%, respectively. Crabs were fed three different supplemental concentrations of dietary methionine at 24 °C and 30 °C, respectively. The trial was divided into six groups with five replicates in each group, and 40 juvenile crabs (initial average weight 0.71 ± 0.01 g) in each replicate. During the trial, crabs were fed twice daily (the diet of 4% of the body weight was delivered daily). The effects of dietary methionine level on nutrient metabolism, antioxidant capacity, apoptosis factors and immunity were evaluated at a normal water temperature of 24 °C and high temperature of 30 °C. Feed conversion ratio decreased under chronic heat stress. Chronic heat stress increased weight gain, specific growth rate, molting frequency, and protein efficiency ratio. The survival of crabs decreased under chronic heat stress, whereas a high level of dietary methionine significantly improved survival. Chronic heat stress induced lipid accumulation and protein content reduction. The high-methionine diet decreased lipid in the body and hepatopancreas, but increased protein in the body, muscle and hepatopancreas under chronic heat stress. Simultaneously, the high dietary methionine levels mitigated oxidative stress by reducing lipid peroxidation, restoring the antioxidant enzyme system, decreasing apoptosis and activating immune function under chronic heat stress. This study suggests that supplementing 1.72% dietary methionine could alleviate the adverse effects of a high water temperature in E. sinensis farming.

8.
Polymers (Basel) ; 15(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36679146

RESUMO

Desertification, one of the world's most pressing serious environmental problems, poses a serious threat to human survival as well as to social, economic, and political development. Nevertheless, the development of environmentally friendly sand-fixing materials is still a tremendous challenge for preventing desertification. This study developed a bio-based attapulgite copolymer (BAC) by grafting copolymerization of attapulgite, starch, sulfomethyl lignin, and biological mycelia. Water retention, anti-water erosion, and anti-wind erosion tests were conducted to assess the application performance of the BAC. Scanning electron microscopy (SEM) was then employed to determine the morphology of the attapulgite and attapulgite graft copolymer sand-fixing material (CSF). The intermolecular interactions in CSF were revealed using Fourier transform infrared spectrum (FT-IR). The role of sand-fixing materials on soil physicochemical properties and seed germination was then discussed based on the germination rate experiments, and 16S rDNA sequencing technology was used to analyze the differences in microbial communities in each sample group. The results demonstrated that the BAC not only has superior application properties and significantly increased seed germination (95%), but also promotes soil development by regulating the structure of the soil microbial community. This work provides novel insights into the design of sand-fixing material for preventing desertification while improving soil fertility.

9.
Regen Biomater ; 10: rbac095, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36683747

RESUMO

Silk as a natural biomaterial is considered as a promising bone substitute in tissue regeneration. Sericin and fibroin are the main components of silk and display unique features for their programmable mechanical properties, biocompatibility, biodegradability and morphological plasticity. It has been reported that sericin recombinant growth factors (GFs) can support cell proliferation and induce stem cell differentiation through cross-talk of signaling pathways during tissue regeneration. The transgenic technology allows the productions of bioactive heterologous GFs as fusion proteins with sericin, which are then fabricated into solid matrix or hydrogel format. Herein, using an injectable hydrogel derived from transgenic platelet-derived GF (PDGF)-BB silk sericin, we demonstrated that the PDGF-BB sericin hydrogel effectively augmented osteogenesis induced by bone morphogenetic protein (BMP9)-stimulated mesenchymal stem cells (MSCs) in vivo and in vitro, while inhibiting adipogenic differentiation. Further gene expression and protein-protein interactions studies demonstrated that BMP9 and PDGF-BB synergistically induced osteogenic differentiation through the cross-talk between Smad and Stat3 pathways in MSCs. Thus, our results provide a novel strategy to encapsulate osteogenic factors and osteoblastic progenitors in transgenic sericin-based hydrogel for robust bone tissue engineering.

10.
Hepatol Int ; 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36626090

RESUMO

OBJECTIVE: Acute-on-chronic liver failure (ACLF) has a high prevalence and short-term mortality. Monocytes play an important role in the development of ACLF. However, the monocyte subpopulations with unique features and functions in ACLF and associated with disease progression remain poorly understood. We investigated the specific monocyte subpopulations associated with ACLF progression and their roles in inflammatory responses using the single-cell RNA sequencing (scRNA-seq). METHODS: We performed scRNA-seq on 17,310 circulating monocytes from healthy controls and ACLF patients and genetically defined their subpopulations to characterize specific monocyte subpopulations associated with ACLF progression. RESULTS: Five monocyte subpopulations were obtained, including pro-inflammatory monocytes, CD16 monocytes, HLA monocytes, megakaryocyte-like monocytes, and NK-like monocytes. Comparisons of the monocytes between ACLF patients and healthy controls showed that the pro-inflammatory monocytes had the most significant gene changes, among which the expressions of genes related to inflammatory responses and cell metabolism were significantly increased while the genes related to cell cycle progression were significantly decreased. Furthermore, compared with the ACLF survival group, the ACLF death group had significantly higher expressions of pro-inflammatory cytokines (e.g., IL-6) and their receptors, chemokines (e.g., CCL4 and CCL5), and inflammation-inducing factors (e.g., HES4). Additionally, validation using scRNA-seq and flow cytometry revealed the presence of a cell type-specific transcriptional signature of pro-inflammatory monocytes THBS1, whose production might reflect the disease progression and poor prognosis. CONCLUSIONS: We present the accurate classification, molecular markers, and signaling pathways of monocytes associated with ACLF progression. Therapies targeting pro-inflammatory monocytes may be a promising approach for blocking ACLF progression.

11.
J Nat Prod ; 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36693198

RESUMO

Chemical redundancy of microbial natural products (NPs) underscores the importance to exploit new resources of microorganisms. Insect-associated microbes are prolific but largely underexplored sources of diverse NPs. Herein, we discovered the new compound α-l-rhamnosyl-actiphenol (1) from a millipede-associated Streptomyces sp. ML6, which is the first glycosylated cycloheximide-class natural product. Interestingly, bioinformatics analysis of the ML6 genome revealed that the biosynthesis of 1 involves a cooperation between two gene clusters (chx and rml) located distantly on the genome of ML6. We also carried out in vitro enzymatic glycosylation of cycloheximide using an exotic promiscuous glycosyltransferase BsGT-1, which resulted in the production of an additional cycloheximide glycoside cycloheximide 7-O-ß-d-glucoside (5). Although the antifungal and cytotoxic activities of the new compounds 1 and 5 were attenuated relative to those of cycloheximide, our work not only enriches the chemical repertoire of the cycloheximide family but also provides new insights into the structure-activity relationship optimization and ecological roles of cycloheximide.

12.
Thromb J ; 21(1): 3, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36624481

RESUMO

BACKGROUND: Antithrombin (AT) is the main physiological anticoagulant involved in hemostasis. Hereditary AT deficiency is a rare autosomal dominant thrombotic disease mainly caused by mutations in SERPINC1, which was usually manifested as venous thrombosis and pulmonary embolism. In this study, we analyzed the clinical characteristics and screened for mutant genes in two pedigrees with hereditary AT deficiency, and the functional effects of the pathogenic mutations were evaluated. METHODS: Candidate gene variants were analyzed by next-generation sequencing to screen pathogenic mutations in probands, followed by segregation analysis in families by Sanger sequencing. Mutant and wild-type plasmids were constructed and transfected into HEK293T cells to observe protein expression and cellular localization of SERPINC1. The structure and function of the mutations were analyzed by bioinformatic analyses. RESULTS: The proband of pedigree A with AT deficiency carried a heterozygous frameshift mutation c.1377delC (p.Asn460Thrfs*20) in SERPINC1 (NM000488.3), a 1377C base deletion in exon 7 resulting in a backward shift of the open reading frame, with termination after translation of 20 residues, and a different residue sequence translated after the frameshift. Bioinformatics analysis suggests that the missing amino acid sequence caused by the frameshift mutation might disrupt the disulfide bond between Cys279 and Cys462 and affect the structural function of the protein. This newly discovered variant is not currently included in the ClinVar and HGMD databases. p.Arg229* resulted in a premature stop codon in exon 4, and bioinformatics analysis suggests that the truncated protein structure lost its domain of interaction with factor IX (Ala414 site) after the deletion of nonsense mutations. However, considering the AT truncation protein resulting from the p.Arg229* variant loss a great proportion of the molecule, we speculate the variant may affect two functional domains HBS and RCL and lack of the corresponding function. The thrombophilia and decreased-AT-activity phenotypes of the two pedigrees were separated from their genetic variants. After lentiviral plasmid transfection into HEK293T cells, the expression level of AT protein decreased in the constructed c.1377delC mutant cells compared to that in the wild-type, which was not only reduced in c.685C > T mutant cells but also showed a significant band at 35 kDa, suggesting a truncated protein. Immunofluorescence localization showed no significant differences in protein localization before and after the mutation. CONCLUSIONS: The p.Asn460Thrfs*20 and p.Arg229* variants of SERPINC1 were responsible for the two hereditary AT deficiency pedigrees, which led to AT deficiency by different mechanisms. The p.Asn460Thrfs*20 variant is reported for the first time.

13.
J Biotechnol ; 363: 32-39, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36610479

RESUMO

As an easily obtained organic waste, by-product acetic acid could be an appropriate co-substrate with blue algae wastes (increase C/N ratio of substrates) for co-fermentation of PHA production. However, there are still acrylic acid and other chemicals in by-product acetic acid, which could cause severe inhibition for fermenting microorganisms during PHA production process. The current study represented that alkali pretreatment (pH level of 12) is a more favorable method compared with thermal pretreatment (80 â„ƒ for 30 min) for breaking cell walls of blue algae. It seemed that there was no synergistic effect of the combination of thermal and alkali pretreatment methods (temperature of 80 â„ƒ and pH level of 12). Optimal parameters during electro-fenton process for removal of inhibitors in by-product acetic acid were under current of 0.5 A, pH level of 3 and reaction time of 120 min. Both the highest dry weight of PHA and PHA concentration were achieved by applying blue algae and by-product acetic acid (after pretreatment) as co-substrates (mixed ratio of 3:1, stirring speed of 200 r/min, 24 h), indicating that using by-product acetic acid (after pretreatment) as co-substrate could increase C/N ratio and promote PHA production successfully. The current study could offer new insights for improving PHA production by co-fermentation.

14.
Artigo em Inglês | MEDLINE | ID: mdl-36674151

RESUMO

Based on the driving force-pressure-state-impact-response (DPSIR) model, a comprehensive evaluation index system is constructed. The index weight is determined by the combination weighting method in combination with the data of 2010-2019. The TOPSIS model is used to comprehensively analyze the water resource carrying capacity of Zhengzhou as the central city in China with a developed economy and relatively short water resources. The study results are as follows. (1) During the sample period, the comprehensive evaluation value of water resources carrying capacity of Zhengzhou increases from 0.4183 in 2010 to 0.5560 in 2019, with an overall fluctuating rise. Simultaneously, the water resource carrying capacity grade improves from Grade III (normal carrying capacity) to Grade II (good carrying capacity). (2) The contribution of each subsystem to the comprehensive evaluation value increases year by year. Among them, S subsystem and I subsystem make the largest contribution to the comprehensive carrying capacity. R subsystem makes a relatively stable contribution to the overall carrying capacity. Affected by GDP growth rate and uneven temporal-spatial distribution of water resources in Zhengzhou, the D subsystem and P subsystem of water resource carrying capacities show the fluctuating change. Finally, based on the above conclusions, this paper puts forward the countermeasures and suggestions to improve the level of water resource carrying capacity of Zhengzhou.


Assuntos
Conservação dos Recursos Naturais , Recursos Hídricos , Conservação dos Recursos Naturais/métodos , Cidades , Urbanização , China
15.
Biomacromolecules ; 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36607255

RESUMO

The development of nanoprobes that have amplified enhanced permeability and retention (EPR) effect is crucial for their precise cancer diagnosis performance. Here, we present the development of functional dendrimer-based nanogels (DNGs) with the generation three primary amine-terminated poly(amidoamine) (PAMAM) dendrimers (G3·NH2) cross-linked by N,N'-bis(acryloyl) cystamine (BAC). The DNGs were prepared through a Michael addition reaction between G3·NH2 dendrimers and BAC via an inverse microemulsion method and entrapped with gold nanoparticles (Au NPs) to form Au-DNGs. The Au-DNGs were sequentially modified with diethylenetriamine penta-acetic acid (DTPA)-gadolinium (Gd) complex, poly(ethylene glycol) (PEG)-linked arginine-glycine-aspartic (RGD) peptide, and 1,3-propanesultone (1,3-PS). The formed multifunctional RGD-Gd@Au-DNGs-PS (R-G@ADP) possessing an average diameter of 122 nm are colloidally stable and display a high X-ray attenuation coefficient, excellent r1 relaxivity (9.13 mM-1 s-1), desired protein resistance rendered by the zwitterionic modification, and cytocompatibility. With the targeting specificity mediated by RGD and the much better tumor penetration capability than the counterpart material of single dendrimer-entrapped Au NPs, the developed multifunctional R-G@ADP enable targeted and enhanced computed tomography (CT)/magnetic resonance (MR) dual-modal imaging of a pancreatic tumor model in vivo. The current work demonstrates a unique design of targeted and zwitterionic DNGs with prolonged blood circulation time as an emerging nanoprobe for specific tumor CT/MR imaging through amplified passive EPR effect.

16.
Adv Mater ; : e2205047, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36609920

RESUMO

Artificial neuronal devices are critical building blocks of neuromorphic computing systems and currently the subject of intense research motivated by application needs from new computing technology and more realistic brain emulation. Researchers have proposed a range of device concepts that can mimic neuronal dynamics and functions. Although the switching physics and device structures of these artificial neurons are largely different, their behaviors can be described by several neuron models in a more unified manner. In this paper, the reports of artificial neuronal devices based on emerging volatile switching materials are reviewed from the perspective of the demonstrated neuron models, with a focus on the neuronal functions implemented in these devices and the exploitation of these functions for computational and sensing applications. Furthermore, the neuroscience inspirations and engineering methods to enrich the neuronal dynamics that remain to be implemented in artificial neuronal devices and networks towards realizing the full functionalities of biological neurons are discussed. This article is protected by copyright. All rights reserved.

17.
Sci Adv ; 9(3): eadd5667, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36652527

RESUMO

The life span of leaves increases with their mass per unit area (LMA). It is unclear why. Here, we show that this empirical generalization (the foundation of the worldwide leaf economics spectrum) is a consequence of natural selection, maximizing average net carbon gain over the leaf life cycle. Analyzing two large leaf trait datasets, we show that evergreen and deciduous species with diverse construction costs (assumed proportional to LMA) are selected by light, temperature, and growing-season length in different, but predictable, ways. We quantitatively explain the observed divergent latitudinal trends in evergreen and deciduous LMA and show how local distributions of LMA arise by selection under different environmental conditions acting on the species pool. These results illustrate how optimality principles can underpin a new theory for plant geography and terrestrial carbon dynamics.

18.
Exp Mol Med ; 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36653443

RESUMO

Mitochondrial dysfunction plays a major role in the development of intervertebral disc degeneration (IDD). Sirtuin 5 (SIRT5) participates in the maintenance of mitochondrial homeostasis through its desuccinylase activity. However, it is still unclear whether succinylation or SIRT5 is involved in the impairment of mitochondria and development of IDD induced by excessive mechanical stress. Our 4D label-free quantitative proteomic results showed decreased expression of the desuccinylase SIRT5 in rat nucleus pulposus (NP) tissues under mechanical loading. Overexpression of Sirt5 effectively alleviated, whereas knockdown of Sirt5 aggravated, the apoptosis and dysfunction of NP cells under mechanical stress, consistent with the more severe IDD phenotype of Sirt5 KO mice than wild-type mice that underwent lumbar spine instability (LSI) surgery. Moreover, immunoprecipitation-coupled mass spectrometry (IP-MS) results suggested that AIFM1 was a downstream target of SIRT5, which was verified by a Co-IP assay. We further demonstrated that reduced SIRT5 expression resulted in the increased succinylation of AIFM1, which in turn abolished the interaction between AIFM1 and CHCHD4 and thus led to the reduced electron transfer chain (ETC) complex subunits in NP cells. Reduced ETC complex subunits resulted in mitochondrial dysfunction and the subsequent occurrence of IDD under mechanical stress. Finally, we validated the efficacy of treatments targeting disrupted mitochondrial protein importation by upregulating SIRT5 expression or methylene blue (MB) administration in the compression-induced rat IDD model. In conclusion, our study provides new insights into the occurrence and development of IDD and offers promising therapeutic approaches for IDD.

19.
J Neurochem ; 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36648213

RESUMO

Depression in astronauts is one of the consequences of spaceflight effects, negatively impacting their work performances. Unfortunately, the underlying molecular mechanisms in spaceflight-induced depression are still unknown; however various neuropsychiatric disorders reported that overexpressed NR2B-PSD-95-nNOS complex in the brain triggers various pathological pathways, and inhibiting NR2B-PSD-95-nNOS complex asserts antidepressant effects. Through our insilico analysis, we found that epigenetic regulator miR-445-3p targets PSD-95 and is hypothesized to downregulate NR2B-PSD-95-nNOS complex to prevent neuronal damage associated with depression. Therefore, the present study is aimed to determine the novel insight of the miR-455-3p against the NR2B-PSD-95-nNOS complex in the neurobiology of spaceflight-induced depressive behavior. Using a simulated space environment complex model (SCSE) for 21 days, we induced depressive behavior in rats to analyze miR-455-3p expression and NR2B-PSD-95-nNOS complex in the cortex and hippocampus of the SCSE depressed rats through qRT-PCR and western blot analysis. Further, an in-vitro microgravity model using rat hippocampus cell lines (RHNC) was utilized to identify the independent role of miR-455-3p on (1) NR2B-PSD-95-nNOS complex and TrKB-BDNF proteins, (2) oxidative stress, (3) nitric oxide level, (4) inflammatory cytokines, (5) mitochondrial biogenesis/ dynamics, (6) cell survival. Our results showed that miR-455-3p regulates NR2B-PSD-95-nNOS complex in the SCSE depressed rats in opposite ways, with the cortex revealing a higher level of miR-455-3p and low-level NR2B-PSD-95-nNOS complex and the hippocampus showing downregulated miR-455-3p and upregulated NR2B-PSD-95-nNOS complex, indicating a region-specific change in the miR-455-3p and NR2B-PSD-95-nNOS complex in the SCSE depressed rats. Further RHNC results also confirmed downregulated miR-455-3p and upregulated NR2B-PSD-95-nNOS complex expression, similar to the findings in the hippocampus of SCSE rats, suggesting that microgravity influences miR-455-3p and associated changes. Additional investigations revealed that miR-455-3p targets PSD-95 and co-regulates NR2B-PSD-95-nNOS complex along with TrkB-BDNF signaling and exert protective effects against NR2B-PSD-95-nNOS complex, oxidative stress, nitric oxide, inflammatory cytokines, and mitochondrial defects, suggesting a valuable biomarker for devising depressive disorders.

20.
Biomater Sci ; 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36628631

RESUMO

Allopurinol (AP) is widely used to treat hyperuricemia which may cause severe side effects upon oral administration. Alternative means for the treatment of hyperuricemia are demanded to simultaneously facilitate drug absorption, patient compliance, and fewer side effects. In this study, a new polymer microneedle (MN) system was developed for the transdermal delivery of AP to acute hyperuricemic mice. This study aims to achieve the controllable regulation of serum uric acid (SUA) levels with fewer side effects compared with oral administration. The matrix of polymer MNs consisted of polyvinylpyrrolidone (PVP) and polycaprolactone (PCL), in which the rapid dissolution of PVP offers a rapid dissolution of AP into the blood and the biodegradability of PCL resulting in a sustainable drug release behavior. An in vivo study demonstrated that the AP-loaded MN system can effectively reduce the SUA levels as oral administration with lower side effects, which will be conducive to reducing the adverse reactions and improving the bioavailability of AP. This MN-mediated strategy can facilitate transcutaneous hyperuricemia treatment and provide a new alternative for the exploration of clinical treatment of hyperuricemia and improvement of patient compliance.

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