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1.
Int J Nanomedicine ; 18: 225-241, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36660337

RESUMO

Background: Gallium (III) metal-organic complexes have been shown to have the ability to inhibit tumor growth, but the poor water solubility of many of the complexes precludes further application. The use of materials with high biocompatibility as drug delivery carriers for metal-organic complexes to enhance the bioavailability of the drug is a feasible approach. Methods: Here, we modified the ligands of gallium 8-hydroxyquinolinate complex with good clinical anticancer activity by replacing the 8-hydroxyquinoline ligands with 5-bromo-8-hydroxyquinoline (HBrQ), and the resulting Ga(III) + HBrQ complex had poor water solubility. Two biocompatible materials, bovine serum albumin (BSA) and graphene oxide (GO), were used to synthesize the corresponding Ga(III) + HBrQ complex nanoparticles (NPs) BSA/Ga/HBrQ NPs and GO/Ga/HBrQ NPs in different ways to enhance the drug delivery of the metal complex. Results: Both of BSA/Ga/HBrQ NPs and GO/Ga/HBrQ NPs can maintain stable existence in different solution states. In vitro cytotoxicity test showed that two nanomedicines had excellent anti-proliferation effect on HCT116 cells, which shown higher level of intracellular ROS and apoptosis ratio than that of cisplatin and oxaliplatin. In addition, the superior emissive properties of BSA/Ga/HBrQ NPs and GO/Ga/HBrQ NPs allow their use for in vivo imaging showing highly effective therapy in HCT116 tumor-bearing mouse models. Conclusion: The use of biocompatible materials for the preparation of NPs against poorly biocompatible metal-organic complexes to construct drug delivery systems is a promising strategy that can further improve drug delivery and therapeutic efficacy.


Assuntos
Antineoplásicos , Portadores de Fármacos , Gálio , Grafite , Nanopartículas Metálicas , Oxiquinolina , Animais , Humanos , Camundongos , Materiais Biocompatíveis , Linhagem Celular Tumoral , Portadores de Fármacos/síntese química , Gálio/química , Grafite/química , Células HCT116 , Nanopartículas Metálicas/análise , Nanopartículas/análise , Oxiquinolina/química , Tamanho da Partícula , Soroalbumina Bovina/farmacologia , Água , Antineoplásicos/síntese química , Antineoplásicos/química
2.
Mar Drugs ; 21(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36662212

RESUMO

It has been reported that dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) exert therapeutic potential for the preservation of functional ß-cell mass. However, the effect of dietary n-3 PUFA deficiency on pancreatic injury and whether the supplementation of n-3 PUFA could prevent the development of pancreatic injury are still not clear. In the present study, an n-3 PUFA deficiency mouse model was established by feeding them with n-3 PUFA deficiency diets for 30 days. Results showed that n-3 PUFA deficiency aggravated streptozotocin (STZ)-induced pancreas injury by reducing the insulin level by 18.21% and the HOMA ß-cell indices by 31.13% and the area of islet by 52.58% compared with the STZ group. Moreover, pre-intervention with DHA and EPA for 15 days could alleviate STZ-induced pancreas damage by increasing the insulin level by 55.26% and 44.33%, the HOMA ß-cell indices by 118.81% and 157.26% and reversed the area of islet by 196.75% and 205.57% compared to the n-3 Def group, and the effects were significant compared to γ-linolenic acid (GLA) and alpha-linolenic acid (ALA) treatment. The possible underlying mechanisms indicated that EPA and DHA significantly reduced the ration of n-6 PUFA to n-3 PUFA and then inhibited oxidative stress, inflammation and islet ß-cell apoptosis levels in pancreas tissue. The results might provide insights into the prevention and alleviation of pancreas injury by dietary intervention with PUFAs and provide a theoretical basis for their application in functional foods.


Assuntos
Ácidos Graxos Ômega-3 , Insulinas , Camundongos , Animais , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Estreptozocina/toxicidade , Ácidos Graxos Insaturados , Ácidos Graxos , Inflamação/tratamento farmacológico , Pâncreas , Suplementos Nutricionais , Apoptose , Estresse Oxidativo , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia
3.
Int J Biol Macromol ; 231: 123310, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36690238

RESUMO

With great interest, we read the paper "Chitosan nano-vehicles as biocompatible delivering tools for a new Ag(I)curcuminoid-Gboxin analog complex in cancer and inflammation therapy" published in the International Journal of Biological Macromolecules. In Elbehairi's report, the human breast carcinoma line MCF-7 were used in the in vitro cytotoxic analysis test of the curcuminoid conjugate and its silver(I) complex. They found that Ag(I)FLLL49-GbA could induce highly significant up-regulation of caspase-3, tumor suppressor proteins P53, and Bax after the 48 h of treatment in MCF-7 cells (Fig. 9), and the expression of caspase-3 was analyzed by western blot assay. However, it's well known that the MCF-7 breast carcinoma line do not express caspase-3. The lack of caspase-3 in MCF-7 cells is caused by a 47-base pair deletion within exon 3 of the CASP-3 gene resulting in the skipping of this exon during pre-mRNA splicing and introduction of a premature stop codon at position 42 that completely abrogates translation of the CASP-3 mRNA. Therefore, the detection of a caspase-3 protein in caspase-3 deficient MCF-7 cells in this study made us confused. We appreciate the authors' efforts in investigating the effects of chitosan nano-vehicles as biocompatible delivering tools for a new Ag(I)curcuminoid-Gboxin analog complex in cancer and inflammation therapy. Nevertheless, we sincerely suggest that appropriate modification may further solidify the findings of the study.

4.
Retina ; 43(2): 191-199, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36695790

RESUMO

PURPOSE: To compare the functional and anatomical outcomes of peeled internal limiting membrane reposition and traditional internal limiting membrane peeling for the treatment of idiopathic macular hole. METHODS: This is a randomized, single-center, and double-blinded, pilot, controlled trial. RESULTS: Of the 30 patients enrolled, 27 (13 in Group 1 and 14 in Group 2) were included in the primary analysis (22 women [81.5%]; mean [SD] age, 61.7 [6.8] years). The BCVA was 0.23 ± 0.18 logMAR in the reposition group and 0.44 ± 0.24 logMAR in the peeling group at 6 months postoperatively (P = 0.02). The primary MH closure rate is 86.7% in the reposition group and 93.3% in the peeling group (P = 0.60). The range of the inner retinal dimpling was significantly lower in the reposition group at 6 months postoperatively (P < 0.0001). The thickness of the full parafovea (P = 0.0092), inner parafovea (P = 0.0007), inner perifovea (P = 0.0044), and outer fovea (P = 0.0392) was significantly greater in the reposition group than that in the peeling group at 6 months postoperatively. The sensitivity threshold and mfERG P1 wave amplitude density in rings one, four, and five were higher in the reposition group than in the peeling group at 6 months postoperatively. CONCLUSION: Our findings suggest that the novel technique of peeled internal limiting membrane reposition has advantages over the traditional internal limiting membrane peeling in better microstructural outcomes of inner retina and functional recoveries. Furthermore, larger RCT studies are warranted.


Assuntos
Perfurações Retinianas , Humanos , Feminino , Pessoa de Meia-Idade , Perfurações Retinianas/cirurgia , Projetos Piloto , Resultado do Tratamento , Vitrectomia/métodos , Acuidade Visual , Retina , Tomografia de Coerência Óptica/métodos , Membrana Basal/cirurgia , Estudos Retrospectivos
5.
Reprod Biol Endocrinol ; 21(1): 8, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36703171

RESUMO

STUDY QUESTION: To construct prediction models based on the Bayesian network (BN) learning method for the probability of fertilization failure (including low fertilization rate [LRF] and total fertilization failure [TFF]) in assisted reproductive technology (ART) treatment. A BN model was developed to predict TFF/LFR. The model showed relatively high calibration in external validation, which could facilitate the identification of risk factors for fertilization disorders and improve the efficiency of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment. WHAT IS KNOWN ALREADY: The prediction of TFF/LFR is very complex. Although some studies attempted to construct prediction models for TFF/LRF, most of the reported models were based on limited variables and traditional regression-based models, which are unsuitable for analyzing real-world clinical data. Therefore, none of the reported models have been widely used in routine clinical practice. To date, BN modeling analysis is a prominent and increasingly popular machine learning method that is powerful in dealing with dynamic and complex real-world data. STUDY DESIGN, SIZE, DURATION: A retrospective study was performed with 106,640 fresh embryo IVF/ICSI cycles from 2009 to 2019 in one of China's largest reproductive health centers. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 106, 640 cycles were included in this study, including 97,102 controls, 4,339 LFR cases, and 5,199 TFF cases. Twenty-four predictors were initially included, including 13 female-related variables, five male-related variables, and six variables related to IVF/ICSI treatment. BN modeling analysis with tenfold cross-validation was performed to construct the predictive model for TFF/LFR. The receiver operating characteristic (ROC) curves and the corresponding area under the curves (AUCs) were used to evaluate the performance of the BN model. MAIN RESULTS AND THE ROLE OF CHANCE: All twenty-four predictors were first organized into seven hierarchical layers in a theoretical BN model, according to prior knowledge from previous literature and clinical practice. A machine-learning BN model was generated based on real-world clinical data, containing a total of eighteen predictors, of which the infertility type, ART method, and number of retrieved oocytes directly influence the probabilities of LFR/TFF. The prediction accuracy of the BN model was 91.7%. The AUC of the TFF versus control groups was 0.779 (95% CI: 0.766-0.791), with a sensitivity of 71.2% and specificity of 70.1%; the AUC of of TFF versus LFR groups was 0.807 (95% CI: 0.790-0.824), with a sensitivity of 49.0% and specificity of 99.0%. LIMITATIONS, REASON FOR CAUTION: First, our study was based on clinical data from a single center, and the results of this study should be further verified by external data. In addition, some critical data (e.g., the detailed IVF laboratory parameters of the sperm and oocytes used for insemination) were not available in this study, which should be given full consideration when further improving the performance of the BN model. WIDER IMPLICATIONS OF THE FINDINGS: Based on extensive clinical real-world data, we developed a BN model to predict the probabilities of fertilization failures in ART, which provides new clues for clinical decision-making support for clinicians in formulating personalized treatment plans and further improving ART treatment outcomes. STUDY FUNDING/COMPETING INTEREST(S): Dr. Y. Wang was supported by grants from the Beijing Municipal Science & Technology Commission (Z191100006619086). We declare that there are no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

6.
Int Immunopharmacol ; 116: 109724, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36696856

RESUMO

BACKGROUND: Dexmedetomidine (DEX) administered before or at 30 min after sepsis induction was reported to alleviate septic cardiomyopathy in experimental models. However, sepsis is a life-threatening organ dysfunction due to infection-induced dysregulated host response, whether DEX treatment in the presence of organ dysfunction affects septic cardiomyopathy is unknown. This study investigated the effect of DEX posttreatment on septic cardiomyopathy. METHODS: Male wild-type and α2A-adrenergic receptor (AR) knockout mice were exposed to lipopolysaccharide (LPS) or cecal ligation puncture (CLP), and cultured cardiac endothelial cells were used. Mouse survival, myocardial function, inflammatory response and related signaling pathways were determined. RESULTS: DEX treatment at 6, 9 h after LPS challenge significantly reduced survival rate of LPS-challenged mice, especially at 9 h. DEX administered at 9 h after LPS injection or CLP significantly reduced survival in LPS or CLP-induced sepsis in wild-type mice, but not in α2A-AR knockout mice. LPS treatment for 20 h decreased the left ventricle + dp/dt, increased myocardial interleukin (IL)-1ß and IL-6 concentrations as well as cardiac endothelial tumor necrosis factor (TNF)-α, vascular cell adhesion molecule-1 (VCAM-1) and ICAM-1 expression, which were enhanced by DEX treated at 9 h after LPS injection in wild-type mice, but not in α2A-AR knockout mice. Furthermore, DEX posttreatment increased p38 phosphorylation, c-Fos nuclear translocation and VCAM-1 expression in LPS-treated cardiac endothelial cells, which were eliminated by α2A-AR knockout or PKC inhibitor. CONCLUSIONS: DEX posttreatment aggravates LPS-induced cardiac inflammation and myocardial dysfunction, at least in part, via activating cardiac endothelial α2A-AR-mediated PKC signal pathway.

7.
Artigo em Inglês | MEDLINE | ID: mdl-36668724

RESUMO

ABSTRACT: Mitochondrial dysfunction plays a key role in the development of heart failure, but targeted therapeutic interventions remain elusive. Previous studies have shown coenzyme Q10 (CoQ10) insufficiency in patients with heart disease with undefined mechanism, and modest effectiveness of CoQ10 supplement therapy. Using two transgenic mouse models of cardiomyopathy owing to cardiac overexpression of Mst1 (Mst1-TG) or ß2-adrenoceptor (ß2AR-TG), we studied changes in cardiac CoQ10 content and alterations in CoQ10 biosynthesis genes. We also studied in Mst1-TG mice effects of CoQ10, delivered by oral or injection regimens, on both cardiac CoQ10 content and cardiomyopathy phenotypes. HPLC and RNA-sequencing revealed in both models significant reduction in cardiac content of CoQ10 and downregulation of majority of genes encoding CoQ10 biosynthesis enzymes. Mst1-TG mice with 70% reduction in cardiac CoQ10 were treated with CoQ10 either by oral gavage or i.p. injection for 4-8 weeks. Oral regimens failed in increasing cardiac CoQ10 content, whereas injection regimen effectively restored cardiac CoQ10 level in a time-dependent manner. However, CoQ10 restoration in Mst1-TG mice did not correct mitochondrial dysfunction measured by energy metabolism, downregulated expression of marker proteins and oxidative stress, nor to preserve cardiac contractile function. In conclusion, mouse models of cardiomyopathy exhibited myocardial CoQ10 deficiency likely due to suppressed endogenous synthesis of CoQ10. In contrast to ineffectiveness of oral administration, CoQ10 administration by injection regimen in cardiomyopathy mice restored cardiac CoQ10 content, which, however, failed in achieving detectable efficacy at molecular and global functional levels.

8.
Org Lett ; 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36668813

RESUMO

A general strategy for the construction of dual-functional carbon-heteroatom bonds has been developed via a light-promoted nickel catalytic system. Employing a simple NiBr2 as the catalyst without any exogeneous ligands and photosensitizers, a variety of esters and sulfonamide N-arylation derivatives, including celecoxib- and glimepiride-derived sulfonamides, were readily accessed with high functional group tolerance and high efficiency. Moreover, the UV-vis absorption spectrum and free radical trapping experiments aimed at revealing the mechanism of the reaction are also presented.

9.
J Tradit Complement Med ; 13(1): 30-38, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36685079

RESUMO

Background and aim: Cannabis sativa L. is a medicinal plant with a long history. Phyto-cannabinoids are a class of compounds from C. sativa L. with varieties of structures. Endocannabinoids exist in the human body. This article provides an overview of natural cannabinoids (phyto-cannabinoids and endocannabinoids) with an emphasis on their pharmacology activities. Experimental procedure: The keywords "Cannabis sativa L″, "cannabinoids", and "central nervous system (CNS) diseases" were used for searching and collecting pieces of literature from PubMed, ScienceDirect, Web of Science, and Google Scholar. The data were extracted and analyzed to explore the effects of cannabinoids on CNS diseases. Result and conclusion: In this paper, schematic diagrams are used to intuitively show the phyto-cannabinoids skeletons' mutual conversion and pharmacological activities, with special emphasis on their relevant pharmacological activities on central nervous system (CNS) diseases. It was found that the endocannabinoid system and microglia play a crucial role in the treatment of CNS diseases. In the past few years, pharmacological studies focused on Δ9-THC, CBD, and the endocannabinoids system. It is expected to encourage new studies on a more deep exploration of other types of cannabinoids and the mechanism of their pharmacological activities in the future.

10.
J Clin Invest ; 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36626227

RESUMO

The role of tumor-associated macrophages (TAMs) along with the regulatory mechanisms underlying distinct macrophage activation states remain poorly understood in prostate cancer (PCa). Herein, we reported that PCa growth in macrophage-specific Ubc9 deficient mice is substantially suppressed compared to their wild-type littermates, an effect partially ascribed to the augmented CD8+ T cell response. Biochemical and molecular analyses revealed that the signal transducer and activator of transcription 4 (STAT4) is a crucial UBC9-mediated SUMOylation target, with lysine residue 350 (K350) as the major modification site. Site-directed mutation of STAT4 (K350R) enhanced its nuclear translocation and stability, thereby facilitating the proinflammatory activation of macrophages. Importantly, administration of UBC9 inhibitor, 2-D08, promoted the antitumor effect of TAMs and increased the expression of PD-1 on CD8+ T cells, supporting a synergistic antitumor efficacy once it combined with the immune checkpoint blockade (ICB) therapy. Together, our results demonstrated that ablation of UBC9 could reverse the immunosuppressive phenotype of TAMs via promoting STAT4 mediated macrophage activation and macrophage-CD8+ T cell crosstalk, which provides valuable insights to halt the pathogenic process of tumorigenesis.

11.
J Appl Microbiol ; 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639131

RESUMO

AIMS: Feathers are keratin-rich byproducts of poultry processing but that are often frequently abandoned as garbage and polluting the environment. Therefore, the study focused on the efficient biodegradation, bioactivity, and high-value application of feather keratin. METHODS AND RESULTS: Feather-degrading bacteria were identified and the degradation properties were characterized. DPPH and ABTS radical scavenging assays, cytotoxicity assays, intracellular reactive oxygen scavenging assays, and cell migration assays were used to examine the biological activities of the feather keratin hydrolysis peptides (FKHPs). The results showed that we screened a feather-degrading strain of B. licheniformis 8-4, which achieved complete degradation of 2% (w/v) feathers within 48 h. Notably, the feather fermentation broth was particularly high in FKHPs, which exhibited good DPPH and ABTS radical scavenging ability. Further studies revealed that FKHPs had both the ability to scavenge H2O2-induced ROS from HaCat cells and to promote HaCat cell migration, while remaining non-toxicity. CONCLUSIONS: The effective feather-degrading ability of B. licheniformis 8-4 allowed for the fermentation of feather medium to yield active peptides that were both antioxidant and pro-cell migration.

12.
J Dermatol ; 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36694424

RESUMO

Epidermolysis bullosa pruriginosa (EBP) is a rare variant of dystrophic epidermolysis bullosa caused by COL7A1 gene mutation. Intense pruritus and nodular prurigo-like lesions are the main features of the disease. To date, the treatment strategies for this condition are not well established. Recent studies have indicated that type 2 inflammation plays a role in the pathophysiology of EBP, suggesting Th2 cytokines could be potential therapeutic targets. In this prospective case series study, we reported three patients with EBP, diagnosed by clinical manifestations, histopathological evaluations, and genetic sequencing, two of whom were treated with dupilumab for 20 weeks. Results showed that the clinical symptoms, pruritus, and quality of life of the patients were significantly improved, as measured by the Epidermolysis Bullosa Disease Activity and Scarring Index, the Visual Analog Scale, and the Children's Dermatology Life Quality Index. Serum immunoglobulin E levels also fell gradually over the 20-week treatment period. Immunotyping of Th1/2/17 cell subsets in peripheral blood by flow cytometry revealed a higher Th2 but parallel Th1 and Th17 cell subsets in patients compared to healthy controls, and a significant decrease in Th2 and an increase in Th17 cells after dupilumab administration. Of note, after 20 weeks of dupilumab treatment, the expression of type VII collagen in the basement membrane of the skin lesion of the patients significantly increased, which was evidenced by immunofluorescence analysis. No treatment-related adverse events were documented. Taken together, targeting type 2 inflammation with dupilumab may be an effective and safe treatment option for EBP.

14.
Inflammation ; 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36598593

RESUMO

Macrophages actively participate in immunomodulatory processes throughout periodontal inflammation. Regulation of M1/M2 polarization affects macrophage chemokine and cytokine secretion, resulting in a distinct immunological status that influences prognosis. Semaphorin 3A (Sema3A), a neurite growth factor, exerts anti-inflammatory effects. In this study, we investigated the immunomodulation of Sema3A on macrophage-related immune responses in vivo and in vitro. Topical medications of Sema3A in mice with periodontitis alleviated inflammatory cell infiltration into gingival tissue and reduced areas with positive IL-6 and TNFα expression. We observed that the positive area with the M2 macrophage marker CD206 increased and that of the M1 macrophage marker iNOS decreased in Sema3A-treated mice. It has been postulated that Sema3A alleviates periodontitis by regulating alternative macrophage activation. To understand the mechanism underlying Sema3A modulation of macrophage polarization, an in vitro macrophage research model was established with RAW264.7 cells, and we demonstrated that Sema3A promotes LPS/IFNγ-induced M1 macrophages to polarize into M2 macrophages and activates the PI3K/AKT/mTOR signaling pathways. Inhibition of the PI3K signaling pathway activation might reduce anti-inflammatory activity and boost the expression of the inflammatory cytokines, iNOS, IL-12, TNFα, and IL-6. This study indicated that Sema3A might be a feasible drug to regulate alternative macrophage activation in the inflammatory response and thus alleviate periodontitis.

15.
Proc Natl Acad Sci U S A ; 120(3): e2208348120, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36623202

RESUMO

As an important free energy source, the membrane voltage (Vm) regulates many essential physiological processes in bacteria. However, in comparison with eukaryotic cells, knowledge of bacterial electrophysiology is very limited. Here, we developed a set of novel genetically encoded bacterial Vm sensors which allow single-cell recording of bacterial Vm dynamics in live cells with high temporal resolution. Using these new sensors, we reveal the electrically "excitable" and "resting" states of bacterial cells dependent on their metabolic status. In the electrically excitable state, frequent hyperpolarization spikes in bacterial Vm are observed, which are regulated by Na+/K+ ratio of the medium and facilitate increased antibiotic tolerance. In the electrically resting state, bacterial Vm displays significant cell-to-cell heterogeneity and is linked to the cell fate after antibiotic treatment. Our findings demonstrate the potential of our newly developed voltage sensors to reveal the underpinning connections between bacterial Vm and antibiotic tolerance.


Assuntos
Antibacterianos , Potenciais da Membrana , Antibacterianos/farmacologia , Diferenciação Celular
16.
Neurosci Bull ; 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36629979

RESUMO

The anterior auditory field (AAF) is a core region of the auditory cortex and plays a vital role in discrimination tasks. However, the role of the AAF corticostriatal neurons in frequency discrimination remains unclear. Here, we used c-Fos staining, fiber photometry recording, and pharmacogenetic manipulation to investigate the function of the AAF corticostriatal neurons in a frequency discrimination task. c-Fos staining and fiber photometry recording revealed that the activity of AAF pyramidal neurons was significantly elevated during the frequency discrimination task. Pharmacogenetic inhibition of AAF pyramidal neurons significantly impaired frequency discrimination. In addition, histological results revealed that AAF pyramidal neurons send strong projections to the striatum. Moreover, pharmacogenetic suppression of the striatal projections from pyramidal neurons in the AAF significantly disrupted the frequency discrimination. Collectively, our findings show that AAF pyramidal neurons, particularly the AAF-striatum projections, play a crucial role in frequency discrimination behavior.

17.
Pest Manag Sci ; 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36606406

RESUMO

BACKGROUND: Haemaphysalis longicornis is an obligate hematophagous ectoparasite, which transmits various pathogens to humans, livestock and wild animals. Hexokinase (HK) is a key regulatory enzyme of the glycolytic pathway in the organisms. However, little is known about hexokinase and its functions in ticks. RESULTS: The open reading frame of the H. longicornis HK (HlHK) gene was 1425 bp and encoded a protein of 474 amino acids, containing conserved domains for glucose, glucose 6-phosphate, and adenosine triphosphate. The expression of HlHK gene was detected at different developmental stages and in different tissues of unfed female ticks. Enzyme-linked immunosorbent assay revealed that both HK protein- and DNA-based vaccines increased the antibody levels of the immunized animals. A vaccination trail on rabbits against H. longicornis infestation indicated that the rHlHK protein and HlHK DNA vaccines reduced the number of attached female ticks by 9% and 12%, egg mass weight by 36% and 34%, and egg hatching rate by 41% and 17%, respectively. Overall, protein vaccination conferred 65.6% protection against adult female ticks, whereas the DNA vaccine conferred 51.8% protection. CONCLUSION: This is the first report of the molecular characterization of the HK protein and sequencing of the HK gene from H. longicornis. Positive results from vaccination trials on rabbits of the recombinant HK protein and HK DNA suggest that these novel anti-tick vaccines potentially can be used as viable tick control tools for the management of the Asian longhorned tick. Additionally, inhibition of glucose metabolism may be a new strategy for tick control. © 2023 Society of Chemical Industry.

18.
Cell Biosci ; 13(1): 9, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639652

RESUMO

BACKGROUND: Vector-borne flaviviruses, including tick-borne encephalitis virus (TBEV), Zika virus (ZIKV), West Nile virus (WNV), yellow fever virus (YFV), dengue virus (DENV), and Japanese encephalitis virus (JEV), pose a growing threat to public health worldwide, and have evolved complex mechanisms to overcome host antiviral innate immunity. However, the underlying mechanisms of flavivirus structural proteins to evade host immune response remain elusive. RESULTS: We showed that TBEV structural protein, pre-membrane (prM) protein, could inhibit type I interferon (IFN-I) production. Mechanically, TBEV prM interacted with both MDA5 and MAVS and interfered with the formation of MDA5-MAVS complex, thereby impeding the nuclear translocation and dimerization of IRF3 to inhibit RLR antiviral signaling. ZIKV and WNV prM was also demonstrated to interact with both MDA5 and MAVS, while dengue virus serotype 2 (DENV2) and YFV prM associated only with MDA5 or MAVS to suppress IFN-I production. In contrast, JEV prM could not suppress IFN-I production. Overexpression of TBEV and ZIKV prM significantly promoted the replication of TBEV and Sendai virus. CONCLUSION: Our findings reveal the immune evasion mechanisms of flavivirus prM, which may contribute to understanding flavivirus pathogenicity, therapeutic intervention and vaccine development.

19.
J Refract Surg ; 39(1): 48-55, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36630430

RESUMO

PURPOSE: To investigate refractive prediction accuracy with the OA-2000 (Tomey), Anterion (Heidelberg Engineering), and IOLMaster 500 (Carl Zeiss Meditec AG) in patients with cataract. METHODS: Patients with cataract referred for phacoemulsification were enrolled and scanned with the OA-2000, Anterion, and IOLMaster 500 in random order. The success rate of axial length (AL) measurements per device was calculated and a chi-square test was used to identify the differences in acquisition rate between the three devices. The Bland-Altman method was used to appraise the agreement of biometric parameters between the three devices. Four different formulas (Barrett Universal II [BUII], Haigis, Holladay 1, and SRK/T) were included in the study. The parameters of refractive prediction accuracy comprised predictive error (PE), absolute PE (AE), and percentages of eyes with a PE within ±0.50, ±0.75, and ±1.00 diopters (D). RESULTS: The acquisition rates of AL measurements with the OA-2000 and Anterion were 97.35% and 94.70%, respectively (chi-square = 3.82, P > .05). A significantly lower acquisition rate of 84.82% was obtained with the IOLMaster 500 compared with the other two devices (P < .05). Bland-Altman analysis identified good agreement between the three biometers with narrow 95% limits of agreement for flat and steep keratometry (K1 and K2), anterior chamber depth (ACD), and AL. For PE, only the differences between the Anterion and IOLMaster 500 with the Barrett UII and Haigis formulas were statistically significant (P < .05). The three devices revealed no statistically significant differences in MAE, MedAE, and the proportion of eyes with a PE within ±0.50, ±0.75, and ±1.00 D (P > .05). CONCLUSIONS: The OA-2000 and Anterion showed a similarly higher acquisition rate of AL measurements than the IOLMaster 500 in patients with cataract. Good agreement for K1, K2, ACD, and AL was found between the three biometers. Regarding refractive prediction accuracy, the Anterion did not significantly outperform both the OA-2000 and IOLMaster 500. [J Refract Surg. 2023;39(1):48-55.].


Assuntos
Extração de Catarata , Catarata , Lentes Intraoculares , Dispositivos Ópticos , Facoemulsificação , Humanos , Refração Ocular , Catarata/diagnóstico , Facoemulsificação/métodos , Biometria/métodos , Óptica e Fotônica , Comprimento Axial do Olho , Estudos Retrospectivos
20.
Theranostics ; 13(2): 560-577, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36632235

RESUMO

Rationale: Chemotherapy is a common clinical strategy for cancer treatment. However, the accompanied cardiomyopathy renders cancer patients under risk of another life-threatening condition. Whereas Hippo pathway is known to play key roles in both cancerogenesis and heart disease, it remains unclear whether Hippo pathway activation mediates chemotherapy-induced cardiomyopathy. Methods and Results: In human breast cancer cells, doxorubicin (DOX) significantly induced upregulation of Hippo kinase Mst1, inhibitory phosphorylation of YAP, mitochondrial damage, reduced cell viability and increased apoptosis. Hippo pathway inactivation by Mst1-siRNA transfection effectively improved cell survival and mitigated mitochondrial damage and cell apoptosis. Another anti-cancer drug YAP inhibitor verteporfin also induced lower cancer cell viability, apoptosis and mitochondrial injury. Chronic treatment with DOX in vivo (4 mg/kg/week for 6 weeks) caused mitochondrial damage and dysfunction, oxidative stress and cardiac fibrosis, while acute DOX treatment (16 mg/kg single bolus) also induced myocardial oxidative stress and mitochondrial abnormalities. Chronic treatment with verteporfin (2 months) resulted in cardiomyopathy phenotypes comparable to that by chronic DOX regimen. In transgenic mice with cardiac overexpression of kinase-dead mutant Mst1 gene, these adverse cardiac effects of DOX were significantly attenuated relative to wild-type littermates. Conclusions: Anti-cancer action of both DOX and verteporfin is associated with Hippo pathway activation. Such action on cardiac Hippo pathway mediates mitochondrial damage and cardiomyopathy.


Assuntos
Cardiomiopatias , Neoplasias , Camundongos , Animais , Humanos , Via de Sinalização Hippo , Miócitos Cardíacos/metabolismo , Verteporfina/farmacologia , Verteporfina/uso terapêutico , Cardiomiopatias/induzido quimicamente , Miocárdio/metabolismo , Doxorrubicina/farmacologia , Neoplasias/tratamento farmacológico , Camundongos Transgênicos , Apoptose , Cardiotoxicidade/etiologia , Estresse Oxidativo
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