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OBJECTIVE: Our research aimed to investigate the therapeutic effects of Tubastatin-A, a glucocorticoid receptor (GR) mitochondrial translocation inhibitor, and mitoquinone (MitoQ), an antioxidant, on attenuating dexamethasone (DEX)-induced macrophage apoptosis. METHODS: We treated RAW264.7 macrophages with different combinations of DEX and either Tubastatin-A or MitoQ. Parameters such as mitochondrial GR translocation, mitochondrial reactive oxygen species levels, mitochondrial membrane potential, mitochondrial permeability transition pore opening, cytochrome C efflux to the cytosol, and apoptosis were subsequently evaluated in the different treatment groups via qRT-PCR, western blotting, and immunofluorescence assays. RESULTS: DEX intervention increased the translocation of GRs into the mitochondria, while reducing the expression of the mitochondrial gene MT-CO1 and the activity of mitochondrial respiratory chain complex IV in macrophages. In addition, DEX administration increased mtROS levels, mitochondrial permeability transition pore opening, and mitochondrial cytochrome C release in macrophages, which promoted their apoptosis. We found that Tubastatin-A inhibited mitochondrial GR translocation and reversed the DEX-induced increase in GR levels within the mitochondria. Furthermore, Tubastatin-A mitigated various mitochondrial changes induced by DEX, including reducing the efflux of mitochondrial cytochrome C and inhibiting macrophage apoptosis. Similarly, MitoQ exerted its effects on macrophage apoptosis by reducing mtROS levels through the mitochondrial pathway. CONCLUSIONS: The DEX-mediated translocation of GR into mitochondria disrupts the mitochondrial function of macrophages, which induces their apoptosis. By inhibiting mitochondrial translocation of GR and reducing mtROS levels, Tubastatin-A and MitoQ can effectively attenuate macrophage apoptosis, which has clinical implications for reducing the notable side effects associated with glucocorticoid use.
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Apoptose , Dexametasona , Glucocorticoides , Macrófagos , Mitocôndrias , Receptores de Glucocorticoides , Receptores de Glucocorticoides/metabolismo , Animais , Camundongos , Apoptose/efeitos dos fármacos , Células RAW 264.7 , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Transporte Proteico/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Ubiquinona/farmacologia , Ubiquinona/análogos & derivados , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Compostos OrganofosforadosRESUMO
Drought is a natural disaster that profoundly impacts on global agricultural production, significantly reduces crop yields, and thereby poses a severe threat to worldwide food security. Addressing the challenge of effectively improving crop drought resistance (DR) to mitigate yield loss under drought conditions is a global issue. An optimal root system architecture (RSA) plays a pivotal role in enhancing crops' capacity to efficiently uptake water and nutrients, which consequently strengthens their resilience against environmental stresses. In this review, we discuss the compositions and roles of crop RSA and summarize the most recent developments in augmenting drought tolerance in crops by manipulating RSA-related genes. Based on the current research, we propose the potential optimal RSA configuration that could be helpful in enhancing crop DR. Lastly, we discussed the existing challenges and future directions for breeding crops with enhanced DR capabilities through genetic improvements targeting RSA.
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ETHNOPHARMACOLOGY RELEVANCE: Zanthoxylum bungeanum Maxim. (Z. bungeanum), a member of the Rutaceae family, has a rich history of traditional use in Asia for treating arthritis and toothache conditions. As characteristic chemical components, numerous kinds of alkaloids have been extracted from plants and their diverse biological activities have been reported. However, research on the isoquinoline alkaloid, a specific type of alkaloids, in Z. bungeanum was scarce. AIM OF THE STUDY: The study aimed to isolate a novel isoquinoline alkaloid from Z. bungeanum and explore its pharmacological activity in vitro and analgesic activity in vivo. MATERIALS AND METHODS: Isoquinoline alkaloid isolation and identification from Z. bungeanum were conducted using chromatographic and spectroscopic methods. The whole-cell patch-clamp technique was applied to assess its impact on neuronal excitability, and endogenous voltage-gated potassium (Kv) and sodium (Nav) currents in acutely isolated mouse small-diameter dorsal root ganglion (DRG) neurons. Its inhibitory impacts on channels were further validated with HEK293 cells stably expressing Nav1.7 and Nav1.8, and Chinese hamster ovary (CHO) cells transiently expressing Kv2.1. The formalin inflammatory pain model was utilized to evaluate the potential analgesic activity in vivo. RESULTS: A novel isoquinoline alkaloid named HJ-69 (N-13-(3-methoxyprop-1-yl)rutaecarpine) was isolated and identified from Z. bungeanum for the first time. HJ-69 significantly suppressed the firing frequency and amplitudes of action potentials in DRG neurons. Consistently, it state-dependently inhibited endogenous Nav currents of DRG neurons, with half maximal inhibitory concentration (IC50) values of 13.06 ± 2.06 µM and 30.19 ± 2.07 µM for the inactivated and resting states, respectively. HJ-69 significantly suppressed potassium currents in DRG neurons, which notably inhibited the delayed rectifier potassium (IK) currents (IC50 = 6.95 ± 1.29 µM) and slightly affected the transient outward potassium (IA) currents (IC50 = 523.50 ± 39.16 µM). Furtherly, HJ-69 exhibited similar potencies on heterologously expressed Nav1.7, Nav1.8, and Kv2.1 channels, which correspondingly represent the main components in neurons. Notably, intraperitoneal administration of 30 mg/kg and 100 mg/kg HJ-69 significantly alleviated pain behaviors in the mouse inflammatory pain model induced by formalin. CONCLUSION: The study concluded that HJ-69 is a novel and active isoquinoline alkaloid, and the inhibition of Nav and Kv channels contributes to its analgesic activity. HJ-69 may be a promising prototype for future analgesic drug discovery based on the isoquinoline alkaloid.
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Analgésicos , Gânglios Espinais , Dor , Zanthoxylum , Animais , Zanthoxylum/química , Humanos , Células HEK293 , Analgésicos/farmacologia , Analgésicos/química , Analgésicos/isolamento & purificação , Analgésicos/uso terapêutico , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Camundongos , Masculino , Dor/tratamento farmacológico , Isoquinolinas/farmacologia , Isoquinolinas/isolamento & purificação , Isoquinolinas/química , Alcaloides/farmacologia , Alcaloides/isolamento & purificação , Alcaloides/química , Alcaloides/uso terapêutico , Bloqueadores dos Canais de Potássio/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Inflamação/tratamento farmacológico , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/isolamento & purificação , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/química , Camundongos Endogâmicos C57BL , CricetulusRESUMO
OBJECTIVE: To assess the effect of luteinized unruptured follicles (LUF) on frozen-thawed embryo transfer cycles performed in natural cycles (FET-NC). METHODS: Retrospective cohort study, held in a university hospital with 3415 cycles for frozen-thawed embryo transfer, performed between June 2019 and September 2022. Using propensity score matching, 242 patients with a diagnosis of LUF (LUF group) were matched with 484 ovulated patients (ovulation group). Stratified by the type of embryo transferred, the LUF group included 168 blastocyst transfer patients (blastocyst group) and 74 cleavage-stage embryo transfer patients (cleavage-embryo group). The ovulation group included 324 patients with blastocyst transfer (blastocyst group) and 160 patients with transferred cleavage-stage embryos. Clinical pregnancy rate was retrospectively analyzed between the LUF and ovulation groups, as well as between each subgroup. RESULTS: After using propensity score matching, the general characteristics of the LUF and ovulation groups were similar. The implantation and clinical pregnancy rates in the LUF group were not significantly different from those in the ovulation group (44.98 % vs. 45.29 %, p = 0.93; 53.72 % vs. 52.48 %, p = 0.75). The implantation and pregnancy rates of transferred cleavage-stage embryos in the LUF group were also not significantly different from those in the ovulation group (32.39 % vs. 36.40 %, p = 0.42; 47.30 % vs. 47.50 %, p = 0.98). The implantation and pregnancy rates of transferred blastocysts in the LUF group were also not significantly different from those in the ovulation group (53.11 % vs. 52.03 %, p = 0.82; 56.55 % vs. 54.94 %, p = 0.73). There was also no significant difference in the miscarriage rate between the groups. CONCLUSION: In the natural cycle, LUF does not affect the clinical pregnancy outcomes of FET. If adequate luteal support is given, the clinical pregnancy outcomes were similar between the LUF group and ovulation group.
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Criopreservação , Transferência Embrionária , Gravidez , Feminino , Humanos , Estudos Retrospectivos , Taxa de Gravidez , Compostos OrgânicosRESUMO
Microglia are resident macrophages within the central nervous system, serving as the first responders to neuroinflammation. Glucocorticoids (GCs) may cause damage to brain tissue, but the specific mechanism remains unclear. This study was divided into two parts: a glucocorticoid receptor (GR) mitochondrial translocation intervention experiment and a mitochondrial oxidative stress inhibition experiment. BV-2 microglia were stimulated with dexamethasone (DEX) and treated with either tubastatin-A or mitoquinone (MitoQ) for 24 h. Our results showed that DEX increased the translocation of GRs to mitochondria, and this effect was accompanied by decreases in the expression of mitochondrially encoded cytochrome c oxidase 1 (MT-CO1) and mitochondrially encoded cytochrome c oxidase 3 (MT-CO3) and increases in the expression of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), caspase-1, and Gasdermin D (GSDMD). The level of mitochondrial respiratory chain complex IV (MRCC IV) and adenosine triphosphate (ATP) was decreased. An elevation in the level of mitochondrial oxidative stress and the opening of the mitochondrial permeability transition pore (mPTP) was also observed. Mechanistically, tubastatin-A significantly suppressed the mitochondrial translocation of GRs, improved the expression of mitochondrial genes, promoted the restoration of mitochondrial function, and inhibited pyroptosis. MitoQ significantly prevented mitochondrial oxidative stress, improved mitochondrial function, and reduced apoptosis and pyroptosis. Both tubastatin-A and MitoQ suppressed DEX-induced pyroptosis. This study substantiates that the increase in the mitochondrial translocation of GRs mediated by GCs exacerbates oxidative stress and pyroptosis in microglia, which indicates that the regulation of mitochondrial pathways by GCs is pathogenic to microglia.
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Glucocorticoides , Piroptose , Glucocorticoides/farmacologia , Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Microglia/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Estresse Oxidativo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismoRESUMO
Prolyl hydroxylase domain 2 (PHD2) is an important enzyme in the human body that perceives changes in oxygen concentration and regulates response in hypoxic environments. Evaluation of PHD2 inhibitory activity of natural products is crucial for drug development of hypoxia related diseases. At present, the detection of low concentration of α-ketoglutaric acid (the substrate of PHD2 enzymatic reaction) requires derivatization reactions or sample pretreatment, which undoubtedly increases the workload of PHD2 inhibitory activity evaluation. In this paper, a direct detection approach of α-ketoglutaric acid was established by using the online stacking strategy of capillary electrophoresis to evaluate the PHD2 inhibitory activity of natural products. Under optimized conditions, detection of a single sample can be achieved within 2 min. By calculation, the intraday precision RSD of the apparent electrophoretic mobility and peak areas of α-ketoglutaric acid are 0.92 % and 0.79 %, respectively, and the interday RSD were 1.27 % and 0.96 % respectively. The recoveries of the present approach were 97.9-105.2 %, and the LOQ and LOD were 2.0 µM and 5.0 µM, respectively. Furthermore, this approach was applied for the evaluation of inhibitory activity of PHD2 for 13 natural products, and PHD2 inhibitory activity of salvianolic acid A was firstly reported. The present work not only realizes evaluation of PHD2 inhibitory activity through direct detection of α-ketoglutaric acid, but also provides technical support for the discovery of potential drug molecules in hypoxia related diseases.
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Produtos Biológicos , Eletroforese Capilar , Prolina Dioxigenases do Fator Induzível por Hipóxia , Ácidos Cetoglutáricos , Humanos , Produtos Biológicos/farmacologia , Eletroforese Capilar/métodos , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Ácidos Cetoglutáricos/análiseRESUMO
A novel actinomycete strain, designated H11425T, was isolated from a sediment sample collected from Baihua Lake, Guizhou Province, PR China, and a polyphasic approach was employed to determine its taxonomic position. 16S rRNA gene sequence comparisons showed that strain H11425T is most closely related to Pseudonocardia sulfidoxydans JCM 10411T (97.9%) and Pseudonocardia kunmingensis JCM 32122T (97.8%). Both of phylogenetic analysis based on 16S rRNA gene sequence and phylogenomic analysis based on whole-genome sequence showed that strain H11425T formed a separate clade within the genus Pseudonocardia. The draft genome had a length of 8,059,576 bp with a G + C content of 74.5%. The average nucleotide identity, average amino acid identity, and digital DNA-DNA hybridization values between strain H11425T and its closely related Pseudonocardia species were 76.8-79.0%, 64.8-69.9% and 21.7-23.3%, respectively, which were significantly lower than the widely accepted species-defined threshold. Strain H11425T contained meso-diaminopimelic acid, arabinose, galactose, glucose and ribose in its whole-cell hydrolysates. Mycolic acids were absent. The menaquinone was identifed as MK-8(H4). The phospholipid profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, hydroxy-phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylcholine, an unknown phospholipid and four unidentified aminophospholipids. The major fatty acids were iso-C16:0, iso-C14:0, iso H-C16:1 and iso-C16:0 2OH. On the basis of the taxonomic evidence, strain H11425T represents a novel species of the genus Pseudonocardia, for which the name Pseudonocardia lacus sp. nov. is proposed. The type strain is H11425T (= JCM 34851T = CICC 25118T).
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Actinobacteria , Actinomycetales , Actinobacteria/genética , Pseudonocardia , Fosfatidiletanolaminas , Lagos , Filogenia , RNA Ribossômico 16S/genética , Fosfolipídeos , DNARESUMO
To evaluate the impact of phosphorus (P) combined with exogenous NAA on flax yield, enhance flax P utilization efficiency and productivity, minimize resource inputs and mitigate negative environmental and human effects. Therefore, it is crucial to comprehend the physiological and biochemical responses of flax to P and naphthylacetic acid (NAA) in order to guide future agronomic management strategies for increasing seed yield. A randomized complete block design trial was conducted under semi-arid conditions in Northwest China, using a factorial split-plot to investigate the effects of three P (0, 67.5, and 135.0 kg P2O5 ha-1) and three exogenous spray NAA levels (0, 20, and 40 mg NAA L-1) on sucrose phosphate synthase (SPS) and diphosphoribulose carboxylase (Rubisco) activities as well as nitrogen (N) and P accumulation and translocation in flax. Results indicated that the SPS and Rubisco activities, N and P accumulation at flowering and maturity along with assimilation and translocation post-flowering, fruiting branches per plant, tillers per plant, capsules per plant, and seed yield were 95, 105, 14, 27, 55, 15, 13, 110, 103, 82, 16, 61, 8, and 13% greater in the P treatments compared to those in the zero P treatment, respectively. Moreover, those characteristics were observed to be greater with exogenous spray NAA treatments compared to that no spray NAA treatment. Additionally, the maximum SPS and Rubisco activities, N and P accumulation, assimilation post-flowering and translocation, capsules per plant, and seed yield were achieved with the application of 67.5 kg P2O5 ha-1 with 20 mg NAA L-1. Therefore, these findings demonstrate that the appropriate combination of P fertilizer and spray NAA is an effective agronomic management strategy for regulating carbon and nitrogen assimilation by maintaining photosynthetic efficiency in plants to increase flax productivity.
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OBJECTIVE: To conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) on the effects of orthokeratology for slowing myopia progression in children. METHODS: We performed a specific search on PubMed, Embase, Cochrane Library, Clinical Trials, CNKI, SinoMed, and Wanfang Data for RCTs conducted up to October 1, 2022. We pooled the weighted mean difference (WMD) between the orthokeratology and control groups for axial length (AL) elongation and the odds ratio (OR) for rates of adverse events and dropout. RESULTS: Seven RCTs involving 655 eyes were included. There were significant differences in the effects of orthokeratology versus control in slowing AL elongation with WMD of -0.11 mm (95% confidence interval (CI), -0.13 to -0.08; P <0.01) at 6 months, -0.16 mm (95% CI, -0.18 to -0.13; P <0.01) at 12 months, -0.23 mm (95% CI, -0.29 to -0.18; P <0.01) at 18 months, and -0.28 mm (95% CI, -0.38 to -0.19; P <0.01) at 24 months, respectively. Myopia control rate declined, with 64%, 53%, 50%, and 47% recorded for 6, 12, 18, and 24 months, respectively. There was no statistical significance for adverse events between orthokeratology and control groups (OR=2.63, 95% CI, 0.72-9.61; P =0.11). CONCLUSION: Orthokeratology can effectively slow myopia progression in children, and the efficacy of myopia control decreases with time.
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Miopia , Procedimentos Ortoceratológicos , Criança , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Miopia/terapia , Comprimento Axial do Olho , Razão de Chances , Refração OcularRESUMO
OBJECTIVE: To evaluate the clinical efficacy of Chinese herbal footbath plus traditional Chinese medicine (TCM) decoction in diabetic peripheral neuropathy. METHODS: This retrospective study enrolled 120 patients with diabetic peripheral neuropathy treated in Shanghai Jinshan TCM-Integrated Hospital from January 2019 to January 2021. The eligible patients received either routine treatment (control group) or Chinese herbal GuBu Decoction footbath plus oral Yiqi Huoxue Decoction (experimental group), with 60 patients in each group. The duration of treatment was one month. Outcome measures included motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) of the common peroneal nerve, blood glucose, TCM symptom scores and clinical efficacy. RESULTS: TCM interventions resulted in significantly faster MNCV and SNCV versus routine treatment (P<0.05). Patients with TCM treatment exhibited lower fasting blood glucose, 2 h postprandial glucose and glycosylated hemoglobin than those with routine treatment (P<0.05). Remarkably lower TCM symptom scores were observed in the experimental group than in the control group (P<0.05). Chinese herbal GuBu Decoction footbath plus oral Yiqi Huoxue Decoction regimen was associated with a significantly higher clinical efficacy when comparing with routine treatment (P<0.05). The incidence of adverse events was not significantly different between the two groups (P>0.05). CONCLUSION: Chinese herbal GuBu Decoction footbath plus oral Yiqi Huoxue Decoction can provide promising blood glucose control, alleviate clinical symptoms, accelerate nerve conduction speed and enhance clinical efficacy.
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OBJECTIVE: To explore the underlying mechanism of inhibition by Jinkui Shenqi Pills (JKSQP) on glucocorticoid-enhanced axial length elongation in experimental lens-induced myopia (LIM) guinea pigs. METHODS: Sixty 2-week old male guinea pigs were randomly divided into 4 groups with 15 guinea pigs in each group, according to the random numbers generated by SPSS software: control, LIM, saline and JKSQP groups. The control group includes animals with no treatment, while the guinea pigs in the other 3 groups received lens-induced myopization on the right eyes throughout the experiment (for 8 weeks). The saline and JKSQP groups were given daily intraperitoneal injections of 10 mg/kg hydrocortisone for 2 consecutive weeks at the same time, and then orally administered either saline or JKSQP [13.5 g/(kgâ¢d) for 6 consecutive weeks. Body weight, anal temperature and animal appearance were observed and recorded to evaluate the GC-associated symptoms. The ocular parameters, including refraction and axial length, were measured by streak retinoscopy and A-scan ultrasonography, respectively. The levels of plasma hormones associated with the hypothalamic-pituitary-adrenal axis (HPAA), including free triiodothyronine, free thyroxine, estradiol and testosterone, were measured by radioimmunoassay, and cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate were measured by enzyme-linked immunosorbent assay. In addition, the mRNA and protein expressions of retinal amphiregulin (AREG) was measured by quantitative real-time polymerase chain reaction and Western blotting, respectively. RESULTS: JKSQP effectively increased body weight and anal temperature, improved animal appearance and suppressed axial length elongation in glucocorticoid-enhanced myopic guinea pigs with normalization of 4 HPAA-associated plasma hormones (all P<0.05). The plasma level of cAMP was significantly increased, whereas the plasma level of cGMP and the mRNA and protein expressions of retinal AREG were decreased after treatment with JKSQP (all P<0.05). CONCLUSION: JKSQP exhibited a significant inhibitory effect on axial length elongation with decreased expression of AREG in the retina, and normalized 4 HPAA-associated plasma hormones and the expression of cAMP and cGMP in GC-enhanced myopic guinea pigs.
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Glucocorticoides , Miopia , Cobaias , Masculino , Animais , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Miopia/tratamento farmacológico , Miopia/metabolismo , Peso Corporal , RNA Mensageiro , Modelos Animais de DoençasRESUMO
Objective: To evaluate the characteristics of full compensation and its association with the prevalence of total astigmatism (TA), and to analyze the effects of TA on uncorrected distance visual acuity (UDVA). Methods: With random cluster sampling based on a school-based cross-sectional design, children aged 4 to 18 years were recruited in September 2020, Shandong Province, China. TA, anterior corneal astigmatism (ACA), and ocular residual astigmatism (ORA) were converted to vectorial components (J0, J45), followed by an assessment of the compensatory effect of ACA by ORA. Astigmatism was defined as a cylinder that was better than or equal to 0.75 diopters (D). Logistic regression analysis was used to assess the related factors for children with full compensation, and the generalized linear model was used to assess the influence of TA on UDVA. Results: Out of 4,494 eligible children, data of 4,145 children (92.3%, 9.23 ± 3.15 years, 50.4% boys) were included in the statistical analysis. The prevalence of TA (27.9%) increased significantly with age (Ptrend < 0.001). The distribution of full compensation in J0 and J45 components were similar (22.1% and 25.6%, respectively), which decreased with age (Ptrend < 0.001). The closer the refractive status was to emmetropization, the higher the proportion of full compensation and the lower the prevalence of TA were. Shorter axial length (J0: Odds Ratio (OR) = 0.76, 95% confidence interval (CI): 0.61 to 0.94, P = 0.010), better UDVA (J0: OR = 0.37, 95% CI: 0.21 to 0.65, P < 0.001; J45: OR = 0.34, 95% CI: 0.20 to 0.59, P < 0.001), and longer average corneal curvature radius (J0: OR = 3.72, 95% CI: 2.18 to 6.34, P < 0.001; J45: OR = 2.82, 95% CI: 1.67 to 4.76, P < 0.001) were associated with full compensation. Higher TA was associated with a worse UDVA (ß = 0.03, 95% CI: 0.02 to 0.04, P < 0.001). Conclusions: The prevalence of TA gradually increased with age, and showed a U-shaped distribution with increased refraction. Full compensation was associated with smaller TA and better UDVA. This indicated that considering the compensatory effect of ORA is vital for astigmatism correction in clinical work, which may improve the visual quality.
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Astigmatismo , Masculino , Criança , Humanos , Feminino , Estudos Transversais , Astigmatismo/epidemiologia , Refração Ocular , Acuidade Visual , CórneaRESUMO
The PI3K/AKT/mTOR signaling pathway is one of the most common abnormal activation pathways in tumor cells, and has associated with multiple functions such as tumor cell growth, proliferation, migration, invasion, and tumor angiogenesis. Here, a series of 3-amino-1H-indazole derivatives were synthesized, and their antiproliferative activities against HT-29, MCF-7, A-549, HepG2 and HGC-27 cells were evaluated. Among them, W24 exhibited the broad-spectrum antiproliferative activity against four cancer cells with IC50 values of 0.43-3.88 µM. Mechanism studies revealed that W24 inhibited proliferation by affecting the DNA synthesis, induced G2/M cell cycle arrest and apoptosis by regulating Cyclin B1, BAD and Bcl-xL, meanwhile induced the change of intracellular ROS and mitochondrial membrane potential in HGC-27 cells. Moreover, W24 inhibited the migration and invasion of HGC-27 cells by decreasing EMT pathway related proteins and reducing the mRNA expression levels of Snail, Slug and HIF-1α. Furthermore, W24 displayed low tissue toxicity profile and good pharmacokinetic properties in vivo. Therefore, 3-amino-1H-indazole derivatives might serve as a new scaffold for the development of PI3K/AKT/mTOR inhibitor and anti-gastric cancer reagent.
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Indazóis , Neoplasias , Humanos , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Indazóis/química , Indazóis/farmacologiaRESUMO
OBJECTIVE: This study aimed to investigate the prevalence of glaucoma with associated factors in the rural populations of 10 provinces in China. DESIGN: A population-based cross-sectional study. METHODS: All participants aged 6 years or older from 10 provinces completed visual acuity testing, slit-lamp examination, ophthalmoscopy and non-contact tonometry. Glaucoma suspects underwent fundus photography, Goldmann applanation tonometry, visual field testing and gonioscopy. Glaucoma was determined according to the International Society of Geographical and Epidemiological Ophthalmology classification scheme. Associations of demographics and medical factors with glaucoma were assessed using multiple logistic regression models. RESULTS: From June 2017 to October 2018, 48 398 of 52 041 participants were included in the final analyses. The age-standardised prevalence of glaucoma was 1.7% (95% CI 1.55% to 1.78%) among the participants older than 6 years, which was 2.1% (95% CI 1.93% to 2.23%) in participants aged over 40 years. The constituent ratios of glaucoma were: 44.4% primary angle-closure glaucoma (PACG), 34.7% primary open-angle glaucoma, 2.6% congenital glaucoma and 18.3% other types of glaucoma. Increasing age, smoking, cerebral stroke, type 2 diabetes, higher education (college or more) and higher personal income were significant risk factors for PACG. The unilateral and bilateral blindness rates in the entire study population were 4.692% and 1.068%, respectively. A family history of glaucoma was a significant risk factor for the prevalence of glaucoma and blindness in at least one eye. CONCLUSIONS: Rural populations have a high prevalence of glaucoma, which should be included in chronic disease management programmes in China for long-term care.
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Diabetes Mellitus Tipo 2 , Glaucoma de Ângulo Fechado , Glaucoma de Ângulo Aberto , Humanos , Adulto , Pessoa de Meia-Idade , Pressão Intraocular , Estudos Transversais , Glaucoma de Ângulo Aberto/diagnóstico , População Rural , Glaucoma de Ângulo Fechado/diagnóstico , Glaucoma de Ângulo Fechado/epidemiologia , Distribuição por Idade , Cegueira/epidemiologia , Gonioscopia , Prevalência , China/epidemiologiaRESUMO
VEGFR-2 is an attractive therapeutic target for antitumor drug research by blocking tumor angiogenesis and PROTAC provides a new technology for targeted protein knockout. Herein, a library of novel VEGFR-2-PROTAC degraders were rationally designed and synthesized based on the Lys residue region on the surface of VEGFR-2 protein using protein structure-based drug design strategy. Among them, P7 exhibited preferable antitumor activity against HGC-27 cells and less toxic to human normal HUVEC, HEK293T and GES-1 cells in vitro, as well as the potent degradation activity of VEGFR-2 protein in HGC-27 cells (DC50: 0.084 ± 0.04 µM, Dmax: 73.7%) and HUVEC cells (DC50: 0.51 ± 0.10 µM, Dmax: 76.6%). Additionally, P7 degraded VEGFR-2 protein by the formation of ternary complex and the ubiquitin proteasome pathway in HGC-27 cells. Furthermore, P7 shortened the half-life of VEGFR-2 protein synthesis and had no inhibitory effect on the expression of VEGFR-2 mRNA in HGC-27 cells. Moreover, P7 inhibited the colony formation, migration and invasion of HGC-27 cells in a time- and dose-dependent manner, and meanwhile induced G2/M phase cycle arrest and apoptosis. All the results demonstrated that P7 could be as a promising VEGFR-2-PROTAC degrader for gastric cancer therapy.
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Antineoplásicos , Neoplasias Gástricas , Humanos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Lisina/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Células HEK293 , Proteólise , Proliferação de Células , Antineoplásicos/farmacologia , Antineoplásicos/química , Proteína Supressora de Tumor Von Hippel-LindauRESUMO
Purpose: The authors described a 7-year-old boy who was diagnosed with morning glory disc (MGD) anomaly in the right eye via fundus examination. However, during the head CT examination, a hyperdense choroidal lesion was discovered around the optic disc. Comprehensive investigations revealed that the lesion's characteristics were extremely consistent with choroidal osteoma (CO), so the patient was diagnosed with MGD with CO on his second visit. However, in the subsequent follow-up, the author discovered pigmentary alterations in the retinal pigment epithelium (RPE) in the patient's right eye. Finally, the diagnosis was corrected to MGD with choroidal ossification following a thorough etiological analysis. Meanwhile, the characteristics of choroidal ossification were described in detail through multimodal imaging in this article. Methods: Retrospective review of a case note. Conclusions: Similar to CO, choroidal ossification is the consequence of structured osseous tissue formation regulated by osteoblasts and osteoclasts. It consists of bone trabecular and vascular components and is difficult to be distinguished from CO on imaging examinations. In contrast to the congenital prevalence of CO, there are often incentives for the occurrence of choroidal ossification. These inducements will eventually mediate the inflammation in the eye, resulting in the activation of many cytokines and the production of choroidal ossification. Around one-third of patients with MGD will experience retinal detachment, and in certain cases, the subretinal fluid will be absorbed spontaneously, resulting in alterations to the RPE. These processes can activate inflammatory factors in the eye, bringing about a cascade of abnormalities, including the development of CO. Therefore, the proper diagnosis of disease should not be made exclusively on the basis of the imaging findings. A thorough analysis of the epidemiology and etiology is crucial.
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This study aims to uncover the relationship among multicultural differences, empathy, and the behaviors of risk prevention and control in the context of crisis events by using a sample of 300 individuals in 10 different multicultural countries. A theoretical logic model was applied to empirical analysis, and the results indicated that cultural differences positively influenced the behavior of empathy communication and risk prevention and control. Further analyses revealed that real-time monitoring of changes in empathy could provide better options of measures for local risk prevention and control when the same crisis event occurred in a multicultural context. With user-generated content (UGC) emerging in the web 2.0 era, this paper proposed a more profound empathy code regarding the periodicity of risk prevention and control. This paper expects to contribute to the circumvention of cognitive errors caused by cultural differences, and to further provide effective conduction for individuals' risk prevention and control behaviors.
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Purpose: Synaptosomal actin dynamics are essential for synaptic structural stability. Whether actin dynamics are involved in structural and functional synaptic plasticity within the primary visual cortex (V1) or behavioral visual acuity in rats has still not been thoroughly investigated. Methods: Synaptosome preparation and western blot analysis were used to analyze synaptosomal actin dynamics. Transmission electron microscopy was used to detect synaptic density and mitochondrial area alterations. A visual water maze task was applied to assess behavioral visual acuity. Microinjection of the actin polymerization inhibitor or stabilizer detected the effect of actin dynamics on visual function. Results: Actin dynamics, the mitochondrial area, and synaptic density within the area of V1 are increased during the critical period for the development of binocularity. Microinjection of the actin polymerization inhibitor cytochalasin D into the V1 decreased the mitochondrial area, synaptic density, and behavioral visual acuity. Long-term monocular deprivation reduced actin dynamics, the mitochondrial area, and synaptic density within the V1 contralateral to the deprived eye compared with those ipsilateral to the deprived eye and impaired visual acuity in the amblyopic eye. In addition, the mitochondrial area, synaptic density, and behavioral visual acuity were improved by stabilization of actin polymerization by jasplakinolide microinjection. Conclusions: During the critical period of visual development of binocularity, synaptosomal actin dynamics regulate synaptic structure and function and play roles in behavioral visual acuity in rats.
Assuntos
Actinas , Plasticidade Neuronal/fisiologia , Sinaptossomos/metabolismo , Acuidade Visual/fisiologia , Córtex Visual/fisiologia , Actinas/química , Actinas/metabolismo , Ambliopia/metabolismo , Ambliopia/fisiopatologia , Animais , Antineoplásicos/farmacologia , Comportamento Animal/fisiologia , Depsipeptídeos/farmacologia , Aprendizagem em Labirinto , Polimerização/efeitos dos fármacos , Ratos , Visão Ocular/fisiologiaRESUMO
AIM: To observe changes in the best-corrected visual acuity (BCVA), central macular thickness (CMT), and central choroidal thickness (CCT) of patients with macular edema (ME) secondary to ischemic retinal vein occlusion (iRVO) following intravitreal Conbercept injection. METHODS: This retrospective study included 33 eyes from 33 patients who received intravitreal injections of Conbercept for ME secondary to iRVO. Treatments were performed on a 3+pro re nata (3+PRN) basis. All of the patients were examined by fundus fluorescein angiography and spectral domain optical coherence tomography at the first visit. Laser photocoagulation was performed in the nonperfusion area of the retina of all eyes after the first injection. BCVA, CMT, and CCT were observed before and after 6mo of treatment. The number of injections necessary to achieve improved vision was also noted. RESULTS: Following Conbercept treatment, the mean BCVA significantly improved from 0.81±0.39 at baseline to 0.41±0.25 and 0.43±0.29 logMAR in the third and sixth months, respectively (both P=0.000). The CMT of the patients at baseline was 556.75±98.57 µm; 304.78±68.53 and 306.85±76.77 µm 3 and 6mo after treatment, respectively (both P=0.000 vs baseline). The CCTs of the patients at baseline, 3 and 6mo after treatment were 304.63±57.83, 271.31±45.53, and 272.29±39.93 µm, respectively (P=0.026 and 0.035 vs baseline). No severe adverse event relevant to the therapy was noted, and the average number of injections delivered was 3.35. CONCLUSION: Intravitreal Conbercept injection combined with laser photocoagulation appears to be a safe and effective treatment for ME secondary to iRVO in the short-term.
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Osthole (OST) is a natural coumarin compound that exerts multiple pharmacologic effects. However, the poor water solubility and the low oral absorption of OST limit its clinical application for the treatment of neurologic diseases. A suitable preparation needs to be tailored to evade these unfavourable properties of OST. In this study, an OST nanoemulsion (OST-NE) was fabricated according to the pseudoternary phase diagram method, which was generally used to optimize the prescription in light of the solubility of OST in surfactants and cosurfactants. The final composition of OST-NE was 3.6% of ethyl oleate as oil phase, 11.4% of the surfactant (polyethylene glycol ester of 15-hydroxystearic acid: polyoxyethylene 35 castor oil = 1 : 1), 3% of polyethylene glycol 400 as cosurfactant, and 82% of the aqueous phase. The pharmacokinetic study of OST-NE showed that the brain-targeting coefficient of OST was larger by the nasal route than that by the intravenous route. Moreover, OST-NE inhibited cell death, decreased the apoptosis-related proteins (Bax and caspase-3), and enhanced the activity of antioxidant enzymes (superoxide dismutase and glutathione) in L-glutamate-induced SH-SY5Y cells. OST-NE improved the spatial memory ability, increased the acetylcholine content in the cerebral cortex, and decreased the activity of acetylcholinesterase in the hippocampus of Alzheimer's disease model mice. In conclusion, this study indicates that the bioavailability of OST was improved by using the OST-NE via the nasal route. A low dose of OST-NE maintained the neuroprotective effects of OST, such as inhibiting apoptosis and oxidative stress and regulating the cholinergic system. Therefore, OST-NE can be used as a possible alternative to improve its bioavailability in the prevention and treatment of Alzheimer's disease.