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Circadian rhythm disruption leads to dysregulation of lipid metabolism, which further drive the occurrence of insulin resistance (IR). Exosomes are natural carrier systems that advantageous for cell communication. In the present study, we aimed to explore whether and how the exosomal microRNAs (miRNAs) in circulation participate in modulating skeletal muscle IR induced by circadian rhythm disruption. In the present study, 24-h constant light (12-h light/12-h light, LL) was used to establish the mouse model of circadian rhythm disruption. Bmal1 interference was used to establish the cell model of circadian rhythm disruption. And in clinical experiments, we chose a relatively large group of rhythm disturbance-shift nurses. We showed that LL-induced circadian rhythm disruption led to increased body weight and visceral fat volume, as well as occurrence of IR in vivo. Furthermore, exosomal miR-22-3p derived from adipocytes in the context of circadian rhythm disruption induced by Bmal1 interference could be uptaken by skeletal muscle cells to promote IR occurrence in vitro. Moreover, miR-22-3p in circulation was positively correlated with the clinical IR-associated factors. Collectively, these data showed that exosomal miR-22-3p in circulation may act as potential biomarker and therapeutic target for skeletal muscle IR, contributing to the prevention of diabetes in the context of rhythm disturbance.
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Ritmo Circadiano , Exossomos , Resistência à Insulina , MicroRNAs , Animais , Camundongos , Adipócitos/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Exossomos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Músculo Esquelético/metabolismoRESUMO
Isoniazid and streptomycin are vital drugs for treating tuberculosis, which are utilized as efficient anti-tuberculosis agents. This paper presents a novel visible-light-driven composite photocatalyst Ti3C2/Bi/BiOI, which was built from Ti3C2 nanosheets and Bi/BiOI microspheres. Photoelectrochemical (PEC) sensors based on Ti3C2/Bi/BiOI were synthesized for isoniazid identification, which showed a linear concentration range of 0.1-125 µM with a detection limit of 0.05 µM (S/N = 3). Moreover, we designed a PEC aptasensors based on aptamer/Ti3C2/Bi/BiOI to detect streptomycin in 0.1 M PBS covering the electron donor isoniazid, because the isoniazid consumes photogenerated holes thus increasing the photocurrent effectively and preventing photogenerated electron-hole pairs from being recombined. Furthermore, PEC aptasensors based on aptamer/Ti3C2/Bi/BiOI were synthesized for streptomycin identification, which exhibited a linear concentration range of 0.01-1000 nM with a detection limit of 2.3 × 10-3 nM (S/N = 3), and are well stable in streptomycin sensing.
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Isoniazida , Estreptomicina , Microesferas , Titânio , Livros , Metais , OligonucleotídeosRESUMO
Soybean (Glycine max) plants first emerged in China, and they have since been established as an economically important oil crop and a major source of daily protein for individuals throughout the world. Seed emergence height is the first factor that ensures seedling adaptability to field management practices, and it is closely related to epicotyl length. In the present study, the Suinong 14 and ZYD00006 soybean lines were used as parents to construct chromosome segment substitution lines (CSSLs) for quantitative trait loci (QTL) identification. Seven QTLs were identified using two years of epicotyl length measurement data. The insertion region of the ZYD00006 fragment was identified through whole genome resequencing, with candidate gene screening and validation being performed through RNA-Seq and qPCR, and Glyma.08G142400 was ultimately selected as an epicotyl length-related gene. Through combined analyses of phenotypic data from the study population, Glyma.08G142400 expression was found to be elevated in those varieties exhibiting longer epicotyl length. Haplotype data analyses revealed that epicotyl data were consistent with haplotype typing. In summary, the QTLs found to be associated with the epicotyl length identified herein provide a valuable foundation for future molecular marker-assisted breeding efforts aimed at improving soybean emergence height in the field, with the Glyma.08G142400 gene serving as a regulator of epicotyl length, offering new insight into the mechanisms that govern epicotyl development.
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Glycine max , Locos de Características Quantitativas , Humanos , Glycine max/genética , Mapeamento Cromossômico , Melhoramento Vegetal , Sementes/metabolismo , Mineração de DadosRESUMO
Epidermal Growth Factor Receptor (EGFR) is a promising therapeutic target for triple-negative breast cancer (TNBC). Recently, specific EGFR-targeting peptide GE11-based delivery nano-system shows excellent potential because of its chemical versatility and good targeting ability. However, no further research focusing on the downstream of EGFR after binding with GE11 was explored. Hence, we tailor-designed a self-assembled nanoplatform named GENP using amphiphilic molecule of stearic acid-modified GE11. After loading doxorubicin (DOX), the resulted nanoplatform GENP@DOX demonstrated high loading efficiency and sustainable drug release. Importantly, our findings proved that GENP alone significantly suppressed the proliferation of MDA-MB-231 cells via EGFR-downstream PI3K/AKT signaling pathways, contributing to the synergistic treatment with its DOX release. Further work illustrated remarkable therapeutic efficacy both in orthotopic TNBC and its bone metastasis models with minimal biotoxicity. Together, the results highlight that our GENP-functionalized nanoplatform is a promising strategy for the synergistic therapeutic efficacy targeting EGFR-overexpressed cancer.
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Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Fosfatidilinositol 3-Quinases , Linhagem Celular Tumoral , Receptores ErbB/química , Doxorrubicina/química , Peptídeos/farmacologia , Peptídeos/químicaRESUMO
BACKGROUND: In China, adolescents account for about a quarter of those treated for mental disorders each year, and adolescent mental health issues have become a social hotspot. Although several epidemiological surveys of mental disorders have been conducted in China, no study has yet focused on the prevalence of mental disorders among adolescents in a certain region of Zhejiang. METHODS: In the first stage, 8219 middle school students aged 12-18 years in a city of Zhejiang Province (Shaoxing) were screened with the mental health screening checklist. In the second stage, participants who screened positive were tested with the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Then, the prevalence of mental disorders were calculated. RESULTS: The overall prevalence in this population was 12.4%, with prevalence rates exceeding 20% in both the 17- and 18-year-old age groups. The most common mental disorders were obsessive-compulsive disorder (OCD) (9.1%) and major depressive disorder (MDD) (8.9%). CONCLUSIONS: Mental disorders are common among middle school students, and girls are at higher risk than boys. As the most prevalent mental disorders, OCD and MDD should receive timely attention, especially for upper grade students.
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Soybeans (Glycine max) are a key food crop, serving as a valuable source of both oil and plant-derived protein. Pseudomonas syringae pv. glycinea (Psg) is among the most aggressive and prevalent pathogens affecting soybean production, causing a form of bacterial spot disease that impacts soybean leaves and thereby reduces crop yields. In this study, 310 natural soybean varieties were screened for Psg resistance and susceptibility. The identified susceptible and resistant varieties were then used for linkage mapping, BSA-seq, and whole genome sequencing (WGS) analyses aimed at identifying key QTLs associated with Psg responses. Candidate Psg-related genes were further confirmed through WGS and qPCR analyses. Candidate gene haplotype analyses were used to explore the associations between haplotypes and soybean Psg resistance. In addition, landrace and wild soybean plants were found to exhibit a higher degree of Psg resistance as compared to cultivated soybean varieties. In total, 10 QTLs were identified using chromosome segment substitution lines derived from Suinong14 (cultivated soybean) and ZYD00006 (wild soybean). Glyma.10g230200 was found to be induced in response to Psg, with the Glyma.10g230200 haplotype corresponding to soybean disease resistance. The QTLs identified herein can be leveraged to guide the marker-assisted breeding of soybean cultivars that exhibit partial resistance to Psg. Moreover, further functional and molecular studies of Glyma.10g230200 have the potential to offer insight into the mechanistic basis for soybean Psg resistance.
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Glycine max , Pseudomonas syringae , Glycine max/genética , Pseudomonas syringae/genética , Melhoramento Vegetal , Locos de Características Quantitativas , Glicina/genéticaRESUMO
Rhizobia secrete effectors that are essential for the effective establishment of their symbiotic interactions with leguminous host plants. However, the signaling pathways governing rhizobial type III effectors have yet to be sufficiently characterized. In the present study, the type III effectors, NopAA and NopD, which perhaps have signaling pathway crosstalk in the regulation of plant defense responses, have been studied together for the first time during nodulation. Initial qRT-PCR experiments were used to explore the impact of NopAA and NopD on marker genes associated with symbiosis and defense responses. The effects of these effectors on nodulation were then assessed by generating bacteria in which both NopAA and NopD were mutated. RNA-sequencing analyses of soybean roots were further utilized to assess signaling crosstalk between NopAA and NopD. NopAA mutant and NopD mutant were both found to repress GmPR1, GmPR2, and GmPR5 expression in these roots. The two mutants also significantly reduced nodules dry weight and the number of nodules and infection threads, although these changes were not significantly different from those observed following inoculation with double-mutant (HH103ΩNopAA&NopD). NopAA and NopD co-mutant inoculation was primarily found to impact the plant-pathogen interaction pathway. Common differentially expressed genes (DEGs) associated with both NopAA and NopD were enriched in the plant-pathogen interaction, plant hormone signal transduction, and MAPK signaling pathways, and no further changes in these common DEGs were noted in response to inoculation with HH103ΩNopAA&NopD. Glyma.13G279900 (GmNAC27) was ultimately identified as being significantly upregulated in the context of HH103ΩNopAA&NopD inoculation, serving as a positive regulator of nodulation. These results provide new insight into the synergistic impact that specific effectors can have on the establishment of symbiosis and the responses of host plant proteins.
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Fabaceae , Glycine max , Glycine max/genética , Nodulação/genética , Fabaceae/metabolismo , Raízes de Plantas/microbiologia , Proteínas de Plantas/metabolismo , Simbiose/genéticaRESUMO
BACKGROUND: This study was to evaluate the efficacy and safety of the implantation of foldable capsular vitreous body (FCVB) in severe retinal detachment eyes. METHODS: A retrospective study in retinal detachment eyes was performed at Shandong Provincial Hospital Affiliated to Shandong First Medical University. A standard three-port pars plana vitrectomy was performed, and the FCVB was triple folded and implanted into the vitreous cavity. The silicone oil (SO) was then injected into the capsule of the FCVB to support the retina and eye. During the follow-up period, The treated eyes were examined by ophthalmoscopy, fundus photography, and tonometry. B-scan ultrasonography, optical coherence tomography (OCT), and computed tomography (CT), were also performed. RESULTS: From May 2020 to November 2021, 31 cases with severe retinal detachment were enrolled in the study. The postoperative follow-up time gradient ranged from 1 to 72 weeks, At various observation time points during the 72 weeks after surgery, The postoperative IOP was maintained at around 10 mmhg at various time points, with a slight decrease compared to the preoperative IOP (14.2 ± 4.6 mmHg n = 18), and was statistically significant. 9 of 31 patients had clear refractive media, both fundus and OCT showed retinal reattachment, OCT showed the 200 µm thick FCVB capsule support retina. The remaining 22 patients with unclear refractive media, B-scan showed arcuate hyperechoes in front of the retina. There was also no significant difference in visual acuity compared to preoperative. The FCVB was well positioned in the vitreous cavity, and no serious complications such as endophthalmitis, glaucoma, silicone oil emulsification, product exposure, or sympathetic uveitis were found. CONCLUSIONS: FCVB has retinal support with certain ability to maintain IOP and eye morphology and avoid eye removal in patients with severe retinal detachment during the 72-week observation period.
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Descolamento Retiniano , Humanos , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/cirurgia , Corpo Vítreo/cirurgia , Óleos de Silicone , Estudos Retrospectivos , Vitrectomia/métodosRESUMO
The lack of effective chemical tools capable of dynamic tracking of labile glyoxal species (GOS) [e.g., methylglyoxal (MGO) and glyoxal (GO)] levels with high selectivity over other relevant electrophilic species, particularly, formaldehyde (FA) and nitric oxide (NO), has significantly hampered the understanding of their roles in a complex metabolic network and disease progressions. Herein, we report the rational design of the bioinspired 4-(2-guanidino)-1,8-naphthalimide fluorescent probes NAP-DCP-1 and NAP-DCP-3 from arginine-specific protein modifications. These probes undergo facile reversible fluorophore-promoted deprotonation-cyclization of a guanidium ion with labile GOS to form exocyclic five-membered dihydroxyimidazolidines. The probe NAP-DCP-1 can differentiate GOS levels in the serum of diabetic mice and patients from nondiabetic ones, which correlate very well with glucose levels, providing the GOS level as a potential new biomarker for diabetes diagnosis. Notably, the endoplasmic reticulum (ER)-targeting probe NAP-DCP-3 enabled the study of GOS perturbation in ER under various stress conditions and led to the discovery that formaldehyde (FA), either exogenously added or endogenously generated, could induce GOS level increases in ER. This finding reveals the previous unknown connection of FA with upregulated GOS levels and suggests that GOS is a key metabolite in bridging one-carbon metabolism with glycolysis and the downstream cell redox status. Moreover, the probes also showed potentials in separate quantification of MGO and GO via ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) and unexpected selectivity modulation for GO over MGO via two-photon excitation. It is expected that probes reported herein provide powerful tools to study GOS level modulations in complex biological networks and would facilitate GOS-associated basic research and discovery.
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Corantes Fluorescentes/química , Glioxal/química , Espectrometria de Massas/métodos , Animais , Arginina/química , Cromatografia Líquida de Alta Pressão , Ciclização , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/diagnóstico , Retículo Endoplasmático/química , Corantes Fluorescentes/síntese química , Formaldeído/química , Glioxal/análise , Glioxal/sangue , Glioxal/metabolismo , Células HeLa , Humanos , Camundongos , Microscopia de FluorescênciaRESUMO
Smart polymers as ideal gene carriers have drawn increasing attentions due to the effective DNA release once triggered by intrinsic stimuli, as well as reduced cytotoxicity. Herein, a stimulus-responsive, positively charged and water-soluble polymer (OEI-TK x) was facilely engineered by cross-linking low molecular weight oligoethylenimine (OEI) via thioketal (TK) linkages that would cleave selectively in reactive oxygen species (ROS)-rich environments induced by hypoxia. Agarose gel electrophoresis assay demonstrated that the threshold N/P ratios for complete retardation of negatively charged DNA migration were above 5 for OEI-TK x. The reduction in DNA-condensing capability and the changes in particle size, size distribution and particle morphology all illustrated that OEI-TK x possessed excellent ROS responsiveness. OEI-TK x/DNA polyplexes showed lower toxicity and higher gene transfection efficiency compared with PEI/DNA polyplexes. The optimum formulation, OEI-TK x/DNA polyplexes (N/P = 40), showed a little better performance than PEI/DNA polyplexes in cellular uptake profile. Furthermore, OEI-TK x/DNA polyplexes could escape from endosomes to the cytosol as efficiently as PEI/DNA polyplexes. Confocal images confirmed that OEI-TK x/DNA polyplexes could more effectively release DNA than PEI/DNA polyplexes, mainly owing to the valid cleavage of thioketal linkages induced by characteristic rich-ROS in Hela cells. These results suggested that OEI-TK x could represent an on-demand stimulus-responsive gene delivery platform.
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Técnicas de Transferência de Genes , Nanopartículas/química , Espécies Reativas de Oxigênio/química , Polímeros Responsivos a Estímulos/química , Aziridinas/química , Hipóxia Celular , Reagentes de Ligações Cruzadas/química , DNA/metabolismo , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Nanopartículas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Polímeros Responsivos a Estímulos/toxicidadeRESUMO
To provide a high-throughput, efficient, and accurate method to monitor multiple-fungicide resistance of Botrytis cinerea in the field, we used the suspension array, sequencing, and mycelial growth assay in our research. Discriminating-dose bioassays for detecting carbendazim, diethofencarb, boscalid, and iprodione resistance (CarR, DieR, BosR, and IprR, respectively) were used to analyze 257 isolates collected from Hebei Province in China during 2016 and 2017. High resistance frequencies to carbendazim (100%), diethofencarb (92.08%), and iprodione (86.59%) were detected. BosR isolates accounted for 11.67% of the total. In addition, 103 isolates were randomly selected for phenotype and genotype detection. The high-throughput suspension array was utilized to detect eight genotypes simultaneously, including BenA-E198, BenA-198A, SdhB-H272, SdhB-272Y, BcOS1-I365, BcOS1-365S, erg27-F412, and erg27-412S, which were associated with resistance toward carbendazim or diethofencarb, boscalid, iprodione, and fenhexamid (FenR), respectively. Most of the benzimidazole-resistant isolates (81.55%) possessed the E198V mutation in the BenA gene. Ninety-three isolates with dual resistance to carbendazim and diethofencarb showed the E198V/K mutation. All BosR isolates carried the H272R mutation in the SdhB gene. The I365S and Q369P+N373S (66.99%) mutations in the BcOS1 gene were more frequently observed. No mutation was detected in the erg27 gene in Hebei isolates. There were 13 resistance profile phenotypes. Phenotypes with triple resistance were the most common (83.50%), and CarRDieRBosSIprRFenS was the major type. CarR isolates that carried E198V/K/A were all highly resistant (HR) and only one F200Y mutant was moderately resistant (MR) to carbendazim. Isolates that possessed E198V/K were MR or HR to diethofencarb. BosR isolates that possessed H272R mutation were lowly resistant (LR). IprR isolates were all LR or MR. The distribution of half maximal effective concentrations of CarR isolates with E198V/K mutations and IprR isolates with Q369P+N373S mutations significantly increased from 2016 to 2017. Combined with our observations, a combination method of the high-throughput suspension array and the mycelial growth assay was suggested to accurately monitor multiple resistance of B. cinerea in the field.
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Botrytis , Farmacorresistência Fúngica , Fungicidas Industriais , Bioensaio , Botrytis/efeitos dos fármacos , Botrytis/crescimento & desenvolvimento , China , Farmacorresistência Fúngica/genética , Fungicidas Industriais/farmacologia , Genes Fúngicos/genéticaRESUMO
An important challenge for reaction-based fluorescent probes is that they generally require analyte consumption for fluorescence signal generation, thus creating potential perturbation of native analyte homeostasis or change of local concentrations. Herein, we reported two formaldehyde (FA) regeneration fluorescent probes, NAP-FAP-1 and NAP-FAP-2. An unprecedented regiospecific FA-induced intramolecularity strategy is implemented in the probe design, which adopts 3-(benzylamino)-succinimide as the FA-selective reaction group. The probes are able to capture the analyte molecule, induce regiospecific imide bond cleavage, and then release the captured FA molecule with simultaneous fluorescence turn-on response via a unique dual PeT/ICT quenching mechanism. The probes have shown potentials in detection, comparison, and imaging of FA levels intracellularly and inside lysosomes. These features make them useful for the study of FA homeostasis and functions in biological systems with minimal perturbation.
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In the progress of designing a gene carrier system, what is urgently needed is a balance of excellent safety and satisfactory efficiency. Herein, a straightforward and versatile synthesis of a cationic guanidine-decorated dendronized pullulan (OGG3P) for efficient genetic photodynamic therapy was proposed. OGG3P was able to block the mobility of DNA from a weight ratio of 2. However, G3P lacking guanidine residues could not block DNA migration until at a weight ratio of 15, revealing guanidination could facilitate DNA condensation via specific guanidinium-phosphate interactions. A zeta potential plateau (â¼+23 mV) of OGG3P complexes indicated the nonionic hydrophilic hydroxyl groups in pullulan might neutralize the excessive detrimental cationic charges. There was no obvious cytotoxicity and hemolysis, but also enhancement of transfection efficiency with regard to OGG3P in comparison with that of native G3P in Hela and HEK293T cells. More importantly, we found that the uptake efficiency in Hela cells between OGG3P and G3P complexes was not markedly different. However, guanidination caused changes in uptake pathway and led to macropinocytosis pathway, which may be a crucial reason for improved transfection efficiency. After introducing a therapeutic pKillerRed-mem plasmid, OGG3P complexes achieved significantly enhanced KillerRed protein expression and ROS production under irradiation. ROS-induced cancer cells proliferation suppression was also confirmed. This study highlights the guanidine-decorated dendronized pullulan could emerge as a reliable nonviral gene carrier to specifically deliver therapeutic genes.
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Dendrímeros , Terapia Genética , Glucanos , Neoplasias/terapia , Fotoquimioterapia , Plasmídeos , Animais , Dendrímeros/química , Dendrímeros/farmacologia , Glucanos/química , Glucanos/farmacologia , Células HEK293 , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/genética , Neoplasias/metabolismo , Plasmídeos/química , Plasmídeos/genética , Plasmídeos/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
In this study, the amphiphilic fluorinated peptide dendrons functionalized dextran (FPD-HZN-Dex) via an acid-sensitive hydrazone linkage was successfully designed and prepared for the first time. We demonstrated a spontaneous self-assembly of amphiphilic FPD-HZN-Dex into the well-defined nanoparticles with the core-shell architecture in aqueous media, which is attributed to the efficient amphiphilic functionalization of dextran by the hydrophobic fluorinated peptide dendrons. The spherical morphology, uniform particle size and good storage stability of the prepared FPD-HZN-Dex nanoparticles were characterized by dynamic light scattering and transmission electron microscopy, respectively. In vitro drug release studies showed a controlled and pH dependent hydrophobic drug release profile. The cell viability assays show excellent biocompatibility of the FPD-HZN-Dex nanoparticles for both normal cells and tumor cells. Moreover, the FPD-HZN-Dex self-assembled systems based on pH-sensitive hydrazone linkage also can serve as stimulus bioresponsive carriers for on-demand intracellular drug delivery. These self-assembled nanoparticles exhibit a stimulus-induced response to endo/lysosome pH (pH 5.0) that causes their disassembly over time, enabling controlled release of encapsulated DOX. This work has unveiled a unique non-covalent interaction useful for engineering amphiphilic dendrons or dendrimers self-assembled systems.
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Dendrímeros/química , Dextranos/química , Sistemas de Liberação de Medicamentos , Nanopartículas/administração & dosagem , Nanopartículas/química , Peptídeos/química , Antineoplásicos/administração & dosagem , Materiais Biocompatíveis/química , Sobrevivência Celular , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Estabilidade de Medicamentos , Células HEK293 , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Espectrometria de Massas , Teste de Materiais , Nanopartículas/ultraestrutura , Tamanho da Partícula , Polilisina/química , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
The traditional prescription of Liangxue-Qushi-Zhiyang decoction (LQZ) has been demonstrated to be efficacious in treating atopic dermatitis (AD), a chronic inflammatory skin disorder marked by intense itching, redness, rashes, and skin thickening. Nevertheless, there has been an inadequate systematic exploration of the potential targets, biological processes, and pathways for AD treatment through LQZ. The study objective was to evaluate the efficacy and possible mechanism of LQZ in AD mice. In our study, we identified the primary compounds of LQZ, analyzed hub targets, and constructed a network. Subsequently, the predicted mechanisms of LQZ in AD were experimentally studied and validated in vivo, as determined by network pharmacological analysis. A total of 80 serum components of LQZ were identified through ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS), among which 49 compounds were absorbed into the bloodstream. Our results indicated that LQZ targets six putative key factors in the MAPK signaling pathway, which play essential roles in AD, namely, EGFR, p-MAPK1/3, p-MAPK14, IL-1ß, IL-6, and TNF-α. We observed spleen coefficient, dermatitis scores, and ear thickness were all downregulated in 2,4-dinitrochlorobenzene (DNCB)-induced mice after LQZ treatment. Histological analysis of the dorsal and ear skin further revealed that LQZ significantly decreased skin inflammation, epidermal thickness, and mast cell numbers compared to the DNCB group. Our study demonstrated the effectiveness of LQZ in reducing epidermal and dermal damage in a mouse model of AD. Furthermore, our findings suggest that downregulating the MAPK signaling pathway could be a potential therapeutic strategy for the treatment of AD.
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Background: Osteoradionecrosis (ORN) is a serious complication of radiotherapy for head and neck cancer. There is currently a lack of data on the dynamic expression of genes related to bone remodeling during the development of mandibular ORN. This study aimed to establish an animal model of ORN in Sprague Dawley (SD) rats, detect the expression of genes related to bone metabolism, observe morphological changes, and clarify the mechanism of ORN. Methods: A total of 24 male SD rats in group 1 were randomly divided into four groups (n=6/group): group a, normal control; group b, simple tooth extraction; group c, simple radiation; and group d, radiation extraction group. The right mandible of rats in groups c and d was irradiated with a single dose of 35 Gy. The right mandibles were taken from each group for morphological observation 90 days after irradiation. SD rats in group 2 (n=144) were randomly divided into four groups (in similar fashion to group 1 but with groups a', b', c', and d'). Samples were collected at six time points after irradiation. Histopathological changes were observed, and Western blotting (WB) was used to analyze protein expression. Results: The formation of dead bone and pathological fracture was visible under micro-computed tomography (micro-CT), and tissue biopsy showed late fibrosis repair. In group d', osteogenesis and osteoclasis coexisted in the early irradiation stage. Vascular endothelial growth factor (VEGF) receptor expression was lower in groups c' and d' than in group a'. On day 45, runt-related transcription factor 2 (RUNX2) expression in group d' was lower than that in the other groups. The ratio of receptor activator of nuclear factor-κß ligand to osteoprotegerin (RANKL:OPG) differed significantly among groups b', c', and d' on the 45th day (d' > c' > b'). Conclusions: Radiation and vascular function damage resulted in the lower expression of VEGF. The first 15 days after radiation was mainly characterized by new bone formation. After 15 days, bone resorption increased. Tooth extraction trauma can aggravate the bone metabolism imbalance and promote ORN occurrence. These findings shed light on the mechanism of ORN.
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Lead (Pb) and cadmium (Cd) are common heavy metal pollutants that are often found in the soil in soybean agricultural production, adversely impacting symbiotic nitrogen fixation in soybean nodules. In this study, the exposure of soybean nodules to Pb and Cd stress was found to reduce nitrogenase activity. Shifts in the RNA methylation profiles of nodules were subsequently examined by profiling the differential expression of genes responsible for regulating m6A modifications and conducting transcriptome-wide analyses of m6A methylation profiles under Pb and Cd stress condition. Differentially methylated genes (DMGs) that were differentially expressed were closely related to reactive oxygen species activity and integral membrane components. Overall, 19 differentially expressed DMGs were ultimately determined to be responsive to both Pb and Cd stress, including Glyma.20G082450, which encodes GmAMT1;1 and was confirmed to be a positive regulator of nodules tolerance to Pb and Cd. Together, these results are the first published data corresponding to transcriptome-wide m6A methylation patterns in soybean nodules exposed to Cd and Pb stress, and provide novel molecular insight into the regulation of Pb and Cd stress responses in nodules, highlighting promising candidate genes related to heavy metal tolerance, that may also be amenable to application in agricultural production. ENVIRONMENTAL IMPLICATIONS: Lead (Pb) and cadmium (Cd) are prevalent heavy metal pollutants in soil, and pose a major threat to crop production, food security and human health. Here, MeRIP-seq approach was employed to analyze the regulatory network activated in soybean nodules under Pb and Cd stress, ultimately leading to the identification of 19 shared differentially expressed DMGs. When overexpressed, GmATM1;1 was found to enhance the Pb and Cd tolerance of soybean nodules. These results provide a theoretical basis for studies on tolerance to heavy metals in symbiotic nitrogen fixation, and provide an approach to enhancing Pb and Cd tolerance in soybean production.
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Poluentes Ambientais , Metais Pesados , Poluentes do Solo , Humanos , Cádmio/metabolismo , Transcriptoma , Glycine max , Chumbo , Metais Pesados/metabolismo , Metilação , Solo , Poluentes do Solo/metabolismoRESUMO
Transarterial chemoembolization (TACE) is a first-line treatment for intermediate to advanced-stage liver cancer, with drug-eluting microspheres commonly used as embolic agents. However, currently available drug-eluting microspheres suffer from low drug-loading capacity and limited drug options. In this work, we developed polydopamine-modified polyvinyl alcohol dual-drug-loaded microspheres encapsulating celecoxib and cisplatin (referred to as PCDMS). Physicochemical characterization revealed that the surface of the microspheres displayed increased roughness after polydopamine modification, and celecoxib and cisplatin were successfully loaded onto the microsphere surface. In vitro cell experiments demonstrated that the PCDMS significantly inhibited the proliferation and migration of highly metastatic human liver cancer cells (MHCC-97H) and human liver cancer cells (SMMC-7721). Furthermore, the dual-loaded microspheres exhibited remarkable tumor growth inhibition and reshaped the tumor microenvironment in both subcutaneous H22 liver cancer model in Balb/c mice and intrahepatic VX2 tumor model in New Zealand rabbits, demonstrating a synergistic antitumor effect where 1 + 1>2. This work provides a potential therapeutic approach for the treatment of refractory liver cancer and holds significant translational potential.
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Tumor metastasis is the main cause of lethality of prostate cancer, because conventional therapies like surgery and hormone treatment rarely work at this stage. Tumor cell migration, invasion and adhesion are necessary processes for metastasis. By providing nutrition and an escape route from the primary site, angiogenesis is also required for tumor metastasis. Phosphatidylinositol 3-kinases (PI3Ks) are well known to play important roles in tumorigenesis as well as metastasis. ZSTK474 is a specific PI3K inhibitor developed for solid tumor therapy. In the present report, antimetastatic activities of ZSTK474 were investigated in vitro by determining the effects on the main metastatic processes. ZSTK474 exhibited inhibitory effects on migration, invasion and adhesive ability of prostate cancer PC3 cells. Furthermore, ZSTK474 inhibited phosphorylation of Akt substrate-Girdin, and the secretion of matrix metalloproteinase (MMP), both of which were reported to be closely involved in migration and invasion. On the other hand, ZSTK474 inhibited the expression of HIF-1α and the secretion of vascular endothelial growth factor (VEGF), suggesting its potential antiangiogenic activity on PC3 cells. Moreover, we demonstrated the antiangiogenesis by determining the effect of ZSTK474-reduced VEGF on tube formation of human umbilical vein endothelial cells (HUVECs). In conclusion, ZSTK474 was demonstrated to have potential in vitro antimetastatic effects on PC3 cells via dual mechanisms: inhibition of metastatic processes including cell migration, invasion and adhesion, and antiangiogenesis via blockade of VEGF secretion.