Background:Scientific evidence to guide clinicians on the use of different antiseizure drugs in combination therapy is either very limited or lacking.In this study,the impact of lacosamide and perampanel alone and in ...Background:Scientific evidence to guide clinicians on the use of different antiseizure drugs in combination therapy is either very limited or lacking.In this study,the impact of lacosamide and perampanel alone and in combination was tested in corneal kindling model in mice,which is a cost-effective mechanism for screening of antiseizure drugs.Methods:The impact of lacosamide(5 mg/kg)and perampanel(0.125 mg/kg)alone and their combination was tested in corneal kindling process(3-mA current for 3 s applied twice daily for consecutive 12 days)in male BALB/c mice.Post-kindling,mice were subjected to a battery of behavioral tests assessing anxiety,memory,and depression-like behaviors.Brain tissues were then harvested for analysis of oxidative stress biomarkers.Results:Our results showed that the combination therapy of lacosamide and perampanel was more effective in reducing seizure progression than monotherapy of these drugs.Animals treated with combination therapy showed significant behavioral improvements,as reduced anxiety and depression were noticed,and their cognitive abilities were notably better compared to animals of all other groups.Moreover,biochemical assays of isolated brains from combination-treated group revealed lesser amount of oxidative stress.In addition,outcomes of dual regime were comparable to the phenytoin in seizure control but showed superior benefits in mitigation of kindling-prompted behavioral dysfunction and oxidative stress.Conclusions:This study suggests that the lacosamide and perampanel combination therapy worked noticeably better in halting the corneal kindling process in mice and improved the epilepsy-associated psychiatric disorders that might be due to antioxidant effects of both drugs.展开更多
Background:Besides seizures,a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy,which further debilitates their quality of life.This study provides an in-depth characte...Background:Besides seizures,a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy,which further debilitates their quality of life.This study provides an in-depth characterization of the impact of brivaracetam and rufinamide individually and in combination at 10 and 20 mg/kg doses,respec-tively,on corneal kindling-induced generalized seizures and behavioral alterations.Furthermore,observed convulsive frequency and behavioral changes were corre-lated to post-kindling-induced changes in the activity of markers of oxidative stress.Methods:Adult C57BL/6 mice were kindled via twice-daily transcorneal 50-Hz elec-trical stimulations(3 mA)for 3 s for 12 days until animals reached a fully kindled state.After the kindling procedure,animals were tested using a set of behavioral tests,and neurochemical alterations were assessed.Results:Corneal-kindled animals exhibited intense generalized convulsions,altered behavioral phenotypes typified by positive symptoms(hyperlocomotion),negative symptoms(anxiety and anhedonia),and deficits in semantic and working memory.BRV 10+RFM 20 dual regime increased convulsive threshold and propensity toward the start of stage 4–5 seizures and improved phenotypical deficits,that is,anxiety,depression,and memory impairments.Moreover,this combination therapy mitigated kindling-induced redox impairments as evidenced by reduced malondialdehyde and acetylcholinesterase levels and increased glutathione antioxidant activity in the brain of animals subjected to repetitive brain insult.Conclusion:Based on our outcomes,this dual therapy provides supporting evidence in alleviating epilepsy-induced neurobehavioral comorbidities and changes in redox homeostasis.展开更多
Several lines of evidence have established that proliferation and differentiation of neural stem cells into neurons within the sub-granular zone of the dentate gyrus,a process named adult hippocampal neurogenesis,cont...Several lines of evidence have established that proliferation and differentiation of neural stem cells into neurons within the sub-granular zone of the dentate gyrus,a process named adult hippocampal neurogenesis,contribute to maintaining healthy cognitive functions throughout life.The rate of adult hippocampal neurogenesis decreases with aging and a premature impairment of adult hippocampal neurogenesis has been observed both in animal models of Alzheimer’s disease and human post-mortem tissues.The causal relationship between adult hippocampal neurogenesis and the development of Alzheimer’s disease pathology has,however,not been established.This is partly due to the limitation of recapitulating the development of Alzheimer’s disease pathology in rodent models and the lack of translatable biomarkers to identify tractable targets in humans.While it is tempting to postulate that adult hippocampal neurogenesis could be leveraged to improve cognitive deficits in Alzheimer’s disease,consensual results have yet to be reached to fully explore this hypothesis.In this review,we discuss how the recent progress in identifying molecular pathways in adult hippocampal neurogenesis provides a good framework to initiate strategies for drug-based intervention in neurodegenerative diseases,especially in Alzheimer’s disease.We outline how discrepancies in pre-clinical disease models and experimental methodology have resulted in contradictory findings and propose a shift towards using more translatable approaches to model neurogenesis in Alzheimer’s disease.In particular,we review how exploring novel experimental paradigms including the use of human induced pluripotent stem cells and more complex cell culture systems,as well as standardizing protocols used to investigate evidence of neurogenesis in human tissues,could deliver deeper mechanistic insights that would kick-start innovative drug discovery efforts to promote healthy aging and cellular rejuvenation.展开更多
The omega-3 fatty acid (n-3 FA) content of broiler tissues can be increased through dietary supplementation of hens with n-3 FA-rich microalgae. The aim of this study was to evaluate the effect of three different diet...The omega-3 fatty acid (n-3 FA) content of broiler tissues can be increased through dietary supplementation of hens with n-3 FA-rich microalgae. The aim of this study was to evaluate the effect of three different dietary inclusion levels of a docosahexaenoic acid (DHA)-rich microalgae (AURA) on broiler performance and the enrichment of tissues with n-3 FA. The randomized study was conducted using 352 birds, housed in 32 pens with 11 birds per pen. Pens were randomly assigned to one of four treatments, with each treatment replicated 8 times. The treatments included one unsupplemented control (0%) and three wheat-soya based experimental diets supplemented with AURA at a level of 0.5%, 1.5% and 2.5% for the starter, grower and finisher periods. Birds were weighed on days 0, 10, 24, 35 and 41, and feed intake was recorded per pen. On day 41, five birds per treatment were euthanized and individually weighed. Thigh muscle, breast muscle, liver, kidney and skin samples were taken post-mortem, freeze dried and DHA content quantified, following fat extraction and methylation, by GC-FID (AOAC 996.06 method). Performance and tissue data were analyzed by ANOVA with Dunnett’s (2-sided) post-hoc test to determine the differences between the mean values for each treatment. Dietary supplementation with AURA had no effect on body weight or feed intake during any period of the study. For thigh muscle, kidney and skin the DHA increased linearly (P < 0.05) with increasing level of dietary AURA, whilst there was a quadratic response in uptake of DHA in breast muscle and liver. The study demonstrated the potential of efficiently enriching broiler meat and organs with DHA by feeding AURA.展开更多
Objective:To evaluate antimicrobial and antioxidant properties of saline extract from Tithonia diversifolia leaves by phytochemical bioprospecting,and investigate its safety against animal cells.Methods:The saline ext...Objective:To evaluate antimicrobial and antioxidant properties of saline extract from Tithonia diversifolia leaves by phytochemical bioprospecting,and investigate its safety against animal cells.Methods:The saline extract was prepared,with NaCl(0.15 M),by constant stirring of the dried and pulverized leaves,followed by volume reduction by lyophilization.The extract was phytochemical characterized using ultra-performance liquid chromatography,and total phenol and flavonoid analysis also was performed.The antioxidant capacity was determined through DPPH*radical,the antimicrobial property was evaluated against standard bacteria and fungi,and the viability assays were performed against mice splenocytes.Results:Fifteen compounds were identified belonging to two main classes terpenoids and phenolics.The extract showed 22.185 mg GAE/g of total phenolic compounds and 3.220 mg QE/g of flavonoid.Moreover,extract showed higher antioxidant ability similar to butylated hydroxytoluene a standard molecule[(3.042±0.019)mg AAE/g and(4.12±0.10)mg AAE/g to saline extract and butylated hydroxytoluene,respectively].The antimicrobial assays demonstrated that the extract had a significant antifungal potential against Candida species and could be used with safety against mice splenocytes,in concentrations lower than 50μg/mL,promoting higher proliferation in these cells.Conclusions:Saline extract from Tithonia diversifolia leaves presents potential antioxidant,antifungal properties and induces immunostimulation in mice splenocytes.展开更多
Objective: To evaluate the structural and chemical composition of plant and the antioxidant and antimicrobial activities promoted by hexanic, ethanolic and ethyl acetate fractions obtained from leaves of Conocarpus er...Objective: To evaluate the structural and chemical composition of plant and the antioxidant and antimicrobial activities promoted by hexanic, ethanolic and ethyl acetate fractions obtained from leaves of Conocarpus erectus.Methods: Organic fractions were characterized through UPLC-MS and GC-MS.Antioxidant potential was performed through DPPH and molybdenum phosphate techniques.Antibacterial and antifungal assays were performed in accordance with Clinical and Laboratory Standards Institute protocols.Results: The obtained biomass of Conocarpus erectus leaves showed the high presence of glucose(0.45 g/L), cellulose(28.69%), Na(55.126 μg/L) and K(31.163 μg/L).We identified seven compounds in the hexanic and ethyl acetate fractions, and eight compounds in ethanolic fraction.Moreover, phenolic compounds are prevalent in all organic fractions with values of(10.04 ± 0.24),(221.26 ± 1.84),(340.53 ± 0.84) mg/g GAE to hexanic, ethyl acetate and ethanolic fraction, respectively.Antioxidant results showed a high potential in ethyl acetate fraction(71.82 ± 6.87)% and(10.89 ± 0.05)% in DPPH and molybdenum phosphate techniques, respectively.The ethanolic fraction showed moderate bacteriostatic and bactericidal activity against Staphylococcus aureus and presented a high fungistatic potential for all Candida species tested.Conclusions: Organic fractions obtained from leaves of Conocarpus erectus present antimicrobial and antioxidant properties, and these findings contribute to scientific information for the effectiveness on use of this plant in the development of a phytotherapic compound.展开更多
Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation,repair and regeneration.Through cell fusion somatic cells undergo rapid nuclear reprogramming and e...Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation,repair and regeneration.Through cell fusion somatic cells undergo rapid nuclear reprogramming and epigenetic modifications to form hybrid cells with new genetic and phenotypic properties at a rate exceeding that achievable by random mutations.Factors that stimulate cell fusion are inflammation and hypoxia.Fusion of cancer cells with non-neoplastic cells facilitates several malignancy-related cell phenotypes,e.g.,reprogramming of somatic cell into induced pluripotent stem cells and epithelial to mesenchymal transition.There is now considerable in vitro,in vivo and clinical evidence that fusion of cancer cells with motile leucocytes such as macrophages plays a major role in cancer metastasis.Of the many changes in cancer cells after hybridizing with leucocytes,it is notable that hybrids acquire resistance to chemo-and radiation therapy.One phenomenon that has been largely overlooked yet plays a role in these processes is polyploidization.Regardless of the mechanism of polyploid cell formation,it happens in response to genotoxic stresses and enhances a cancer cell’s ability to survive.Here we summarize the recent progress in research of cell fusion and with a focus on an important role for polyploid cells in cancer metastasis.In addition,we discuss the clinical evidence and the importance of cell fusion and polyploidization in solid tumors.展开更多
Objective: To evaluate the antiplasmodial activity of aqueous-methanolic plant extracts of nine plant species selected, based on ethnobotanical data. Methods: Based on ethnobotanical database, the selected plants were...Objective: To evaluate the antiplasmodial activity of aqueous-methanolic plant extracts of nine plant species selected, based on ethnobotanical data. Methods: Based on ethnobotanical database, the selected plants were tested for their antiplasmodial activity against chloroquinesensitive(3 D7) strain of Plasmodium falciparum. Qualitative tests and high performance thin layer chromatography analysis were carried out to explore the phytocomponents present in the plant extracts. 1,1-diphenyl-2-picrylhydrazyl antioxidant activity was also determined to check the antioxidant activity of the plant extracts. Results: Moringa oleifera(IC_(50): 3.906 μg/mL),Acalypha indica(IC_(50): 3.906 μg/mL), Hyptis suaveolens(IC_(50): 3.906 μg/mL), Mangifera indica(IC_(50): 4.150 μg/mL) and Averrhoa bilimbi(IC_(50): 4.881 μg/mL) showed very good antiplasmodial activity. Conclusions: Crude extracts of Mangifera indica and Hyptis suaveolens demonstrated the most efficacious antimalarial activity. A bioassay-guided fractionation of these extracts to identify the lead compound is proved to be useful. The results validate the traditional use of the selected plants as antimalarials.展开更多
Genetic diversity evaluation of mutant lines is essential to facilitate their conservation and utility in breeding programs. Characterization of plant genotypes using morphological markers has limitations which make t...Genetic diversity evaluation of mutant lines is essential to facilitate their conservation and utility in breeding programs. Characterization of plant genotypes using morphological markers has limitations which make the procedure inefficient. Application of molecular tools for characterization and diversity assessment has been found useful to complement phenotypic evaluation of plant population. Therefore genetic diversity of some cowpea mutant lines was studied using simple sequence repeats (SSR) markers. DNA barcoding marker, ribulose-1,5-bisphosphate carboxylase(rbcL) of the chloroplast DNA (cpDNA) was also used for characterization and identification of the mutants to species level. The mean polymorphic information content (0.51) obtained from the microsatellites showed high polymorphism in accessing wide genetic diversity among the mutants and their parents. Dendrogram generated revealed 8 groups with most mutants clustered separately from their parents. Sequence analysis revealed insertions/deletions (InDels) and base substitutions as the two main classes of mutations induced in the plastid DNA of the mutants studied. The nucleotide frequencies were 26.95% (A), 34.43% (T), 24.09% (C) and 14.53% (G). A total of 61.38% AT rich region was identified, while GC rich region was found to be 38.62%. Highest rate of mutations were observed in region 3 - 4 indicating that the region is less conserved in cowpea rbcL gene. The present study proved that SSR markers are useful for the genetic diversity assessment of cowpea mutants. It also proved the efficiency of rbcL markers in mutants’ identification. The results indicate that the mutants are valuable genetic resources that have been developed to widen cowpea genetic base.展开更多
This paper describes the synthesis of peptide fragments for use in a new type of combinatorial discovery technology, in which the building blocks are brought together by non-covalent interactions, rather than direct c...This paper describes the synthesis of peptide fragments for use in a new type of combinatorial discovery technology, in which the building blocks are brought together by non-covalent interactions, rather than direct chemical bonding. The building blocks of interest—in this case different amino acids—are converted to amphiphiles by attachment to lipid tails. The amphiphiles, when mixed together in aqueous phase, are designed so that they aggregate spontaneously to form micelles. The building blocks form the headgroups of each of the amphiphiles, and these headgroups cover the surface of the micelle in a dynamic close-packed fluid mosaic array. These building blocks come together so closely that two- or three-dimensional structures are created on the surface of the micelles, and these can be screened in biological assays to find out which combination of building blocks is able to elicit a biological response. Lipopeptides consisting of two residues of lipoamino acid and other amino acids moieties have been designed, synthesized, characterized and the ability of these constructs to form supra-molecular assemblies is demonstrated.展开更多
Nanomaterial-based drug delivery systems are susceptible to premature drug leakage and systemic toxicity due to lack of specific targeting,and live-cell drug delivery is also prone to be restricted by drug carrier-cel...Nanomaterial-based drug delivery systems are susceptible to premature drug leakage and systemic toxicity due to lack of specific targeting,and live-cell drug delivery is also prone to be restricted by drug carrier-cellinteractions.Here,a method is established to adsorb drug-loaded nanomaterials externally to the live cells,which reduces cytotoxicity caused by drug uptake and improves the bioactivity of the carrier cells and drug release at the lesion site.It was found that polyphenols act like"doublesided tape"to bridge metal-organic framework(MOF)nanoparticles with live macrophages(Mop),attaching MOFs to the Mp surface and minimizing intracellular uptake,with no negative effect on cell proliferation.On this basis,a"macrophage missile"with peroxymonosulfate(PMS)-loaded MOF nanoparticles on the cell surface was constructed.As a"propellant",the Mo,in which bioactivity is preserved,can selectively identify and target tumor cells,precisely bringing nanomedicines to the lesion.MOF nanoparticles are used to load and catalyze PMS,which acts as an exogenous source of reactive oxygen species,showing higher efficacy and lower toxicity in an oxygen-independent manner.The primary study results demonstrate that this innovative combination of biology and nanomaterials remarkably enhances tumor targeting and therapeutic efficacy while reducing systemic side effects.This approach is expected to provide a more effective and safer treatment for lung cancer and holds promise for broader applications in other cancer therapies.展开更多
Hydrogel-based patches have demonstrated their values in diabetic wounds repair,particularly those intelligent dressings with continuous repair promoting and monitoring capabilities.Here,we propose a type of dual phys...Hydrogel-based patches have demonstrated their values in diabetic wounds repair,particularly those intelligent dressings with continuous repair promoting and monitoring capabilities.Here,we propose a type of dual physiological responsive structural color particles for wound repair.The particles are composed of a hyaluronic acid methacryloyl(HAMA)-sodium alginate(Alg)inverse opal scaffold,filled with oxidized dextran(ODex)/quaternized chitosan(QCS)hydrogel.The photo-polymerized HAMA and ionically cross-linked Ca-Alg constitute to the dual-network hydrogel with stable structural color.Furthermore,the ODex/QCS hydrogel,combined with glucose oxidase(GOX),exhibits pH/glucose dual responsiveness.Moreover,antimmicrobial peptide(AMP)plus vascular endothelial growth factor(VEGF)are comprised within the GOX-doped ODex/QCS hydrogel.In the high-glucose wound environment,GOX catalyzes glucose to generate acidic products,triggering rapid release of AMP and VEGF.Importantly,this process also leads to structural color changes of the particles,offering significant potential for wound monitoring.It has been demonstrated that such particles greatly promote the healing progress of diabetic wound in vivo.These results indicate that the present dual responsive particles would find valuable applications in diabetic wounds repair and the associated areas.展开更多
Microneedles have demonstrated valuable applications in diabetic wound management.Many endeavors are devoted to developing microneedles with well-designed structures and enhanced functions.Herein,we present an elabora...Microneedles have demonstrated valuable applications in diabetic wound management.Many endeavors are devoted to developing microneedles with well-designed structures and enhanced functions.Herein,we present an elaborate microneedle patch with breathability for wound healing by a multi-step replication method.The microneedle patch consists of a breathable porous supporting substrate and core-shell tips involving poly(vinyl alcohol)shells loaded with antimicrobial peptides(PVA@AMPs shell)and crosslinked Gelma cores encapsulated with exosomes(Gelma@exo core).The PVA was crosslinked with a ROS-responsive linker,which results in degradation of the microneedle shell in the inflammatory microenvironment,thus inducing the release of loaded AMPs to inhibit bacteria.Further,the exosomes continuously release from the exposed Gelma@exo core,promoting tissue regeneration and regulating the immune response.Besides,the high porosity of the supporting substrate makes the microneedle patches more suitable for chronic wounds.Based on these features,it was demonstrated that the microneedle patch exhibits desirable performance in in vivo animal tests.Thus,we believe that the proposed microneedle patches have remarkable potential in wound healing and related fields.展开更多
Long-term exposure to ultraviolet radiation compromises skin structural integrity and results in disruption of normal physiological functions.Stem cells have gained attention in anti-photoaging,while controlling the t...Long-term exposure to ultraviolet radiation compromises skin structural integrity and results in disruption of normal physiological functions.Stem cells have gained attention in anti-photoaging,while controlling the tissue mechanical microenvironment of cell delivery sites is crucial for regulating cell fate and achieving optimal therapeutic performances.Here,we introduce a mechanically regulated human recombinant collagen(RHC)microcarrier generated through microfluidics,which is capable of modulating stem cell differentiation to treat photoaged skin.By controlling the cross-linking parameters,the mechanical properties of microcarriers could precisely tuned to optimize the stem cell differentiation.The microcarriers are surface functionalized with fibronectin(Fn)-platelet derived growth factor-BB(PDGF-BB)to facilitate adipose derived mesenchymal stem cells(Ad-MSCs)loading.In in vivo experiments,subcutaneous injection of stem cell loaded RHC microcarriers significantly reduced skin wrinkles after ultraviolet-injury,effectively promoted collagen synthesis,and increased vascular density.These encouraging results indicate that the present mechanically regulated microcarriers have great potential to deliver stem cells and regulate their differentiation for anti-photoaging treatments.展开更多
Luminescent nanoparticles(LNPs)have emerged as a promising approach for enhanced cell labelling and disease diagnosis by leveraging their unique photophysical and surface characteristics.Advanced generations of LNPs,s...Luminescent nanoparticles(LNPs)have emerged as a promising approach for enhanced cell labelling and disease diagnosis by leveraging their unique photophysical and surface characteristics.Advanced generations of LNPs,such as quantum dots,dye-loaded nanoparticles and up-converting nanoparticles,exhibit distinct properties and advantages tailored for specialised applications.Consequently,there is a growing focus and demand to develop organelle-specific LNPs to identify,treat and elucidate disease mechanisms.The endoplasmic reticulum(ER)represents one such organelle,playing crucial roles in protein synthesis and modification,calcium homeostasis,lipid trafficking,and regulation of cellular stress.The unfolded protein response,regulated by ER stress,is a clinically significant pathway within the ER,implicated in cellular dysfunction and disease.The growing understanding of ER stress and the unfolded protein response has led to a rapid emergence of endoplasmic reticulum-targeting LNPs(ERLNPs)for precise intracellular diagnosis and therapy.This review discusses current advances and design principles of ERLNPs,highlights current achievements and applications,and discusses the challenges and interdisciplinarity needed for future development.展开更多
The development of tumor drug microcarriers has attracted considerable interest due to their distinctive therapeutic performances.Current attempts tend to elab-orate on the micro/nano-structure design of the microcarr...The development of tumor drug microcarriers has attracted considerable interest due to their distinctive therapeutic performances.Current attempts tend to elab-orate on the micro/nano-structure design of the microcarriers to achieve multiple drug delivery and spatiotemporal responsive features.Here,the desired hydrogel microspheres are presented with spatiotemporal responsiveness for the treatment of gastric cancer.The microspheres are generated based on inverse opals,their skele-ton is fabricated by biofriendly hyaluronic acid methacrylate(HAMA)and gelatin methacrylate(GelMA),and is thenfilled with a phase-changing hydrogel composed offish gelatin and agarose.Besides,the incorporated black phosphorus quantum dots(BPQDs)within thefilling hydrogel endow the microspheres with outstanding pho-tothermal responsiveness.Two antitumor drugs,sorafenib(SOR)and doxorubicin(DOX),are loaded in the skeleton andfilling hydrogel,respectively.It is found that the drugs show different release profiles upon near-infrared(NIR)irradiation,which exerts distinct performances in a controlled manner.Through both in vitro and in vivo experiments,it is demonstrated that such microspheres can significantly reduce tumor cell viability and enhance the efficiency in treating gastric cancer,indicating a promising stratagem in thefield of drug delivery and tumor therapy.展开更多
Bladder cancer is one of the concerning malignancies worldwide,which is lacking effective targeted therapy.Gene therapy is a potential approach for bladder cancer treatment.While,a safe and effective targeted gene del...Bladder cancer is one of the concerning malignancies worldwide,which is lacking effective targeted therapy.Gene therapy is a potential approach for bladder cancer treatment.While,a safe and effective targeted gene delivery system is urgently needed for prompting the bladder cancer treatment in vivo.In this study,we confirmed that the bladder cancer had CD44 overexpression and small interfering RNAs(siRNA)with high interfere to Bcl2 oncogene were designed and screened.Then hyaluronic acid dialdehyde(HAD)was prepared in an ethanol-water mixture and covalently conjugated to the chitosan nanoparticles(CS-HAD NPs)to achieve CD44 targeted siRNA delivery.The in vitro and in vivo evaluations indicated that the siRNA-loaded CS-HAD NPs(siRNA@CS-HAD NPs)were approximately 100 nm in size,with improved stability,high siRNA encapsulation efficiency and low cytotoxicity.CS-HAD NPs could target to CD44 receptor and deliver the therapeutic siRNA into T24 bladder cancer cells through a ligand-receptor-mediated targeting mechanism and had a specific accumulation capacity in vivo to interfere the targeted oncogene Bcl2 in bladder cancer.Overall,a CD44 targeted gene delivery system based on natural macromolecules was developed for effective bladder cancer treatment,which could be more conducive to clinical application due to its simple preparation and high biological safety.展开更多
Here, we evaluate the contribution of two major biological processes--DNA replication and transcription--to mutation rate variation in human genomes. Based on analysis of the public human tissue transcriptomics data, ...Here, we evaluate the contribution of two major biological processes--DNA replication and transcription--to mutation rate variation in human genomes. Based on analysis of the public human tissue transcriptomics data, high-resolution replicating map of Hela cells and dbSNP data, we present significant correlations between expres- sion breadth, replication time in local regions and SNP density. SNP density of tissue-specific （TS） genes is sig- nificantly higher than that of housekeeping （HK） genes. TS genes tend to locate in late-replicating genomic re- gions and genes in such regions have a higher SNP density compared to those in early-replication regions. In addi- tion, SNP density is found to be positively correlated with expression level among HK genes. We conclude that the process of DNA replication generates stronger mutational pressure than transcription-associated biological processes do, resulting in an increase of mutation rate in TS genes while having weaker effects on HK genes. In contrast, transcription-associated processes are mainly responsible for the accumulation of mutations in highly-expressed HK genes.展开更多
Biofunctionalization of artificial nerve implants by incorporation of specific bioactive factors has greatly enhanced the success of grafting procedures for peripheral nerve regeneration.However,most studies on novel ...Biofunctionalization of artificial nerve implants by incorporation of specific bioactive factors has greatly enhanced the success of grafting procedures for peripheral nerve regeneration.However,most studies on novel biofunctionalized implants have emphasized the promotion of neuronal and axonal repair over vascularization,a process critical for long-term functional restoration.We constructed a dual-biofunctionalized chitosan/collagen composite scaffold with Ile-Lys-Val-Ala-Val(IKVAV)and vascular endothelial growth factor(VEGF)by combining solution blending,in situ lyophilization,and surface biomodification.Immobilization of VEGF and IKVAV on the scaffolds was confirmed both qualitatively by staining and quantitatively by ELISA.Various single-and dual-biofunctionalized scaffolds were compared for the promotion of endothelial cell(EC)and Schwann cell(SC)proliferation as well as the induction of angiogenic and neuroregeneration-associated genes by these cells in culture.The efficacy of these scaffolds for vascularization was evaluated by implantation in chicken embryos,while functional repair capacity in vivo was assessed in rats subjected to a 10mm sciatic nerve injury.Dual-biofunctionalized scaffolds supported robust EC and SC proliferation and upregulated the expression levels of multiple genes and proteins related to neuroregeneration and vascularization.Dual-biofunctionalized scaffolds demonstrated superior vascularization induction in embryos and greater promotion of vascularization,myelination,and functional recovery in rats.These findings support the clinical potential of VEGF/IKVAV dual-biofunctionalized chitosan/collagen composite scaffolds for facilitating peripheral nerve regeneration,making it an attractive candidate for repairing critical nerve defect.The study may provide a critical experimental and theoretical basis for the development and design of new artificial nerve implants with excellent biological performance.展开更多
Therapeutic oligonucleotides(TOs)represent one of the most promising drug candidates in the targeted cancer treatment due to their high specificity and capability of modulating cellular pathways that are not readily d...Therapeutic oligonucleotides(TOs)represent one of the most promising drug candidates in the targeted cancer treatment due to their high specificity and capability of modulating cellular pathways that are not readily druggable.However,efficiently delivering of TOs to cancer cellular targets is still the biggest challenge in promoting their clinical translations.Emerging as a significant drug delivery vector,nanoparticles(NPs)can not only protect TOs from nuclease degradation and enhance their tumor accumulation,but also can improve the cell uptake efficiency of TOs as well as the following endosomal escape to increase the therapeutic index.Furthermore,targeted and on-demand drug release of TOs can also be approached to minimize the risk of toxicity towards normal tissues using stimuli-responsive NPs.In the past decades,remarkable progresses have been made on the TOs delivery based on various NPs with specific purposes.In this review,we will first give a brief introduction on the basis of TOs as well as the action mechanisms of several typical TOs,and then describe the obstacles that prevent the clinical translation of TOs,followed by a comprehensive overview of the recent progresses on TOs delivery based on several various types of nanocarriers containing lipid-based nanoparticles,polymeric nanoparticles,gold nanoparticles,porous nanoparticles,DNA/RNA nanoassembly,extracellular vesicles,and imaging-guided drug delivery nanoparticles.展开更多
基金The authors extended their appreciation to Distinguished Scientist Fellowship program at King Saud University,Riyadh,Saudi Arabia,for funding this work through research supporting project number(RSP2024R131).
文摘Background:Scientific evidence to guide clinicians on the use of different antiseizure drugs in combination therapy is either very limited or lacking.In this study,the impact of lacosamide and perampanel alone and in combination was tested in corneal kindling model in mice,which is a cost-effective mechanism for screening of antiseizure drugs.Methods:The impact of lacosamide(5 mg/kg)and perampanel(0.125 mg/kg)alone and their combination was tested in corneal kindling process(3-mA current for 3 s applied twice daily for consecutive 12 days)in male BALB/c mice.Post-kindling,mice were subjected to a battery of behavioral tests assessing anxiety,memory,and depression-like behaviors.Brain tissues were then harvested for analysis of oxidative stress biomarkers.Results:Our results showed that the combination therapy of lacosamide and perampanel was more effective in reducing seizure progression than monotherapy of these drugs.Animals treated with combination therapy showed significant behavioral improvements,as reduced anxiety and depression were noticed,and their cognitive abilities were notably better compared to animals of all other groups.Moreover,biochemical assays of isolated brains from combination-treated group revealed lesser amount of oxidative stress.In addition,outcomes of dual regime were comparable to the phenytoin in seizure control but showed superior benefits in mitigation of kindling-prompted behavioral dysfunction and oxidative stress.Conclusions:This study suggests that the lacosamide and perampanel combination therapy worked noticeably better in halting the corneal kindling process in mice and improved the epilepsy-associated psychiatric disorders that might be due to antioxidant effects of both drugs.
基金The authors extend their appreciation to the Distinguished Scientist Fellowship program at King Saud University,Riyadh,Saudi Arabia,for funding this work through Research Supporting Project Number RSP2024R131.
文摘Background:Besides seizures,a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy,which further debilitates their quality of life.This study provides an in-depth characterization of the impact of brivaracetam and rufinamide individually and in combination at 10 and 20 mg/kg doses,respec-tively,on corneal kindling-induced generalized seizures and behavioral alterations.Furthermore,observed convulsive frequency and behavioral changes were corre-lated to post-kindling-induced changes in the activity of markers of oxidative stress.Methods:Adult C57BL/6 mice were kindled via twice-daily transcorneal 50-Hz elec-trical stimulations(3 mA)for 3 s for 12 days until animals reached a fully kindled state.After the kindling procedure,animals were tested using a set of behavioral tests,and neurochemical alterations were assessed.Results:Corneal-kindled animals exhibited intense generalized convulsions,altered behavioral phenotypes typified by positive symptoms(hyperlocomotion),negative symptoms(anxiety and anhedonia),and deficits in semantic and working memory.BRV 10+RFM 20 dual regime increased convulsive threshold and propensity toward the start of stage 4–5 seizures and improved phenotypical deficits,that is,anxiety,depression,and memory impairments.Moreover,this combination therapy mitigated kindling-induced redox impairments as evidenced by reduced malondialdehyde and acetylcholinesterase levels and increased glutathione antioxidant activity in the brain of animals subjected to repetitive brain insult.Conclusion:Based on our outcomes,this dual therapy provides supporting evidence in alleviating epilepsy-induced neurobehavioral comorbidities and changes in redox homeostasis.
文摘Several lines of evidence have established that proliferation and differentiation of neural stem cells into neurons within the sub-granular zone of the dentate gyrus,a process named adult hippocampal neurogenesis,contribute to maintaining healthy cognitive functions throughout life.The rate of adult hippocampal neurogenesis decreases with aging and a premature impairment of adult hippocampal neurogenesis has been observed both in animal models of Alzheimer’s disease and human post-mortem tissues.The causal relationship between adult hippocampal neurogenesis and the development of Alzheimer’s disease pathology has,however,not been established.This is partly due to the limitation of recapitulating the development of Alzheimer’s disease pathology in rodent models and the lack of translatable biomarkers to identify tractable targets in humans.While it is tempting to postulate that adult hippocampal neurogenesis could be leveraged to improve cognitive deficits in Alzheimer’s disease,consensual results have yet to be reached to fully explore this hypothesis.In this review,we discuss how the recent progress in identifying molecular pathways in adult hippocampal neurogenesis provides a good framework to initiate strategies for drug-based intervention in neurodegenerative diseases,especially in Alzheimer’s disease.We outline how discrepancies in pre-clinical disease models and experimental methodology have resulted in contradictory findings and propose a shift towards using more translatable approaches to model neurogenesis in Alzheimer’s disease.In particular,we review how exploring novel experimental paradigms including the use of human induced pluripotent stem cells and more complex cell culture systems,as well as standardizing protocols used to investigate evidence of neurogenesis in human tissues,could deliver deeper mechanistic insights that would kick-start innovative drug discovery efforts to promote healthy aging and cellular rejuvenation.
文摘The omega-3 fatty acid (n-3 FA) content of broiler tissues can be increased through dietary supplementation of hens with n-3 FA-rich microalgae. The aim of this study was to evaluate the effect of three different dietary inclusion levels of a docosahexaenoic acid (DHA)-rich microalgae (AURA) on broiler performance and the enrichment of tissues with n-3 FA. The randomized study was conducted using 352 birds, housed in 32 pens with 11 birds per pen. Pens were randomly assigned to one of four treatments, with each treatment replicated 8 times. The treatments included one unsupplemented control (0%) and three wheat-soya based experimental diets supplemented with AURA at a level of 0.5%, 1.5% and 2.5% for the starter, grower and finisher periods. Birds were weighed on days 0, 10, 24, 35 and 41, and feed intake was recorded per pen. On day 41, five birds per treatment were euthanized and individually weighed. Thigh muscle, breast muscle, liver, kidney and skin samples were taken post-mortem, freeze dried and DHA content quantified, following fat extraction and methylation, by GC-FID (AOAC 996.06 method). Performance and tissue data were analyzed by ANOVA with Dunnett’s (2-sided) post-hoc test to determine the differences between the mean values for each treatment. Dietary supplementation with AURA had no effect on body weight or feed intake during any period of the study. For thigh muscle, kidney and skin the DHA increased linearly (P < 0.05) with increasing level of dietary AURA, whilst there was a quadratic response in uptake of DHA in breast muscle and liver. The study demonstrated the potential of efficiently enriching broiler meat and organs with DHA by feeding AURA.
文摘Objective:To evaluate antimicrobial and antioxidant properties of saline extract from Tithonia diversifolia leaves by phytochemical bioprospecting,and investigate its safety against animal cells.Methods:The saline extract was prepared,with NaCl(0.15 M),by constant stirring of the dried and pulverized leaves,followed by volume reduction by lyophilization.The extract was phytochemical characterized using ultra-performance liquid chromatography,and total phenol and flavonoid analysis also was performed.The antioxidant capacity was determined through DPPH*radical,the antimicrobial property was evaluated against standard bacteria and fungi,and the viability assays were performed against mice splenocytes.Results:Fifteen compounds were identified belonging to two main classes terpenoids and phenolics.The extract showed 22.185 mg GAE/g of total phenolic compounds and 3.220 mg QE/g of flavonoid.Moreover,extract showed higher antioxidant ability similar to butylated hydroxytoluene a standard molecule[(3.042±0.019)mg AAE/g and(4.12±0.10)mg AAE/g to saline extract and butylated hydroxytoluene,respectively].The antimicrobial assays demonstrated that the extract had a significant antifungal potential against Candida species and could be used with safety against mice splenocytes,in concentrations lower than 50μg/mL,promoting higher proliferation in these cells.Conclusions:Saline extract from Tithonia diversifolia leaves presents potential antioxidant,antifungal properties and induces immunostimulation in mice splenocytes.
基金CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior) for the grant of a master’s degree scholarship during the entire research period
文摘Objective: To evaluate the structural and chemical composition of plant and the antioxidant and antimicrobial activities promoted by hexanic, ethanolic and ethyl acetate fractions obtained from leaves of Conocarpus erectus.Methods: Organic fractions were characterized through UPLC-MS and GC-MS.Antioxidant potential was performed through DPPH and molybdenum phosphate techniques.Antibacterial and antifungal assays were performed in accordance with Clinical and Laboratory Standards Institute protocols.Results: The obtained biomass of Conocarpus erectus leaves showed the high presence of glucose(0.45 g/L), cellulose(28.69%), Na(55.126 μg/L) and K(31.163 μg/L).We identified seven compounds in the hexanic and ethyl acetate fractions, and eight compounds in ethanolic fraction.Moreover, phenolic compounds are prevalent in all organic fractions with values of(10.04 ± 0.24),(221.26 ± 1.84),(340.53 ± 0.84) mg/g GAE to hexanic, ethyl acetate and ethanolic fraction, respectively.Antioxidant results showed a high potential in ethyl acetate fraction(71.82 ± 6.87)% and(10.89 ± 0.05)% in DPPH and molybdenum phosphate techniques, respectively.The ethanolic fraction showed moderate bacteriostatic and bactericidal activity against Staphylococcus aureus and presented a high fungistatic potential for all Candida species tested.Conclusions: Organic fractions obtained from leaves of Conocarpus erectus present antimicrobial and antioxidant properties, and these findings contribute to scientific information for the effectiveness on use of this plant in the development of a phytotherapic compound.
文摘Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation,repair and regeneration.Through cell fusion somatic cells undergo rapid nuclear reprogramming and epigenetic modifications to form hybrid cells with new genetic and phenotypic properties at a rate exceeding that achievable by random mutations.Factors that stimulate cell fusion are inflammation and hypoxia.Fusion of cancer cells with non-neoplastic cells facilitates several malignancy-related cell phenotypes,e.g.,reprogramming of somatic cell into induced pluripotent stem cells and epithelial to mesenchymal transition.There is now considerable in vitro,in vivo and clinical evidence that fusion of cancer cells with motile leucocytes such as macrophages plays a major role in cancer metastasis.Of the many changes in cancer cells after hybridizing with leucocytes,it is notable that hybrids acquire resistance to chemo-and radiation therapy.One phenomenon that has been largely overlooked yet plays a role in these processes is polyploidization.Regardless of the mechanism of polyploid cell formation,it happens in response to genotoxic stresses and enhances a cancer cell’s ability to survive.Here we summarize the recent progress in research of cell fusion and with a focus on an important role for polyploid cells in cancer metastasis.In addition,we discuss the clinical evidence and the importance of cell fusion and polyploidization in solid tumors.
文摘Objective: To evaluate the antiplasmodial activity of aqueous-methanolic plant extracts of nine plant species selected, based on ethnobotanical data. Methods: Based on ethnobotanical database, the selected plants were tested for their antiplasmodial activity against chloroquinesensitive(3 D7) strain of Plasmodium falciparum. Qualitative tests and high performance thin layer chromatography analysis were carried out to explore the phytocomponents present in the plant extracts. 1,1-diphenyl-2-picrylhydrazyl antioxidant activity was also determined to check the antioxidant activity of the plant extracts. Results: Moringa oleifera(IC_(50): 3.906 μg/mL),Acalypha indica(IC_(50): 3.906 μg/mL), Hyptis suaveolens(IC_(50): 3.906 μg/mL), Mangifera indica(IC_(50): 4.150 μg/mL) and Averrhoa bilimbi(IC_(50): 4.881 μg/mL) showed very good antiplasmodial activity. Conclusions: Crude extracts of Mangifera indica and Hyptis suaveolens demonstrated the most efficacious antimalarial activity. A bioassay-guided fractionation of these extracts to identify the lead compound is proved to be useful. The results validate the traditional use of the selected plants as antimalarials.
文摘Genetic diversity evaluation of mutant lines is essential to facilitate their conservation and utility in breeding programs. Characterization of plant genotypes using morphological markers has limitations which make the procedure inefficient. Application of molecular tools for characterization and diversity assessment has been found useful to complement phenotypic evaluation of plant population. Therefore genetic diversity of some cowpea mutant lines was studied using simple sequence repeats (SSR) markers. DNA barcoding marker, ribulose-1,5-bisphosphate carboxylase(rbcL) of the chloroplast DNA (cpDNA) was also used for characterization and identification of the mutants to species level. The mean polymorphic information content (0.51) obtained from the microsatellites showed high polymorphism in accessing wide genetic diversity among the mutants and their parents. Dendrogram generated revealed 8 groups with most mutants clustered separately from their parents. Sequence analysis revealed insertions/deletions (InDels) and base substitutions as the two main classes of mutations induced in the plastid DNA of the mutants studied. The nucleotide frequencies were 26.95% (A), 34.43% (T), 24.09% (C) and 14.53% (G). A total of 61.38% AT rich region was identified, while GC rich region was found to be 38.62%. Highest rate of mutations were observed in region 3 - 4 indicating that the region is less conserved in cowpea rbcL gene. The present study proved that SSR markers are useful for the genetic diversity assessment of cowpea mutants. It also proved the efficiency of rbcL markers in mutants’ identification. The results indicate that the mutants are valuable genetic resources that have been developed to widen cowpea genetic base.
文摘This paper describes the synthesis of peptide fragments for use in a new type of combinatorial discovery technology, in which the building blocks are brought together by non-covalent interactions, rather than direct chemical bonding. The building blocks of interest—in this case different amino acids—are converted to amphiphiles by attachment to lipid tails. The amphiphiles, when mixed together in aqueous phase, are designed so that they aggregate spontaneously to form micelles. The building blocks form the headgroups of each of the amphiphiles, and these headgroups cover the surface of the micelle in a dynamic close-packed fluid mosaic array. These building blocks come together so closely that two- or three-dimensional structures are created on the surface of the micelles, and these can be screened in biological assays to find out which combination of building blocks is able to elicit a biological response. Lipopeptides consisting of two residues of lipoamino acid and other amino acids moieties have been designed, synthesized, characterized and the ability of these constructs to form supra-molecular assemblies is demonstrated.
基金supported by the National Natural Science Foundation of China(82073388 and 82201287)the Affiliated Hospital of Guangdong Medical University Clinical Research Program(LCYJ2020B005)+7 种基金the Natural Out-standing Youth Fund of Guangdong Province(2022B1515020090)Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases(2022B1212030003)Guangzhou Science and Technology Plan Project(Grant No.202102021238)Academy of Finland Research Fellow(353146)Project(347897)Solutions for Health Profile(336355)InFLAMES Flagship(337531)Tor,Joe och Pentti Borgs minnesfond,and Finland China Food and Health International Pilot Project funded by the Finnish Ministry of Education and Culture.
文摘Nanomaterial-based drug delivery systems are susceptible to premature drug leakage and systemic toxicity due to lack of specific targeting,and live-cell drug delivery is also prone to be restricted by drug carrier-cellinteractions.Here,a method is established to adsorb drug-loaded nanomaterials externally to the live cells,which reduces cytotoxicity caused by drug uptake and improves the bioactivity of the carrier cells and drug release at the lesion site.It was found that polyphenols act like"doublesided tape"to bridge metal-organic framework(MOF)nanoparticles with live macrophages(Mop),attaching MOFs to the Mp surface and minimizing intracellular uptake,with no negative effect on cell proliferation.On this basis,a"macrophage missile"with peroxymonosulfate(PMS)-loaded MOF nanoparticles on the cell surface was constructed.As a"propellant",the Mo,in which bioactivity is preserved,can selectively identify and target tumor cells,precisely bringing nanomedicines to the lesion.MOF nanoparticles are used to load and catalyze PMS,which acts as an exogenous source of reactive oxygen species,showing higher efficacy and lower toxicity in an oxygen-independent manner.The primary study results demonstrate that this innovative combination of biology and nanomaterials remarkably enhances tumor targeting and therapeutic efficacy while reducing systemic side effects.This approach is expected to provide a more effective and safer treatment for lung cancer and holds promise for broader applications in other cancer therapies.
基金supported by the National Key Research and Development Program of China(2022YFA1105300)the National Natural Science Foundation of China(82372145,82102181,52403189)+5 种基金the Natural Science Foundation of Jiangsu Province(BK20210009)the Nanjing Distinguished Young Scholars Foundation(JQX22002)supported by the Research Project(347897)Solution for Health Profile(336355)InFLAMES Flagship(337531)"Printed Intelligence Infrastructure(PII-FIRI)"from Research Council of Finland.
文摘Hydrogel-based patches have demonstrated their values in diabetic wounds repair,particularly those intelligent dressings with continuous repair promoting and monitoring capabilities.Here,we propose a type of dual physiological responsive structural color particles for wound repair.The particles are composed of a hyaluronic acid methacryloyl(HAMA)-sodium alginate(Alg)inverse opal scaffold,filled with oxidized dextran(ODex)/quaternized chitosan(QCS)hydrogel.The photo-polymerized HAMA and ionically cross-linked Ca-Alg constitute to the dual-network hydrogel with stable structural color.Furthermore,the ODex/QCS hydrogel,combined with glucose oxidase(GOX),exhibits pH/glucose dual responsiveness.Moreover,antimmicrobial peptide(AMP)plus vascular endothelial growth factor(VEGF)are comprised within the GOX-doped ODex/QCS hydrogel.In the high-glucose wound environment,GOX catalyzes glucose to generate acidic products,triggering rapid release of AMP and VEGF.Importantly,this process also leads to structural color changes of the particles,offering significant potential for wound monitoring.It has been demonstrated that such particles greatly promote the healing progress of diabetic wound in vivo.These results indicate that the present dual responsive particles would find valuable applications in diabetic wounds repair and the associated areas.
基金funded by Research Project(347897)Solution for Health Profile(336355)InFLAMES Flagship(337531)Grants and Printed Intelligence Infrastructure(PII-FIRI)from Research Council of Finland.
文摘Microneedles have demonstrated valuable applications in diabetic wound management.Many endeavors are devoted to developing microneedles with well-designed structures and enhanced functions.Herein,we present an elaborate microneedle patch with breathability for wound healing by a multi-step replication method.The microneedle patch consists of a breathable porous supporting substrate and core-shell tips involving poly(vinyl alcohol)shells loaded with antimicrobial peptides(PVA@AMPs shell)and crosslinked Gelma cores encapsulated with exosomes(Gelma@exo core).The PVA was crosslinked with a ROS-responsive linker,which results in degradation of the microneedle shell in the inflammatory microenvironment,thus inducing the release of loaded AMPs to inhibit bacteria.Further,the exosomes continuously release from the exposed Gelma@exo core,promoting tissue regeneration and regulating the immune response.Besides,the high porosity of the supporting substrate makes the microneedle patches more suitable for chronic wounds.Based on these features,it was demonstrated that the microneedle patch exhibits desirable performance in in vivo animal tests.Thus,we believe that the proposed microneedle patches have remarkable potential in wound healing and related fields.
基金supported by the National Key Research and Development Program of China(2022YFA1105300)the National Natural Science Foundation of China(52073060,61927805 and 82400718)+5 种基金the Nanjing Medical Science and Technique Development Foundation(ZKX21019)the Clinical Trials from Nanjing Drum Tower Hospital(2022-LCYJ-ZD-01)supported by the Research Project(347897)Solution for Health Profile(336355)InFLAMES Flagship(337531)"Printed Intelligence Infrastructure"(PII-FIRI)"from Research Council of Finland.
文摘Long-term exposure to ultraviolet radiation compromises skin structural integrity and results in disruption of normal physiological functions.Stem cells have gained attention in anti-photoaging,while controlling the tissue mechanical microenvironment of cell delivery sites is crucial for regulating cell fate and achieving optimal therapeutic performances.Here,we introduce a mechanically regulated human recombinant collagen(RHC)microcarrier generated through microfluidics,which is capable of modulating stem cell differentiation to treat photoaged skin.By controlling the cross-linking parameters,the mechanical properties of microcarriers could precisely tuned to optimize the stem cell differentiation.The microcarriers are surface functionalized with fibronectin(Fn)-platelet derived growth factor-BB(PDGF-BB)to facilitate adipose derived mesenchymal stem cells(Ad-MSCs)loading.In in vivo experiments,subcutaneous injection of stem cell loaded RHC microcarriers significantly reduced skin wrinkles after ultraviolet-injury,effectively promoted collagen synthesis,and increased vascular density.These encouraging results indicate that the present mechanically regulated microcarriers have great potential to deliver stem cells and regulate their differentiation for anti-photoaging treatments.
基金supported by UTS Science Seed Funding,UTS Chancellor’s Research Fellowship Program(No.PRO22-15457)the National Health and Medical Research Council(No.2025442).
文摘Luminescent nanoparticles(LNPs)have emerged as a promising approach for enhanced cell labelling and disease diagnosis by leveraging their unique photophysical and surface characteristics.Advanced generations of LNPs,such as quantum dots,dye-loaded nanoparticles and up-converting nanoparticles,exhibit distinct properties and advantages tailored for specialised applications.Consequently,there is a growing focus and demand to develop organelle-specific LNPs to identify,treat and elucidate disease mechanisms.The endoplasmic reticulum(ER)represents one such organelle,playing crucial roles in protein synthesis and modification,calcium homeostasis,lipid trafficking,and regulation of cellular stress.The unfolded protein response,regulated by ER stress,is a clinically significant pathway within the ER,implicated in cellular dysfunction and disease.The growing understanding of ER stress and the unfolded protein response has led to a rapid emergence of endoplasmic reticulum-targeting LNPs(ERLNPs)for precise intracellular diagnosis and therapy.This review discusses current advances and design principles of ERLNPs,highlights current achievements and applications,and discusses the challenges and interdisciplinarity needed for future development.
基金National Natural Science Foundation of China,Grant/Award Number:82372145Research Fellow,Grant/Award Number:353146+3 种基金Research Project,Grant/Award Number:347897Solutions for Health Profile,Grant/Award Number:336355InFLAMES Flagship,Grant/Award Number:337531Finland China Food and Health International Pilot project funded by Finnish MInistry of Education and Culture。
文摘The development of tumor drug microcarriers has attracted considerable interest due to their distinctive therapeutic performances.Current attempts tend to elab-orate on the micro/nano-structure design of the microcarriers to achieve multiple drug delivery and spatiotemporal responsive features.Here,the desired hydrogel microspheres are presented with spatiotemporal responsiveness for the treatment of gastric cancer.The microspheres are generated based on inverse opals,their skele-ton is fabricated by biofriendly hyaluronic acid methacrylate(HAMA)and gelatin methacrylate(GelMA),and is thenfilled with a phase-changing hydrogel composed offish gelatin and agarose.Besides,the incorporated black phosphorus quantum dots(BPQDs)within thefilling hydrogel endow the microspheres with outstanding pho-tothermal responsiveness.Two antitumor drugs,sorafenib(SOR)and doxorubicin(DOX),are loaded in the skeleton andfilling hydrogel,respectively.It is found that the drugs show different release profiles upon near-infrared(NIR)irradiation,which exerts distinct performances in a controlled manner.Through both in vitro and in vivo experiments,it is demonstrated that such microspheres can significantly reduce tumor cell viability and enhance the efficiency in treating gastric cancer,indicating a promising stratagem in thefield of drug delivery and tumor therapy.
基金This study was financially supported by the National Natural Science Foundation of China(81772713,81472411,81401899,81372752)Taishan Scholar Program of Shandong Province(tsqn20161077)+4 种基金Key Research and Development Program of Shandong Province(2018GSF118197)China Postdoctoral Science Foundation(2017M622144)Qingdao Postdoctoral Application Research Project.Prof.Zhang acknowledged the support from Academy of Finland(Grant no.328933)Sigrid Juselius Foundation(Grant no.28002247K1)We thank Dr.Chang Liu fromÅbo Akademi University for giving some advice to analyze the TGA data,and Ms.Qian Wen from Biomedical Center of Qingdao University for her guidance and support of in vivo fluorescence imaging.
文摘Bladder cancer is one of the concerning malignancies worldwide,which is lacking effective targeted therapy.Gene therapy is a potential approach for bladder cancer treatment.While,a safe and effective targeted gene delivery system is urgently needed for prompting the bladder cancer treatment in vivo.In this study,we confirmed that the bladder cancer had CD44 overexpression and small interfering RNAs(siRNA)with high interfere to Bcl2 oncogene were designed and screened.Then hyaluronic acid dialdehyde(HAD)was prepared in an ethanol-water mixture and covalently conjugated to the chitosan nanoparticles(CS-HAD NPs)to achieve CD44 targeted siRNA delivery.The in vitro and in vivo evaluations indicated that the siRNA-loaded CS-HAD NPs(siRNA@CS-HAD NPs)were approximately 100 nm in size,with improved stability,high siRNA encapsulation efficiency and low cytotoxicity.CS-HAD NPs could target to CD44 receptor and deliver the therapeutic siRNA into T24 bladder cancer cells through a ligand-receptor-mediated targeting mechanism and had a specific accumulation capacity in vivo to interfere the targeted oncogene Bcl2 in bladder cancer.Overall,a CD44 targeted gene delivery system based on natural macromolecules was developed for effective bladder cancer treatment,which could be more conducive to clinical application due to its simple preparation and high biological safety.
基金supported by grants from the National Basic Research Program (973 Program 2006CB9-10401 and 2006CB910403) awarded to JY and SH
文摘Here, we evaluate the contribution of two major biological processes--DNA replication and transcription--to mutation rate variation in human genomes. Based on analysis of the public human tissue transcriptomics data, high-resolution replicating map of Hela cells and dbSNP data, we present significant correlations between expres- sion breadth, replication time in local regions and SNP density. SNP density of tissue-specific （TS） genes is sig- nificantly higher than that of housekeeping （HK） genes. TS genes tend to locate in late-replicating genomic re- gions and genes in such regions have a higher SNP density compared to those in early-replication regions. In addi- tion, SNP density is found to be positively correlated with expression level among HK genes. We conclude that the process of DNA replication generates stronger mutational pressure than transcription-associated biological processes do, resulting in an increase of mutation rate in TS genes while having weaker effects on HK genes. In contrast, transcription-associated processes are mainly responsible for the accumulation of mutations in highly-expressed HK genes.
基金the financial support of the National Natural Science Foundation of China(31771054,81871472,and 31830028)Academy of Finland Research Fellow(328933)+5 种基金Sigrid Jusélius Foundation grant(28002247k1)Natural Key Science Research Program of Jiangsu Provincial Department of Education(19KJA320006)National Key Research and Development Program of China(2016YFC1101600)Directive Project of Science and Technology Plan of Nantong City(MS12018028)226 High-Level Talent Training Project(2nd level,2018 II-182)of Nantong CityQinglan Project of Jiangsu Province(2018).
文摘Biofunctionalization of artificial nerve implants by incorporation of specific bioactive factors has greatly enhanced the success of grafting procedures for peripheral nerve regeneration.However,most studies on novel biofunctionalized implants have emphasized the promotion of neuronal and axonal repair over vascularization,a process critical for long-term functional restoration.We constructed a dual-biofunctionalized chitosan/collagen composite scaffold with Ile-Lys-Val-Ala-Val(IKVAV)and vascular endothelial growth factor(VEGF)by combining solution blending,in situ lyophilization,and surface biomodification.Immobilization of VEGF and IKVAV on the scaffolds was confirmed both qualitatively by staining and quantitatively by ELISA.Various single-and dual-biofunctionalized scaffolds were compared for the promotion of endothelial cell(EC)and Schwann cell(SC)proliferation as well as the induction of angiogenic and neuroregeneration-associated genes by these cells in culture.The efficacy of these scaffolds for vascularization was evaluated by implantation in chicken embryos,while functional repair capacity in vivo was assessed in rats subjected to a 10mm sciatic nerve injury.Dual-biofunctionalized scaffolds supported robust EC and SC proliferation and upregulated the expression levels of multiple genes and proteins related to neuroregeneration and vascularization.Dual-biofunctionalized scaffolds demonstrated superior vascularization induction in embryos and greater promotion of vascularization,myelination,and functional recovery in rats.These findings support the clinical potential of VEGF/IKVAV dual-biofunctionalized chitosan/collagen composite scaffolds for facilitating peripheral nerve regeneration,making it an attractive candidate for repairing critical nerve defect.The study may provide a critical experimental and theoretical basis for the development and design of new artificial nerve implants with excellent biological performance.
基金This work was financially supported by the Natural Science Foundation of China(81871472)Natural Science Foundation of Guangdong Province(Project No.2019A1515010696 and 2021A1515012333)+1 种基金Shenzhen Municipal Science,Technology and Innovation Commission(Project No.JCYJ20190807163003704)“100 Talents Program”of the start-up foundation from Sun Yat-sen University,Academy of Finland(328933)and Sigrid Jus´elius Foundation.
文摘Therapeutic oligonucleotides(TOs)represent one of the most promising drug candidates in the targeted cancer treatment due to their high specificity and capability of modulating cellular pathways that are not readily druggable.However,efficiently delivering of TOs to cancer cellular targets is still the biggest challenge in promoting their clinical translations.Emerging as a significant drug delivery vector,nanoparticles(NPs)can not only protect TOs from nuclease degradation and enhance their tumor accumulation,but also can improve the cell uptake efficiency of TOs as well as the following endosomal escape to increase the therapeutic index.Furthermore,targeted and on-demand drug release of TOs can also be approached to minimize the risk of toxicity towards normal tissues using stimuli-responsive NPs.In the past decades,remarkable progresses have been made on the TOs delivery based on various NPs with specific purposes.In this review,we will first give a brief introduction on the basis of TOs as well as the action mechanisms of several typical TOs,and then describe the obstacles that prevent the clinical translation of TOs,followed by a comprehensive overview of the recent progresses on TOs delivery based on several various types of nanocarriers containing lipid-based nanoparticles,polymeric nanoparticles,gold nanoparticles,porous nanoparticles,DNA/RNA nanoassembly,extracellular vesicles,and imaging-guided drug delivery nanoparticles.
