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1.
Meat Sci ; 183: 108663, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34481233

RESUMO

Carcinogens such as heterocyclic amine (HCA), produced during meat cooking, pose a risk of digestive and reproductive cancers in humans. Nevertheless, the exact mechanisms for HCA formation in meat and the control of HCA formation are not known. In this review, we provide an overview of the main cause of HCA formation in cooked meat, fundamental data on natural materials to inhibit HCA carcinogenicity, and methods to analyze HCA in cooked meat. Related past studies has shown that natural substances contain various components that act as antioxidants, and these antioxidants can prevent HCA and mutagenic factors. Free radicals and DNA adducts produced by HCA metabolism have carcinogenic properties. Antioxidants have been found to inhibit oxidative stress caused by free radicals and DNA adducts. Therefore, we can be hypothesized that various natural materials can inhibit HCA carcinogens and mutagens.

2.
BMC Geriatr ; 21(1): 524, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34600472

RESUMO

BACKGROUND: The Mini-Mental State Examination (MMSE) is the most widely used instrument to test cognitive functioning. The present study prospectively investigated the association between MMSE scores, MMSE domains, and all-cause mortality. METHODS: A total of 2134 participants aged 60 years or over, selected from one urban community-dwelling population in China, were enrolled in the study. The cognitive test was performed by use of the MMSE at baseline, and covariates were recorded simultaneously. Cox regression models were used for examining the cognitive function, expressed by different MMSE transformations, and all-cause mortality. After followed up for a median of 10.8 years (ranging from 1.0 to 11.3 years), loss to follow-up was 13.1% and 1854 individuals were finally included in the analyses. RESULTS: The subjects had the mean (SD) age of 71.01 (7.00) years, and 754 (40.67%) of them were women. Per point increase on MMSE scores was associated a 4% decreased risk of all-cause mortality [hazard ratio (HR): 0.96; 95%confidence interval (CI): 0.93-0.98]; compared to MMSE scores of ≥24, MMSE scores of < 24 was associated with a 43% increased risk of all-cause mortality (HR: 1.43; 95% CI: 1.05-1.95); compared to MMSE scores of 30, MMSE scores of 27-29 (HR: 1.27; 95% CI: 0.89-1.82), 24-26 (HR: 1.30; 95% CI: 0.86-1.99), and < 24 (HR: 1.79; 95% CI: 1.15-2.77) had a graded increase in risk of all-cause mortality (p for trend =0.003). Of MMSE domains, orientation to time (HR: 2.00; 95% CI: 1.29-3.11), attention and calculation (HR: 1.49; 95% CI: 1.16-1.92), recall (HR: 2.59; 95% CI: 1.22-5.47), and language (HR: 1.68; 95% CI: 1.25-2.26) were significantly associated with all-cause mortality in the unadjusted model; for one increase in the number of impaired MMSE domains, the unadjusted HR (95% CI) of mortality is 1.51 (1.38, 1.65), and the HR (95% CI) of mortality is 1.12 (1.01, 1.25) with full adjustment; compared to 0 and 1 impaired MMSE domains, the HRs of all-cause mortality associated with 2, 3, 4, and ≥ 5 impaired MMSE domains were 1.14 (95% CI: 0.84-1.54), 1.50 (95% CI: 0.98-2.28), 2.14 (95% CI: 1.12-4.09) and 2.29 (95% CI: 1.24-5.04), respectively, and a dose-dependent relationship was significant (p for trend =0.003). CONCLUSION: Cognitive impairment is associated with the increased risk of all-cause mortality in the Chinese elderly. Similarly, reduced MMSE scores, as well as impaired MMSE domains, are also associated with the increasing risk of all-cause mortality.

3.
Food Funct ; 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34609395

RESUMO

Changes in secretory immunoglobulin A (SIgA) coated bacteria from early to late pregnancy were associated with the development of gestational diabetes mellitus (GDM). SIgA coated beneficial gut bacteria, which are depleted in GDM, are potential probiotics for the prevention of GDM. We investigated blood biochemistry, chronic inflammation, mucosal barrier biomarkers and faecal SIgA coated microbiota in healthy early pregnancy (T1H, n = 50), late pregnancy (T3H, n = 30) and women with GDM (T3D, n = 27). The "leaky gut" markers, zonulin and lipopolysaccharide (LPS), significantly increased in T3D compared to the T3H group. The Shannon index of SIgA coated microbiota was elevated in late pregnancy compared to early pregnancy and was the highest in the T3D group (p < 0.001). The T3D group was enriched in SIgA coated Escherichia and Streptococcus and depleted in Lactobacillus and Bifidobacterium. Blood glucose (BG) positively correlated with zonulin (p < 0.001) and LPS (p < 0.05). Lactobacillus reuteri negatively correlated with BG (p < 0.05), zonulin (p < 0.05) and LPS (p < 0.01). Lactobacillus reuteri QS01 isolated from the feces of T1H significantly reduced LPS released by the gut microbiota of GDM individuals in vitro. In conclusion, GDM may be related to intestinal mucosal damage and inflammation-induced dysbiosis of SIgA coated microbiota. SIgA coated L. reuteri can reduce the level of LPS of GDM in vitro.

4.
Adv Healthc Mater ; : e2101407, 2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34601824

RESUMO

Prodrug nanoassemblies have emerged as a promising platform for the delivery of anticancer drugs. PEGylation is a "gold standard" to improve colloidal stability and pharmacokinetics of nanomedicines. However, the clinical application of PEG materials is challenged by in vivo oxidative degradation and immunogenicity. Rational design of advanced biomaterials for the surface modification of nanomedicines is the hot spot of research. Here, a zwitterionic sulfobetaine surfactant is constructed as a novel surface modifier to coassemble with 10-hydroxycamptothecin-linoleic acid conjugate, with the classical PEGylated material as control. Interestingly, both the type and ratio of surfactants have profound impacts on the molecular mechanisms of the assembly of prodrugs, thereby affecting the pharmaceutical properties. Compared with PEGylated spherical prodrug nanoassemblies, zwitterion-modified prodrug nanoassemblies have distinct rod shape and superhydrophilic surface, and exhibit potent antitumor activity due to the combination of multiple advantages in terms of colloidal stability, cellular uptake, and pharmacokinetics. The findings illustrate the crucial role of zwitterionic surfactants as the surface modifier in the determination of in vivo fate of the prodrug nanoassemblies, and pave the way for the development of advanced nanomedicines.

5.
Food Chem ; 372: 131213, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34638060

RESUMO

The metabolic fate of dietary compounds is closely related to their biological functions. Pterostilbene (PT) is a methylated stilbene found in many plant foods. Herein, we investigated gastrointestinal biotransformation and tissue distribution of PT in mice fed with 0.05% PT (w/w) for 5 weeks. PT and its major metabolites i.e. PT sulfate (PT-S), pinostilbene, pinostilbene sulfate, hydroxylated PT and hydroxylated PT sulfate were identified and quantified in the mucosa and content of the digestive tissues, blood, urine and vital organs. The results showed PT underwent demethylation, hydroxylation and conjugation in the small intestine, while the conjugated metabolites were largely deconjugated in the colon. Anaerobic fermentation with mouse cecal bacteria demonstrated the microbiota mediated deconjugation and demethylation of PT-S and PT, respectively. In conclusion, oral consumption of PT led to extensive biotransformation in mouse gastrointestinal tract and the metabolites of PT might play important roles in the bioactivity of PT.

6.
Acta Biomater ; 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34496282

RESUMO

Over 30,000 protein-protein interactions with pathological implications have been identified; yet, discovering and investigating drugs that target these specific interactions is greatly limited by the inability to monitor native protein-protein interactions (PPIs) efficiently. The two most frequently used tools to monitor PPIs, resonance-energy transfer (RET) assays and protein complementation assays (PCA), face significant limitations. RET assays have a narrow working range of 10 to 50 Å, while PCA require permanent attachment of a reporter probe to a protein of interest by chemical conjugation or genetic engineering. We developed a non-invasive assay platform to measure PPIs without modifications to the proteins of interest and is functional at a greater working range than RET assays. We demonstrate our approach by monitoring the EGFR-HER2 heterodimerization on relevant cell surfaces, utilizing various EGFR- and HER2-specific binders (e.g., Fab, DARPin, and VHH) fused with small fragments of a tri-part split-luciferase derived from NanoLuc®. Following independent binding of the binder fusions to their respective targets, the dimerization of EGFR and HER2 induces complementation of the luciferase fragments into a functional native structure, producing glow-type luminescence. We have confirmed the functionality of the platform to monitor EGFR-HER2 dimerization induction and inhibition. STATEMENT OF SIGNIFICANCE: We describe a platform technology for rapid monitoring of protein-protein interactions (PPIs). Our approach is uses a luciferase split into three parts - two short peptide "tags" and a large third fragment. Each of the short peptides can be fused to antibodies which bind to domains of a target antigens which orients the two tags and facilitates refolding of an active enzyme. To our knowledge this is the first example of a split-enzyme used to monitor PPIs without requiring any modification of the target proteins. We demonstrate our approach on the important PPI of HER2 and EGFR. Significantly, we quantify stimulation and inhibition of these partners, opening the possibility of using our approach to assess potential drugs without engineering cells.

7.
J Biol Chem ; 297(4): 101160, 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34480896

RESUMO

Pheromone receptors (PRs) recognize specific pheromone compounds to guide the behavioral outputs of insects, which are the most diverse group of animals on earth. The activation of PRs is known to couple to the calcium permeability of their coreceptor (Orco) or putatively with G proteins; however, the underlying mechanisms of this process are not yet fully understood. Moreover, whether this transverse seven transmembrane domain (7TM)-containing receptor is able to couple to arrestin, a common effector for many conventional 7TM receptors, is unknown. Herein, using the PR BmOR3 from the silk moth Bombyx mori and its coreceptor BmOrco as a template, we revealed that an agonist-induced conformational change of BmOR3 was transmitted to BmOrco through transmembrane segment 7 from both receptors, resulting in the activation of BmOrco. Key interactions, including an ionic lock and a hydrophobic zipper, are essential in mediating the functional coupling between BmOR3 and BmOrco. BmOR3 also selectively coupled with Gi proteins, which was dispensable for BmOrco coupling. Moreover, we demonstrated that trans-7TM BmOR3 recruited arrestin in an agonist-dependent manner, which indicates an important role for BmOR3-BmOrco complex formation in ionotropic functions. Collectively, our study identified the coupling of G protein and arrestin to a prototype trans-7TM PR, BmOR3, and provided important mechanistic insights into the coupling of active PRs to their downstream effectors, including coreceptors, G proteins, and arrestin.

8.
Proc Natl Acad Sci U S A ; 118(37)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34507982

RESUMO

Arrestins were initially identified for their role in homologous desensitization and internalization of G protein-coupled receptors. Receptor-bound arrestins also initiate signaling by interacting with other signaling proteins. Arrestins scaffold MAPK signaling cascades, MAPK kinase kinase (MAP3K), MAPK kinase (MAP2K), and MAPK. In particular, arrestins facilitate ERK1/2 activation by scaffolding ERK1/2 (MAPK), MEK1 (MAP2K), and Raf (MAPK3). However, the structural mechanism underlying this scaffolding remains unknown. Here, we investigated the mechanism of arrestin-2 scaffolding of cRaf, MEK1, and ERK2 using hydrogen/deuterium exchange-mass spectrometry, tryptophan-induced bimane fluorescence quenching, and NMR. We found that basal and active arrestin-2 interacted with cRaf, while only active arrestin-2 interacted with MEK1 and ERK2. The ATP binding status of MEK1 or ERK2 affected arrestin-2 binding; ATP-bound MEK1 interacted with arrestin-2, whereas only empty ERK2 bound arrestin-2. Analysis of the binding interfaces suggested that the relative positions of cRaf, MEK1, and ERK2 on arrestin-2 likely facilitate sequential phosphorylation in the signal transduction cascade.

9.
Mol Biol Evol ; 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34534352

RESUMO

Hydrothermal vents and hydrocarbon seeps in the deep ocean are rare oases fuelled by chemosynthesis. Biological communities inhabiting these ecosystems are often distributed in widely separated habitats, raising intriguing questions on how these organisms achieve connectivity and whether habitat types facilitate intraspecific divergence. The deep-sea patellogastropod limpet Bathyacmaea nipponica that colonises both vents and seeps across ∼2,400 km in the Northwest Pacific is a feasible model to answer these questions. We analysed 123 individuals from four vents and three seeps using a comprehensive method incorporating population genomics and physical ocean modelling. Genome survey sequencing and genotyping-by-sequencing resulted in 9,838 single-nucleotide polymorphisms (SNPs) for population genomic analyses. Genetic divergence and demographic analyses revealed four habitat-linked (i.e., three seep and one vent) genetic groups, with the vent genetic group established via the opportunistic invasion of a few limpet larvae from a nearby seep genetic group. TreeMix analysis uncovered three historical seep-to-vent migration events. ADMIXTURE and divMigrate analyses elucidated weak contemporary gene flow from a seep genetic group to the vent genetic group. Physical ocean modelling underlined the potential roles of seafloor topography and ocean currents in shaping the genetic connectivity, contemporary migration, and local hybridisation of these deep-sea limpets. Our study highlighted the power of integrating genomic and oceanographic approaches in deciphering the demography and diversification of deep-sea organisms. Given the increasing anthropogenic activities (e.g., mining and gas hydrate extraction) affecting the deep ocean, our results have implications for the conservation of deep-sea biodiversity and establishment of marine protected areas.

10.
Confl Health ; 15(1): 69, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535155

RESUMO

COVAX, the global initiative on COVID-19 vaccines, has set the target of achieving a COVID-19 vaccination coverage of up to 30% of the population of 135 countries in 2 years. Here, we argue that COVAX should anticipate important and unforeseen challenges with regard to sanctioned countries. For those, COVAX needs to provide a higher percentage of the vaccines. Otherwise, the problems of vaccination will linger, risking the advent of new variants and preventing an effective global response in reigning the pandemic under control.

11.
Adv Healthc Mater ; : e2100950, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34541825

RESUMO

Bacterial therapy, which targets the tumor site and aims at exerting an antitumor immune response, has displayed a great potential against malignant tumors. However, failure of the phase I clinical trial of Salmonella strain VNP20009 alone demonstrates that bacterial treatment alone can unsatisfy the requirements of high efficiency and biosafety. Herein, a strategy of both-in-one hybrid bacteria is proposed, wherein the chemotherapeutic drug doxorubicin (DOX) is integrated onto the surface of glucose dehydrogenase (GDH)-overexpressed non-pathogenic Escherichia coli (E. coli) strain, to potentiate the antitumor efficacy. Nicotinamide adenine dinucleotide phosphate (NADPH), which is produced by GDH from E. coli, promotes the generation of toxic reactive oxygen species (ROS) within the tumor, and ROS is then catalyzed by the DOX-activated NADPH oxidases. Importantly, the hybrid bacteria enhance stimulated systemic antitumor immune responses, thereby leading to effective tumor eradication. When this strategy is applied in four different tumor models, the hybrid bacteria significantly inhibited tumor metastasis, postsurgical regrowth, and primary/distal tumor relapse. The both-in-one ROS-immunity-boosted hybrid bacteria strategy provides knowledge for the rational design of bacteria-based synergistic cancer therapy.

12.
Ann Palliat Med ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34498475

RESUMO

BACKGROUND: We investigated the feasibility and safety of an exercise intervention in patients with metastatic solid cancer. METHODS: Patients scheduled to receive first-line chemotherapy for metastatic cancer with a life expectancy of ≥4 months, no brain metastases, and no high risk of fracture were recruited to participate in a 12-week, combined resistance and aerobic exercise program consisting of supervised, hospital-based (2×/week) and home-based training (3×/week) during palliative chemotherapy. Feasibility and safety of the exercise intervention were the primary outcomes. The secondary outcomes were skeletal muscle mass and strength, functional capacity, quality of life (QoL), and fatigue. RESULTS: Nineteen patients were enrolled in this pilot study. Five patients withdrew consent before the exercise intervention due to fear of exacerbating cancer-related symptoms (n=2), transportation issues (n=2), and unknown reasons (n=1). Ten patients (71.4%) completed the 12-week exercise program. Mean attendance rate of the supervised exercise sessions was 64.9% (range, 16.7-95.8%). No adverse events or skeletal complications occurred during the supervised exercise sessions. Among participants, there were no significant changes in muscle area at the third lumbar level (mean change=-0.7 cm2 , P=0.869) or appendicular skeletal muscle mass (mean change=0.1 kg, P=0.661). The overall QoL assessed using the Functional Assessment of Cancer Therapy-General significantly improved post-exercise interventions (P=0.037). There were significant improvements in the QoL subdomains of emotional well-being and physical, social, and cognitive functions. CONCLUSIONS: Exercise interventions are feasible and safe in patients with metastatic cancer. Exercise interventions can improve QoL and prevent skeletal muscle loss during palliative chemotherapy.

13.
Chin J Nat Med ; 19(9): 656-665, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34561076

RESUMO

The first-generation taxanes (including paclitaxel and docetaxel) are widely used for the treatment of various cancers in clinical settings. In the past decade, a series of new-generation taxanes have been developed which are effective in the inhibition of tumor resistance. However, intravenous (i.v.) infusion is still the only route of administration, and may result in serious adverse reactions with respect to the utilization of Cremophor EL or Tween-80 as solvent. Besides, the dosing schedule is also limited. Therefore, oral administration of taxanes is urgently needed to avoid the adverse reactionss and increase dosing frequency. In this review, we first outlined the discovery and development of taxane-based anticancer agents. Furthermore, we summarized the research progress on the oral formulations of taxanes and proposed some thoughts on the future development of oral taxane formulations.

14.
Int J Cardiol ; 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34563597

RESUMO

Immune-checkpoint inhibitors (ICIs), a unique antibody-based therapeutic strategy, have revolutionized the treatment landscape of solid and hematological cancers. Despite the proven benefits of ICIs, the cardiotoxicity from unspecific immune activation (uncommon but potentially fatal) is a continuing concern. Accumulating preclinical research has demonstrated that ICIs initiate inflammation in the myocardium, while clinically significant cardiotoxicity were reported in few patients receiving ICI therapy, probably due to the low incidence and unspecific symptoms. The subtle signs and symptoms (e.g., chest pain, dizziness, and dyspnea) were likely attributed to cancer and/or non-cardiac events by previous studies, thus limiting the understanding of the incidence, outcomes, risk factors, and management of ICI-related cardiotoxicity. The heterogeneous clinical presentation and complex diagnostic procedure further make it challenging to accurately identify ICI-related cardiac events in clinical trials. Therefore, ICI-related cardiotoxicity, whose incidence is probably underestimated, has not been well recognized. In this article, we provide an overview of potential mechanisms underlying ICI-related cardiotoxicity and review accumulating clinical evidence of ICI-related cardiotoxicity, with a focus on myocarditis. Moreover, we discuss possible strategies to manage ICI-related cardiotoxicity and highlight the importance of developing cardio-oncology.

15.
Eur J Med Chem ; 226: 113806, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34517305

RESUMO

Poor selectivity, potential systemic toxicity and drug resistance are the main challenges associated with chemotherapeutic drugs. MCT1 and MCT4 and LAT1 play vital roles in tumour metabolism and growth by taking up nutrients and are thus potential targets for tumour therapy. An increasing number of studies have shown the feasibility of including these transporters as components of tumour-targeting therapy. Here, we summarize the recent progress in MCT1-, MCT4-and LAT1-based therapeutic strategies. First, protein structures, expression, relationships with cancer, and substrate characteristics are introduced. Then, different drug targeting and delivery strategies using these proteins have been reviewed, including designing protein inhibitors, prodrugs and nanoparticles. Finally, a dual targeted strategy is discussed because these proteins exert a synergistic effect on tumour proliferation. This article concentrates on tumour treatments targeting MCT1, MCT4 and LAT1 and delivery techniques for improving the antitumour effect. These innovative tactics represent current state-of-the-art developments in transporter-based antitumour drugs.

16.
J Mater Chem B ; 9(39): 8321-8329, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34522945

RESUMO

Designing a coating material with efficient bactericidal property to cope with bacterial associated infections is highly desirable for metallic implants and devices. Here, we report phosphonate/quaternary ammonium copolymers, p(DEMMP-co-TMAEMA), as the new type of metal anchorable high-efficiency antibacterial coating. Seven p(DEMMP-co-TMAEMA) polymers with varied cationic components were precisely prepared via random radical polymerization. Copolymers were constructed on titanium alloy (TC4) substrates based on strong covalent bonding between the phosphonate group and metallic substrates through a one-step process as evidenced by XPS and water contact angle tests. A robust relationship between the composition of the copolymers and the bactericidal ability endowed to TC4 substrates was established. Results showed that the copolymer, with the pDEMMP content even as low as 6.3%, was able to anchor onto TC4 substrates. With the increase of cationic pTMAEMA content from 4.0 to 93.7% in the coating copolymer, the bactericidal ability endowed to the TC4 substrates was steadily increased from 39.4 to 98.8% for S. aureus and from 70.0 to 99.4% for E. coli after 8 h's of contacting. All p(DEMMP-co-TMAEMA) coating on TC4 substrates showed limited cytotoxicity to C2C12 cells. Notably, the phosphonate/quaternary amine copolymers can be easily constructed on diverse biomedical metals such as titanium (Ti), stainless steel (SS), and Ni/Cr alloys with significantly increased antibacterial performance, demonstrating the potency of the copolymer as the general high-efficiency antibacterial coating for diverse bio-metals.

17.
Int J Mol Sci ; 22(17)2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34502270

RESUMO

Implant topography affects early peri-implant bone healing by changing the osteoconduction rate in the surrounding biological environment. Implant surfaces have been designed to promote faster and stronger bone formation for rapid and stable prosthesis loading. Early peri-implant bone healing has been observed with a sandblasted, acid-etched implant that was chemically modified to be hydrophilic (cmSLA). The present study investigates whether early peri-implant bone healing extends to a rough surface implant with a high crystalline hydroxyapatite surface (TSV MP-1 HA). Three implants were randomly placed in porous trabecular bone within both medial femoral condyles of 10 sheep. Early peri-implant bone stability was measured at 3- and 6-weeks healing time following implant insertion. Results indicated a similar implant stability quotient between the implants at insertion and over time. The significant increase over time of reverse torque values with respect to insertion torque (p < 0.001) did not differ between the implants. However, the bone-to-implant contact of TSV MP-1 HA was significantly higher than that of cmSLA implants at 6 weeks (p < 0.01). These data validate previous findings of a hydrophilic implant surface and extend the observation of early osseointegration to a rough surface implant in porous trabecular bone.

18.
Vaccine ; 39(36): 5173-5186, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34353682

RESUMO

Zika virus (ZIKV) caused over two million human infections in more than 80 countries around 2015-2016. Current vaccines under development are mostly focused on inducing antibodies that despite capable of inhibiting the virus, may have the potential to trigger antibody dependent enhancement (ADE). T cell vaccines that do not induce antibodies targeting viral surface will unlikely cause ADE, but be capable of potentiating the effectiveness of an antibody-inducing vaccine. To develop such a protective T cell vaccine, we first examined the repertoire of antigen-specific T cells in immunocompetent mice that have been transiently infected by ZIKV. Through epitope mapping using 427 overlapping peptides spanning the entire length of ZIKV polyprotein, we discovered 27 immunodominant epitopes scattered throughout the virus on C, E, NS1-NS5 proteins. Among them, 8 were confirmed as CD4+ T cell epitopes, and 16 as CD8+ T cell epitopes, while 3 for both T cell subsets. From these 27 newly identified epitopes, the top 10 epitopes were selected to formulate three T cell vaccines comprised of either CD4+ T cell epitopes, or CD8+ T cell epitopes, or a mixture of both. Immunization with these T cell epitopes induced T cell-mediated cytotoxicity and cytokine production, and conferred varying degrees of protection against ZIKV challenge. Moreover, these new T cell vaccines also improved the protective efficacy of a neutralizing antibody-inducing recombinant E80 protein vaccine. Together, our results provided additional evidence in support of the protective role of ZIKV-specific CD4+ and CD8+ T cells, and laid foundation for future development of T cell vaccines for ZIKV.


Assuntos
Infecção por Zika virus , Zika virus , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Mapeamento de Epitopos , Epitopos de Linfócito T , Epitopos Imunodominantes , Camundongos , Vacinas Sintéticas , Infecção por Zika virus/prevenção & controle
19.
Plant Physiol Biochem ; 167: 309-320, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34392044

RESUMO

Photosynthesis is a fundamental biosynthetic process in plants that can enhance carbon absorption and increase crop productivity. Heat stress severely inhibits photosynthetic efficiency. Melatonin is a bio-stimulator capable of regulating diverse abiotic stress tolerances. However, the underlying mechanisms of melatonin-mediated photosynthesis in plants exposed to heat stress largely remain elucidated. Our results revealed that melatonin treatment (100 µM) in tomato seedlings increased the endogenous melatonin levels and photosynthetic pigment content along with upregulated of their biosynthesis gene expression under high-temperature stress (42 °C for 24 h), whereas heat stress significantly decreased the values of gas exchange parameters. Under heat stress, melatonin boosted CO2 assimilation, i.e., Vc,max (maximum rate of ribulose-1,5-bisphosphate carboxylase, Rubisco), and Jmax (electron transport of Rubisco generation) and also enhanced the Rubisco and FBPase activities, which resulted in upregulated photosynthetic related gene expression. In addition, heat stress greatly reduced the photochemical chemistry of photosystem II (PSII) and photosystem I (PSI), particularly the maximum quantum efficiency of PSII (Fv/Fm) and PSI (Pm). Conversely, melatonin supplementation increased the chlorophyll a fluorescence parameters led to amplifying the electron transport efficiency. Moreover, heat stress decreased the actual PSII efficiency (ΦPSII), electron transport rate (ETR) and photochemical quenching coefficient (qP), while increasing nonphotochemical quenching (NPQ); however, melatonin reversed these values, which helps to fostering the dissipation of excess excitation energy. Taken together, our results provide a concrete insight into the efficacy of melatonin-mediated photosynthesis performance in a high-temperature regime.

20.
Eur J Cancer ; 157: 21-30, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34464782

RESUMO

BACKGROUND: The efficacy of modified FOLFIRINOX (mFOLFIRINOX) as a second-line chemotherapy treatment for metastatic pancreatic adenocarcinoma (mPAC), remains unclear. This multi-center randomised phase III trial aimed to elucidate the efficacy of mFOLFIRINOX as a second-line chemotherapy treatment for mPAC patients with good performance status. PATIENTS AND METHODS: Eighty mPAC patients (age, 19-75 years) refractory to first-line gemcitabine-based chemotherapy were randomly selected to receive mFOLFIRINOX or S-1. mFOLFIRINOX comprised oxaliplatin (65 mg/m2), irinotecan (135 mg/m2), and leucovorin (400 mg/m2) on day 1 and continuous 5-FU infusion (1000 mg/m2) over 24 h on days 1-2 every 2 weeks. S-1 comprised body surface area-dependent oral S-1, divided into two doses per day on days 1-28 every 6 weeks. RESULTS: Overall survival was the primary endpoint. The objective response and disease control rates were higher in the mFOLFIRINOX than in the S-1 group (15% versus 2%; p = .04 and 67% versus 37%; p = .007). The median progression-free survival rates were 5.2 and 2.2 months in the mFOLFIRINOX and S-1 groups, respectively (adjusted hazard ratio [HR]: .4; 95% confidence interval [CI]: .2-.6; p < .001). The median overall survival rates were 9.2 and 4.9 months in the mFOLFIRINOX and S-1 groups, respectively (adjusted HR: .4; 95% CI: .2-.7; p = .002). Grade 3-4 adverse events occurred in 56% and 17% of the patients in the mFOLFIRINOX and S-1 groups, respectively (p < .001). CONCLUSION: Administration of mFOLFIRINOX as a second-line chemotherapy treatment for mPAC patients refractory to gemcitabine-based chemotherapy resulted in increased survival rates than S-1 treatment alone.

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