Precise nanomedicine has been extensively explored for efficient cancer imaging and targeted cancer therapy, as evidenced by a few breakthroughs in their preclinical and clinical explorations. Here, we demonstrate the...Precise nanomedicine has been extensively explored for efficient cancer imaging and targeted cancer therapy, as evidenced by a few breakthroughs in their preclinical and clinical explorations. Here, we demonstrate the recent advances of intelligent cancer nanomedicine, and discuss the comprehensive understanding of their structure-function relationship for smart and efficient cancer nanomedicine including various imaging and therapeutic applications, as well as nanotoxicity. In particular, a few emerging strategies that have advanced cancer nanomedicine are also highlighted as the emerging focus such as tumor imprisonment, supramolecular chemotherapy, and DNA nanorobot. The challenge and outlook of some scientific and engineering issues are also discussed in future development. We wish to highlight these new progress of precise nanomedicine with the ultimate goal to inspire more successful explorations of intelligent nanoparticles for future clinical translations.展开更多
Investigation of metal–organic frameworks(MOFs)for biomedical applications has attracted much attention in recent years.MOFs are regarded as a promising class of nanocarriers for drug delivery owing to well-defined s...Investigation of metal–organic frameworks(MOFs)for biomedical applications has attracted much attention in recent years.MOFs are regarded as a promising class of nanocarriers for drug delivery owing to well-defined structure,ultrahigh surface area and porosity,tunable pore size,and easy chemical functionalization.In this review,the unique properties of MOFs and their advantages as nanocarriers for drug delivery in biomedical applications were discussed in the first section.Then,state-ofthe-art strategies to functionalize MOFs with therapeutic agents were summarized,including surface adsorption,pore encapsulation,covalent binding,and functional molecules as building blocks.In the third section,the most recent biological applications of MOFs for intracellular delivery of drugs,proteins,and nucleic acids,especially aptamers,were presented.Finally,challenges and prospects were comprehensively discussed to provide context for future development of MOFs as efficient drug delivery systems.展开更多
Advanced bioanalysis,including accurate quantitation,has driven the need to understand biology and medicine at the molecular level.Bioconjugated silica nanoparticles have the potential to address this emerging challen...Advanced bioanalysis,including accurate quantitation,has driven the need to understand biology and medicine at the molecular level.Bioconjugated silica nanoparticles have the potential to address this emerging challenge.Particularly intriguing diagnostic and therapeutic applications in cancer and infectious disease as well as uses in gene and drug delivery,have also been found for silica nanoparticles.In this review,we describe the synthesis,bioconjugation,and applications of silica nanoparticles in different bioanalysis formats,such as selective tagging,barcoding,and separation of a wide range of biomedically important targets.Overall,we envisage that further development of these nanoparticles will provide a variety of advanced tools for molecular biology,genomics,proteomics and medicine.展开更多
Chlorin e6-pHLIPss-AuNRs, a gold nanorod-photosensitizer conjugate containing a pH （low） insertion peptide （pHLIP） with a disulfide bond which imparts extracellular pH （pHe）-driven tumor targeting ability, has b...Chlorin e6-pHLIPss-AuNRs, a gold nanorod-photosensitizer conjugate containing a pH （low） insertion peptide （pHLIP） with a disulfide bond which imparts extracellular pH （pHe）-driven tumor targeting ability, has been successfully developed for bimodal photodynamic and photothermal therapy. In this bimodal therapy, chlorin e6 （Ce6）, a second-generation photosensitizer （PS）, is used for photodynamic therapy （PDT）. Gold nanorods （AuNRs） are used as a hyperthermia agent for photothermal therapy （PTT） and also as a nanocarrier and quencher of Ce6. pHLIPss is designed as a pile-driven targeting probe to enhance accumulation of Ce6 and AuNRs in cancer cells at low pH. In Ce6- pHLIPss-AuNRs, Ce6 is close to and quenched by AuNRs, causing little PDT effect. When exposed to normal physiological pH 7.4, Ce6-pHLIPs^-AuNRs loosely associate with the cell membrane. However, once exposed to acidic pH 6.2, pHLIP actively inserts into the cell membrane, and the conjugates are translocated into cells. When this occurs, Ce6 separates from the AuNRs as a result of disulfide bond cleavage caused by intracellular glutathione （GSH）, and singlet oxygen is produced for PDT upon light irradiation. In addition, as individual PTT agent, AuNRs can enhance the accumulation of PSs in the tumor by the enhanced permeation and retention （EPR） effect. Therefore, as indicated by our data, when exposed to acidic pH, Ce6-pHLIPss-AuNRs can achieve synergistic PTT/PDT bimodality for cancer treatment.展开更多
Cancer chemotherapy has been limited by its side effects and multidrug resistance （MDR）, the latter of which is partially caused by drug efflux from cancer cells. Thus, targeted drug delivery systems that can circum...Cancer chemotherapy has been limited by its side effects and multidrug resistance （MDR）, the latter of which is partially caused by drug efflux from cancer cells. Thus, targeted drug delivery systems that can circumvent MDR are needed. Here, we report multifunctional DNA nanoflowers （NFs） for targeted drug delivery to both chemosensitive and MDR cancer cells that circumvented MDR in both leukemia and breast cancer cell models. NFs are self-assembled via potential co-precipitation of DNA and magnesium pyrophosphate generated by rolling circle replication, during which NFs are incorporated using aptamers for specific cancer cell recognition, fluorophores for bioimaging, and doxorubicin （Dox）- binding DNA for drug delivery. NF sizes are tunable （down to N200 nm in diameter）, and the densely packed drug-binding motifs and porous intrastructures endow NFs with a high drug-loading capacity （71.4%, wt/wt）. Although the Dox- loaded NFs （NF-Dox） are stable at physiological pH, drug release is facilitated under acidic or basic conditions. NFs deliver Dox into target chemosensitive and MDR cancer cells, preventing drug efflux and enhancing drug retention in MDR cells. NF-Dox induces potent cytotoxicity in both target chemosensitive cells and MDR cells, but not in nontarget cells, thus concurrently circumventing MDR and reducing side effects. Overall, these NFs are promising tools for circumventing MDR in targeted cancer therapy.展开更多
Our recent findings have demonstrated that rodent models of closed head traumatic brain injury exhibit comprehensive evidence of progressive and enduring orofacial allodynias, a hypersensitive pain response induced by...Our recent findings have demonstrated that rodent models of closed head traumatic brain injury exhibit comprehensive evidence of progressive and enduring orofacial allodynias, a hypersensitive pain response induced by non-painful stimulation. These allodynias, tested using thermal hyperalgesia, correlated with changes in several known pain signaling receptors and molecules along the trigeminal pain pathway, especially in the trigeminal nucleus caudalis. This study focused to extend our previous work to investigate the changes in monoamine neurotransmitter immunoreactivity changes in spinal trigeminal nucleus oralis, pars interpolaris and nucleus tractus solitaries following mild to moderate closed head traumatic brain injury, which are related to tactile allodynia, touch-pressure sensitivity, and visceral pain. Our results exhibited significant alterations in the excitatory monoamine, serotonin, in spinal trigeminal nucleus oralis and pars interpolaris which usually modulate tactile and mechanical sensitivity in addition to the thermal sensitivity. Moreover, we also detected a robust alteration in the expression of serotonin, and inhibitory molecule norepinephrine in the nucleus tractus solitaries, which might indicate the possibility of an alteration in visceral pain, and existence of other morbidities related to solitary nucleus dysfunction in this rodent model of mild to moderate closed head traumatic brain injury. Collectively, widespread changes in monoamine neurotransmitter may be related to orofacial allodynhias and headache after traumatic brain injury.展开更多
Background:It remains unknow whether retinal tissue perfusion occurs in patients with Alzheimer’s disease.The goal was to determine retinal tissue perfusion in patients with clinical Alzheimer’s disease(CAD).Methods...Background:It remains unknow whether retinal tissue perfusion occurs in patients with Alzheimer’s disease.The goal was to determine retinal tissue perfusion in patients with clinical Alzheimer’s disease(CAD).Methods:Twenty-four CAD patients and 19 cognitively normal(CN)age-matched controls were recruited.A retinal function imager(RFI,Optical Imaging Ltd.,Rehovot,Israel)was used to measure the retinal blood flow supplying the macular area of a diameter of 2.5 mm centered on the fovea.Blood flow volumes of arterioles(entering the macular region)and venules(exiting the macular region)of the supplied area were calculated.Macular blood flow was calculated as the average of arteriolar and venular flow volumes.Custom ultra-high-resolution optical coherence tomography(UHR–OCT)was used to calculate macular tissue volume.Automated segmentation software(Orion,Voxeleron LLC,Pleasanton,CA)was used to segment six intra-retinal layers in the 2.5 mm(diameter)area centered on the fovea.The inner retina(containing vessel network),including retinal nerve fiber layer(RNFL),ganglion cell-inner plexiform layer(GCIPL),inner nuclear layer(INL)and outer plexiform layer(OPL),was segmented and tissue volume was calculated.Perfusion was calculated as the flow divided by the tissue volume.Results:The tissue perfusion in CAD patients was 2.58±0.79 nl/s/mm^(3)(mean±standard deviation)and was significantly lower than in CN subjects(3.62±0.44 nl/s/mm^(3),P<0.01),reflecting a decrease of 29%.The flow volume was 2.82±0.92 nl/s in CAD patients,which was 31%lower than in CN subjects(4.09±0.46 nl/s,P<0.01).GCIPL tissue volume was 0.47±0.04 mm^(3) in CAD patients and 6%lower than CN subjects(0.50±0.05 mm^(3),P<0.05).No other significant alterations were found in the intra-retinal layers between CAD and CN participants.Conclusions:This study is the first to show decreased retinal tissue perfusion that may be indicative of diminished tissue metabolic activity in patients with clinical Alzheimer’s disease.展开更多
Aptamer guided nano medicine shows great promise in targeted cancer therapies.However the loss of targeting capacity duri ng in vivo or clinical trials has largely hindered its popularity and there are no systematic s...Aptamer guided nano medicine shows great promise in targeted cancer therapies.However the loss of targeting capacity duri ng in vivo or clinical trials has largely hindered its popularity and there are no systematic studies to elucidate the causes.Herein,we investigated such loss of targeting capacity by examining how the physiological milieu affected targeting effect.Aptamer functionalized gold nanoparticle(AuNP)was chosen as the model and exposed to human blood serum that is used to mimic physiological milieu.Dynamic light scattering(DLS),flow cytometry and label-free liquid chromatography tan dem mass spectrometry(LC-MS/MS)were employed to determi ne variations of NPs'surface chemistry and biological identities changes after serum exposure.Results showed that the targeting ability loss was caused by protein corona blocking,replacement and enzymatic cleavage of surface aptamer targeting ligands.Noteworthy,the aggregation issue is critical for the smaller NPs.Analysis of the protein corona profile indicated the accumulation of immune-related proteins on the surface of aptamer-conjugated NPs,which could induce immune response,resulting in rapid clearanee of NPs.展开更多
Early and accurate diagnosis and treatment of cancer depend on rapid,sensitive,and selective detection of tumor cells.Current diagnosis of cancers,especially leukemia,relies on histology and fl ow cytometry using sing...Early and accurate diagnosis and treatment of cancer depend on rapid,sensitive,and selective detection of tumor cells.Current diagnosis of cancers,especially leukemia,relies on histology and fl ow cytometry using single dye-labeled antibodies.However,this combination may not lead to high signal output,which can hinder detection,especially when the probes have relatively weak affi nities or when the receptor is expressed in a low concentration on the target cell surface.To solve these problems,we have developed a novel method for sensitive and rapid detection of cancer cells using dye-doped silica nanoparticles(NPs)which increases detection sensitivity in fl ow cytometry analyses between 10-and 100-fold compared to standard methods.Our NPs are~60 nm in size and can encapsulate thousands of individual dye molecules within their matrix.We have extensively investigated surface modifi cation strategies in order to make the NPs suitable for selective detection of cancer cells using fl ow cytometry.The NPs are functionalized with polyethylene glycol(PEG)to prevent nonspecifi c interactions and with neutravidin to allow universal binding with biotinylated molecules.By virtue of their reliable and selective detection of target cancer cells,these NPs have demonstrated their promising usefulness in conventional fl ow cytometry.Moreover,they have shown low background signal,high signal enhancement,and effi cient functionalization,either with antibody-or aptamer-targeting moieties.展开更多
The progress of modern medicine would be impossible without the use of general anesthetics(GAs).Despite advancements in refining anesthesia approaches,the effects of GAs are not fully reversible upon GA withdrawal.Neu...The progress of modern medicine would be impossible without the use of general anesthetics(GAs).Despite advancements in refining anesthesia approaches,the effects of GAs are not fully reversible upon GA withdrawal.Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly.Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research,but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects.The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents,which are far more extensively studied than any other species.Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated.Specifically,we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities(somatic effects),but also epigenetic reprogramming of germ cells(germ cell effects).The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring,who may be affected even at levels of anesthesia that are not harmful to the exposed parents.The large number of patients who require general anesthesia,the even larger number of their future unexposed offspring whose health may be affected,and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs.In this mini review,we discuss emerging experimental findings on neuroendocrine,epigenetic,and intergenerational effects of GAs.展开更多
The mounting endemic of prescription iatrogenic opioid dependence in pain patients provoked this treatise about an alternative method that can be used to treat pain, improve function and reduce the risk of opioid depe...The mounting endemic of prescription iatrogenic opioid dependence in pain patients provoked this treatise about an alternative method that can be used to treat pain, improve function and reduce the risk of opioid dependence. It is well known that as well as the side effects reported for chronic opioid therapy, genetically predisposed individuals are at risk for opioid dependence. We propose the use of the Genetic Addiction Risk Score (GARS) assessment to identify patients early in treatment who should avoid narcotic pain medications. Primarily, this review will be an exploration of the mechanisms of action of an electrotherapeutic alternative to narcotic treatment that can be used to augment tissue healing and reduce the pain associated with human injuries and neuropathies. This particular electrotherapeutic device was developed at the Electronic Waveform Laboratory in Huntington Beach, California and is called the H-Wave? device. The primary effect of the H-Wave?device is stimulation (HWDS) of small diameter fibers of “red-slow-twitch” skeletal muscle. Mechanisms of action of HWDS have been investigated in both animal and human studies. They include edema reduction, induction of nitric oxide dependent augmented microcirculation and angiogenesis, small muscle contraction that eliminates transcapillary fluid shifts, reducing the painful effects of tetanizing fatigue and gradual loading of healing injured muscle tissue that helps repair and remodeling. A recent metaanalysis found a moderate-to-strong-positive effect of the HWDS in providing pain relief, reducing the requirement for pain medication, with the most robust effect being increased functionality. We are proposing that GARS can be used to identify those at risk of developing opioid dependence and that the need for opioid analgesia can be reduced by use of this electro therapeutic alternative to opioid analgesia in the treatment of pain and injuries.展开更多
In fMRI experiments on object representation in visual cortex, we designed two types of stimuli: one is the gray face image and its line drawing, and the other is the illusion and its corresponding completed illusion....In fMRI experiments on object representation in visual cortex, we designed two types of stimuli: one is the gray face image and its line drawing, and the other is the illusion and its corresponding completed illusion. Both of them have the same global features with different minute details so that the results of fMRI experiments can be compared with each other. The first kind of visual stimuli was used in a block design fMRI experiment, and the second was used in an event-related fMRI experiment. Comparing and analyzing interesting visual cortex activity patterns and blood oxygenation level dependent (BOLD)- fMRI signal, we obtained results to show some invariance of global features of visual images. A plau- sible explanation about the invariant mechanism is related with the cooperation of synchronized re- sponse to the global features of the visual image with a feedback of shape perception from higher cortex to cortex V1, namely the integration of global features and embodiment of sparse representation and distributed population code.展开更多
Precisely designed protein-based nanodrugs, as a kind of colloidal drug system, have attracted significant attention in tumor therapy because of their refined drug loading ratio, controlled delivery efficacy and natur...Precisely designed protein-based nanodrugs, as a kind of colloidal drug system, have attracted significant attention in tumor therapy because of their refined drug loading ratio, controlled delivery efficacy and natural biocompatibility. However, most drugs are conjugated to the protein carriers randomly without specific binding sites. Moreover, such sites could easily be replaced by lipophilic molecules in the physiological environment and result in low delivery efficiency. With strong and specific binding locations especially comparatively narrow spatial binding sites and nonflexible structure, hemin (FePPIX)-free hemoglobin or apohemoglobin (apoHb), as a natural metalloporphyrin protein carrier, represents great potential in bioapplication. Therefore, we herein introduce a folate acid (FA) modified, zinc-substituted hemoglobin (ZnPHb-FA) as a naturally occurring protein matrix-based photosensitizer for cancer photodynamic therapy (PDT). Noncovalent inserted ZnPPIX molecules in apoHb possess an extremely stable property and significant recovered photoproperties with superior biocompatibility and phototoxicity, both in vitro and in vivo. This stability was verified by molecular docking analysis and calculation of binding constant, representing a total of five drug binding sites of apoHb for ZnPPIX molecules, four of which are energetically favorable (△G value of -11.9 kcal/mol), and one which is energetically acceptable (△G value of -9 kcal/mol). Folate acid modification has been shown to efficiently enhance the internalization and retention time of ZnPHb nanodrug. ZnPHb-FA is also an efficient depressor of hemin oxygenase-1 (HO-1), which could, in turn, lower the antioxidant ability of cancer cells by decreasing the production of biiirublin. Results in vitro and in vivo both indicated that the firmly combination of apoHb and ZnPPIX described here represents a novel and efficient protein nanodrug systems for cancer therapy.展开更多
Neuroglial cells are homeostatic neural cells. Generally, they are electrically non-excitable and their activation is associated with the generation of complex intracellular Ca^2＋ signals that define the ＂Ca^2＋ exc...Neuroglial cells are homeostatic neural cells. Generally, they are electrically non-excitable and their activation is associated with the generation of complex intracellular Ca^2＋ signals that define the ＂Ca^2＋ excitability＂ of glia. In mammalian glial cells the major source of Ca^2＋ for this excitability is the lumen of the endoplasmic reticulum （ER）, which is ultimately （re）filled from the extracellular space. This occurs via store-operated Ca^2＋ entry （SOCE） which is supported by a specific signaling system connecting the ER with plasmalemmal Ca^2＋ entry. Here, emptying of the ER Ca^2＋ store is necessary and sufficient for the activation of SOCE, and without Ca^2＋ influx via SOCE the ER store cannot be refilled. The molecular arrangements underlying SOCE are relatively complex and include plasmalemmal channels, ER Ca^2＋ sensors, such as stromal interaction molecule, and possibly ER Ca^2＋ pumps （of the SERCA type）. There are at least two sets of plasmalemmal channels mediating SOCE, the Ca2＊-release activated channels, Orai, and transient receptor potential （TRP） channels. The molecular identity of neuroglial SOCE has not been yet identified unequivocally. However, it seems that Orai is predominantly expressed in microglia, whereas astrocytes and oligodendrocytes rely more on TRP channels to produce SOCE. In physiological conditions the SOCE pathway is instrumental for the sustained phase of the Ca^2＋ signal observed following stimulation of metabotropic receptors on glial cells.展开更多
Unfortunately,ag ing is not a reversible phenomenon and the processes of senescence are unavoidable.However,the biological effects of aging may be turned back,and with those,it can be reduced risk of all age-related i...Unfortunately,ag ing is not a reversible phenomenon and the processes of senescence are unavoidable.However,the biological effects of aging may be turned back,and with those,it can be reduced risk of all age-related illnesses,such as cardiovascular diseases,cancer,diabetes,and neurodegenerative diseases,including Alzheimer’s disease(AD),and Parkinson’s diseases(PD).In the latest decades,scientists worldwide therefore have developed several strategies,either natural or pharmacological,to counteract aging phenomena,with the final goal to improve human life expectancy.The main scientific rationale beyond these strategies focuses on the opportunity to reduce chronic low-grade inflammation(inflammaging),the increase in oxidative stress damage,and the impairment in the immune system,all typical mechanisms of senescence(Verdaguer et al.,2012).展开更多
Given the interdependence of multiple factors in age-related vestibular loss (e.g., balance, vision,cognition), it is important to examine the individual contributions of these factors with ARVL. While therelationship...Given the interdependence of multiple factors in age-related vestibular loss (e.g., balance, vision,cognition), it is important to examine the individual contributions of these factors with ARVL. While therelationship between the vestibular and visual systems has been well studied (Bronstein et al., 2015),little is known about the association of the peripheral vestibular system with neurodegenerative disorders (Cronin et al., 2017). Further, emerging research developments implicate the vestibular system asan opportunity for examining brain function beyond balance, and into other areas, such as cognition andpsychological functioning. Additionally, the bidirectional impact of psychological functioning is understudied in ARVL. Recognition of ARVL as part of a multifaceted aging process will help guide thedevelopment of integrated interventions for patients who remain at risk for decline. In this review, wewill discuss a wide variety of characteristics of the peripheral vestibular system and ARVL, how it relatesto neurodegenerative diseases, and correlations between ARVL and balance, vision, cognitive, and psychological dysfunction. We also discuss clinical implications as well as future directions for research, withan emphasis on improving care for patients with ARVL.展开更多
Trial Registration:May 11th,2018 ClinicalTrials.gov Identifier:NCT03522129 https://clini caltr ials.gov/ct2/show/NCT03522129.Investigational therapies for Alzheimer’s disease(AD)target a wide range of mechanisms,yet ...Trial Registration:May 11th,2018 ClinicalTrials.gov Identifier:NCT03522129 https://clini caltr ials.gov/ct2/show/NCT03522129.Investigational therapies for Alzheimer’s disease(AD)target a wide range of mechanisms,yet promising dis-ease-modifying therapies remain a huge unmet need.Much evidence indicates that the oligomeric form of amyloid-beta(Aβ)is a toxic species contributing to AD through synaptic damage and neuronal toxicity[1].展开更多
Nowadays,it is a truism that chemists,bioengineers and others must be schooled in cell and molecular biology,including knowledge of the cellular,elemental and molecular building blocks of living systems.Inspired by ex...Nowadays,it is a truism that chemists,bioengineers and others must be schooled in cell and molecular biology,including knowledge of the cellular,elemental and molecular building blocks of living systems.Inspired by exquisite and efficient biomolecular machines in living cells,such as ATPases that catalyze the decomposition of ATP into ADP and free phosphate ion,researchers representing multiple disciplines are actively engaged in developing artificial nanostructures with well-defined geometry and nanoscale addressability.A successful outcome of these studies could lead to the development and clinical application of smart molecular machines for the drug delivery of theranostics in vivo.展开更多
Ultrathin two-dimensional （2D） porous Zn（OH）2 nanosheets （PNs） were fabricated by means of one-dimensional Cu nanowires as backbones. The PNs have thickness of approximately 3.8 nm and pore size of 4-10 nm. To f...Ultrathin two-dimensional （2D） porous Zn（OH）2 nanosheets （PNs） were fabricated by means of one-dimensional Cu nanowires as backbones. The PNs have thickness of approximately 3.8 nm and pore size of 4-10 nm. To form ＂smart＂ porous nanosheets, DNA aptamers were covalently conjugated to the surface of PNs. These ultrathin nanosheets show good biocompatibility, effident cellular uptaker and promising pH-stimulated drug release.展开更多
基金supported by the National Natural Science Foundation of China (11621505, 11435002, 31671016)
文摘Precise nanomedicine has been extensively explored for efficient cancer imaging and targeted cancer therapy, as evidenced by a few breakthroughs in their preclinical and clinical explorations. Here, we demonstrate the recent advances of intelligent cancer nanomedicine, and discuss the comprehensive understanding of their structure-function relationship for smart and efficient cancer nanomedicine including various imaging and therapeutic applications, as well as nanotoxicity. In particular, a few emerging strategies that have advanced cancer nanomedicine are also highlighted as the emerging focus such as tumor imprisonment, supramolecular chemotherapy, and DNA nanorobot. The challenge and outlook of some scientific and engineering issues are also discussed in future development. We wish to highlight these new progress of precise nanomedicine with the ultimate goal to inspire more successful explorations of intelligent nanoparticles for future clinical translations.
基金supported by the National Natural Science Foundation of China(Grant No.21827811)Research and development plan of key areas in Hunan Province(Grant No.2019SK2201)Innovation science and technology plan of Hunan Province(Grant No.2017XK2103).
文摘Investigation of metal–organic frameworks(MOFs)for biomedical applications has attracted much attention in recent years.MOFs are regarded as a promising class of nanocarriers for drug delivery owing to well-defined structure,ultrahigh surface area and porosity,tunable pore size,and easy chemical functionalization.In this review,the unique properties of MOFs and their advantages as nanocarriers for drug delivery in biomedical applications were discussed in the first section.Then,state-ofthe-art strategies to functionalize MOFs with therapeutic agents were summarized,including surface adsorption,pore encapsulation,covalent binding,and functional molecules as building blocks.In the third section,the most recent biological applications of MOFs for intracellular delivery of drugs,proteins,and nucleic acids,especially aptamers,were presented.Finally,challenges and prospects were comprehensively discussed to provide context for future development of MOFs as efficient drug delivery systems.
基金US NIH grants,NSF NIRT and State of Florida Center of Excellence for nano-biosensors。
文摘Advanced bioanalysis,including accurate quantitation,has driven the need to understand biology and medicine at the molecular level.Bioconjugated silica nanoparticles have the potential to address this emerging challenge.Particularly intriguing diagnostic and therapeutic applications in cancer and infectious disease as well as uses in gene and drug delivery,have also been found for silica nanoparticles.In this review,we describe the synthesis,bioconjugation,and applications of silica nanoparticles in different bioanalysis formats,such as selective tagging,barcoding,and separation of a wide range of biomedically important targets.Overall,we envisage that further development of these nanoparticles will provide a variety of advanced tools for molecular biology,genomics,proteomics and medicine.
文摘Chlorin e6-pHLIPss-AuNRs, a gold nanorod-photosensitizer conjugate containing a pH （low） insertion peptide （pHLIP） with a disulfide bond which imparts extracellular pH （pHe）-driven tumor targeting ability, has been successfully developed for bimodal photodynamic and photothermal therapy. In this bimodal therapy, chlorin e6 （Ce6）, a second-generation photosensitizer （PS）, is used for photodynamic therapy （PDT）. Gold nanorods （AuNRs） are used as a hyperthermia agent for photothermal therapy （PTT） and also as a nanocarrier and quencher of Ce6. pHLIPss is designed as a pile-driven targeting probe to enhance accumulation of Ce6 and AuNRs in cancer cells at low pH. In Ce6- pHLIPss-AuNRs, Ce6 is close to and quenched by AuNRs, causing little PDT effect. When exposed to normal physiological pH 7.4, Ce6-pHLIPs^-AuNRs loosely associate with the cell membrane. However, once exposed to acidic pH 6.2, pHLIP actively inserts into the cell membrane, and the conjugates are translocated into cells. When this occurs, Ce6 separates from the AuNRs as a result of disulfide bond cleavage caused by intracellular glutathione （GSH）, and singlet oxygen is produced for PDT upon light irradiation. In addition, as individual PTT agent, AuNRs can enhance the accumulation of PSs in the tumor by the enhanced permeation and retention （EPR） effect. Therefore, as indicated by our data, when exposed to acidic pH, Ce6-pHLIPss-AuNRs can achieve synergistic PTT/PDT bimodality for cancer treatment.
基金Acknowledgements We thank Dr. M. M. Gottesman at the National Cancer Institute for providing MCF7/MDR cells. We thank Dr. K. R. Williams for manuscript review. This work was supported by the National Institutes of Health （Nos. GM079359 and CA133086） and National Key Scientific Program of China （No. 2011CB911000）, the National Natural Science Foundation of China （NSFC） （Nos. 21325520, J1210040, 20975034 and 21177036）, the Foundation for Innovative Research Groups of NSFC （No. 21221003）, the National Key Natural Science Foundation of China （No. 21135001）, National Instru- mentation Program （No. 2011YQ030124）, the Ministry of Education of China （No. 20100161110011）, and the Hunan Provincial Natural Science Foundation （Nos. 12JJ6012 and 11JJ1002）.
文摘Cancer chemotherapy has been limited by its side effects and multidrug resistance （MDR）, the latter of which is partially caused by drug efflux from cancer cells. Thus, targeted drug delivery systems that can circumvent MDR are needed. Here, we report multifunctional DNA nanoflowers （NFs） for targeted drug delivery to both chemosensitive and MDR cancer cells that circumvented MDR in both leukemia and breast cancer cell models. NFs are self-assembled via potential co-precipitation of DNA and magnesium pyrophosphate generated by rolling circle replication, during which NFs are incorporated using aptamers for specific cancer cell recognition, fluorophores for bioimaging, and doxorubicin （Dox）- binding DNA for drug delivery. NF sizes are tunable （down to N200 nm in diameter）, and the densely packed drug-binding motifs and porous intrastructures endow NFs with a high drug-loading capacity （71.4%, wt/wt）. Although the Dox- loaded NFs （NF-Dox） are stable at physiological pH, drug release is facilitated under acidic or basic conditions. NFs deliver Dox into target chemosensitive and MDR cancer cells, preventing drug efflux and enhancing drug retention in MDR cells. NF-Dox induces potent cytotoxicity in both target chemosensitive cells and MDR cells, but not in nontarget cells, thus concurrently circumventing MDR and reducing side effects. Overall, these NFs are promising tools for circumventing MDR in targeted cancer therapy.
基金supported by Merit Review Awards(No.B6570R,B78071,and B1005-R)from the United States(U.S.)Department of Veterans Affairs Rehabilitation Research and Development Service
文摘Our recent findings have demonstrated that rodent models of closed head traumatic brain injury exhibit comprehensive evidence of progressive and enduring orofacial allodynias, a hypersensitive pain response induced by non-painful stimulation. These allodynias, tested using thermal hyperalgesia, correlated with changes in several known pain signaling receptors and molecules along the trigeminal pain pathway, especially in the trigeminal nucleus caudalis. This study focused to extend our previous work to investigate the changes in monoamine neurotransmitter immunoreactivity changes in spinal trigeminal nucleus oralis, pars interpolaris and nucleus tractus solitaries following mild to moderate closed head traumatic brain injury, which are related to tactile allodynia, touch-pressure sensitivity, and visceral pain. Our results exhibited significant alterations in the excitatory monoamine, serotonin, in spinal trigeminal nucleus oralis and pars interpolaris which usually modulate tactile and mechanical sensitivity in addition to the thermal sensitivity. Moreover, we also detected a robust alteration in the expression of serotonin, and inhibitory molecule norepinephrine in the nucleus tractus solitaries, which might indicate the possibility of an alteration in visceral pain, and existence of other morbidities related to solitary nucleus dysfunction in this rodent model of mild to moderate closed head traumatic brain injury. Collectively, widespread changes in monoamine neurotransmitter may be related to orofacial allodynhias and headache after traumatic brain injury.
基金supported by the McKnight Brain Institute,NIH Center Grant P30 EY014801,UM Dean's NIH Bridge Award(UM DBA 2019-3)a grant from Research to Prevent Blindness(RPB)and the North American Neuroophthalmology Society.
文摘Background:It remains unknow whether retinal tissue perfusion occurs in patients with Alzheimer’s disease.The goal was to determine retinal tissue perfusion in patients with clinical Alzheimer’s disease(CAD).Methods:Twenty-four CAD patients and 19 cognitively normal(CN)age-matched controls were recruited.A retinal function imager(RFI,Optical Imaging Ltd.,Rehovot,Israel)was used to measure the retinal blood flow supplying the macular area of a diameter of 2.5 mm centered on the fovea.Blood flow volumes of arterioles(entering the macular region)and venules(exiting the macular region)of the supplied area were calculated.Macular blood flow was calculated as the average of arteriolar and venular flow volumes.Custom ultra-high-resolution optical coherence tomography(UHR–OCT)was used to calculate macular tissue volume.Automated segmentation software(Orion,Voxeleron LLC,Pleasanton,CA)was used to segment six intra-retinal layers in the 2.5 mm(diameter)area centered on the fovea.The inner retina(containing vessel network),including retinal nerve fiber layer(RNFL),ganglion cell-inner plexiform layer(GCIPL),inner nuclear layer(INL)and outer plexiform layer(OPL),was segmented and tissue volume was calculated.Perfusion was calculated as the flow divided by the tissue volume.Results:The tissue perfusion in CAD patients was 2.58±0.79 nl/s/mm^(3)(mean±standard deviation)and was significantly lower than in CN subjects(3.62±0.44 nl/s/mm^(3),P<0.01),reflecting a decrease of 29%.The flow volume was 2.82±0.92 nl/s in CAD patients,which was 31%lower than in CN subjects(4.09±0.46 nl/s,P<0.01).GCIPL tissue volume was 0.47±0.04 mm^(3) in CAD patients and 6%lower than CN subjects(0.50±0.05 mm^(3),P<0.05).No other significant alterations were found in the intra-retinal layers between CAD and CN participants.Conclusions:This study is the first to show decreased retinal tissue perfusion that may be indicative of diminished tissue metabolic activity in patients with clinical Alzheimer’s disease.
基金the National Natural Science Foundation of China(Nos.21522501,21521063 and 61673405)Hunan Provincial Natural Science Foundation of China(No.2018JJ1007)the Science and Technology Development Fund of Macao S.A.R(FDCT,09772015/A3).
文摘Aptamer guided nano medicine shows great promise in targeted cancer therapies.However the loss of targeting capacity duri ng in vivo or clinical trials has largely hindered its popularity and there are no systematic studies to elucidate the causes.Herein,we investigated such loss of targeting capacity by examining how the physiological milieu affected targeting effect.Aptamer functionalized gold nanoparticle(AuNP)was chosen as the model and exposed to human blood serum that is used to mimic physiological milieu.Dynamic light scattering(DLS),flow cytometry and label-free liquid chromatography tan dem mass spectrometry(LC-MS/MS)were employed to determi ne variations of NPs'surface chemistry and biological identities changes after serum exposure.Results showed that the targeting ability loss was caused by protein corona blocking,replacement and enzymatic cleavage of surface aptamer targeting ligands.Noteworthy,the aggregation issue is critical for the smaller NPs.Analysis of the protein corona profile indicated the accumulation of immune-related proteins on the surface of aptamer-conjugated NPs,which could induce immune response,resulting in rapid clearanee of NPs.
基金by the NIH National Cancer Institute,R21CA122648,ONR N00014-07-1-0982,and the State of Florida Center of Excellence.M.-C.E.acknowledges fi nancial support from the Department d’Universitats,Recerca i Societat de la Informacióde la Generalitat de Catalunya,Spain.
文摘Early and accurate diagnosis and treatment of cancer depend on rapid,sensitive,and selective detection of tumor cells.Current diagnosis of cancers,especially leukemia,relies on histology and fl ow cytometry using single dye-labeled antibodies.However,this combination may not lead to high signal output,which can hinder detection,especially when the probes have relatively weak affi nities or when the receptor is expressed in a low concentration on the target cell surface.To solve these problems,we have developed a novel method for sensitive and rapid detection of cancer cells using dye-doped silica nanoparticles(NPs)which increases detection sensitivity in fl ow cytometry analyses between 10-and 100-fold compared to standard methods.Our NPs are~60 nm in size and can encapsulate thousands of individual dye molecules within their matrix.We have extensively investigated surface modifi cation strategies in order to make the NPs suitable for selective detection of cancer cells using fl ow cytometry.The NPs are functionalized with polyethylene glycol(PEG)to prevent nonspecifi c interactions and with neutravidin to allow universal binding with biotinylated molecules.By virtue of their reliable and selective detection of target cancer cells,these NPs have demonstrated their promising usefulness in conventional fl ow cytometry.Moreover,they have shown low background signal,high signal enhancement,and effi cient functionalization,either with antibody-or aptamer-targeting moieties.
基金Supported by National Institutes of Health,No.R01NS091542National Natural Science Foundation of China,No.81771149,No.U1704165。
文摘The progress of modern medicine would be impossible without the use of general anesthetics(GAs).Despite advancements in refining anesthesia approaches,the effects of GAs are not fully reversible upon GA withdrawal.Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly.Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research,but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects.The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents,which are far more extensively studied than any other species.Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated.Specifically,we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities(somatic effects),but also epigenetic reprogramming of germ cells(germ cell effects).The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring,who may be affected even at levels of anesthesia that are not harmful to the exposed parents.The large number of patients who require general anesthesia,the even larger number of their future unexposed offspring whose health may be affected,and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs.In this mini review,we discuss emerging experimental findings on neuroendocrine,epigenetic,and intergenerational effects of GAs.
文摘The mounting endemic of prescription iatrogenic opioid dependence in pain patients provoked this treatise about an alternative method that can be used to treat pain, improve function and reduce the risk of opioid dependence. It is well known that as well as the side effects reported for chronic opioid therapy, genetically predisposed individuals are at risk for opioid dependence. We propose the use of the Genetic Addiction Risk Score (GARS) assessment to identify patients early in treatment who should avoid narcotic pain medications. Primarily, this review will be an exploration of the mechanisms of action of an electrotherapeutic alternative to narcotic treatment that can be used to augment tissue healing and reduce the pain associated with human injuries and neuropathies. This particular electrotherapeutic device was developed at the Electronic Waveform Laboratory in Huntington Beach, California and is called the H-Wave? device. The primary effect of the H-Wave?device is stimulation (HWDS) of small diameter fibers of “red-slow-twitch” skeletal muscle. Mechanisms of action of HWDS have been investigated in both animal and human studies. They include edema reduction, induction of nitric oxide dependent augmented microcirculation and angiogenesis, small muscle contraction that eliminates transcapillary fluid shifts, reducing the painful effects of tetanizing fatigue and gradual loading of healing injured muscle tissue that helps repair and remodeling. A recent metaanalysis found a moderate-to-strong-positive effect of the HWDS in providing pain relief, reducing the requirement for pain medication, with the most robust effect being increased functionality. We are proposing that GARS can be used to identify those at risk of developing opioid dependence and that the need for opioid analgesia can be reduced by use of this electro therapeutic alternative to opioid analgesia in the treatment of pain and injuries.
基金Supported by the National Natural Science Foundation of China (Grant Nos. 60371045 & 60628101)the National High Technology Research and Development Program of China (Grant No. 2006AA01Z132)
文摘In fMRI experiments on object representation in visual cortex, we designed two types of stimuli: one is the gray face image and its line drawing, and the other is the illusion and its corresponding completed illusion. Both of them have the same global features with different minute details so that the results of fMRI experiments can be compared with each other. The first kind of visual stimuli was used in a block design fMRI experiment, and the second was used in an event-related fMRI experiment. Comparing and analyzing interesting visual cortex activity patterns and blood oxygenation level dependent (BOLD)- fMRI signal, we obtained results to show some invariance of global features of visual images. A plau- sible explanation about the invariant mechanism is related with the cooperation of synchronized re- sponse to the global features of the visual image with a feedback of shape perception from higher cortex to cortex V1, namely the integration of global features and embodiment of sparse representation and distributed population code.
基金supported by the National Natural Science Foundation of China (Nos.21522501, 21521063, 31701249, and 31601125)Hunan Provincial Natural Science Foundation of China (Nos.2018JJ1007 and 2018JJ3037)+1 种基金the keypoint research and invention program of Hunan province (No.2017DK2011)the Science and Technology Development Fund of Macao S.A.R (FDCT, 196/2017/A3).
文摘Precisely designed protein-based nanodrugs, as a kind of colloidal drug system, have attracted significant attention in tumor therapy because of their refined drug loading ratio, controlled delivery efficacy and natural biocompatibility. However, most drugs are conjugated to the protein carriers randomly without specific binding sites. Moreover, such sites could easily be replaced by lipophilic molecules in the physiological environment and result in low delivery efficiency. With strong and specific binding locations especially comparatively narrow spatial binding sites and nonflexible structure, hemin (FePPIX)-free hemoglobin or apohemoglobin (apoHb), as a natural metalloporphyrin protein carrier, represents great potential in bioapplication. Therefore, we herein introduce a folate acid (FA) modified, zinc-substituted hemoglobin (ZnPHb-FA) as a naturally occurring protein matrix-based photosensitizer for cancer photodynamic therapy (PDT). Noncovalent inserted ZnPPIX molecules in apoHb possess an extremely stable property and significant recovered photoproperties with superior biocompatibility and phototoxicity, both in vitro and in vivo. This stability was verified by molecular docking analysis and calculation of binding constant, representing a total of five drug binding sites of apoHb for ZnPPIX molecules, four of which are energetically favorable (△G value of -11.9 kcal/mol), and one which is energetically acceptable (△G value of -9 kcal/mol). Folate acid modification has been shown to efficiently enhance the internalization and retention time of ZnPHb nanodrug. ZnPHb-FA is also an efficient depressor of hemin oxygenase-1 (HO-1), which could, in turn, lower the antioxidant ability of cancer cells by decreasing the production of biiirublin. Results in vitro and in vivo both indicated that the firmly combination of apoHb and ZnPPIX described here represents a novel and efficient protein nanodrug systems for cancer therapy.
基金supported by an Alzheimer’s Research Trust(UK)Programme Grant(ART/PG2004A/1)to A.V.by a National Science Foundation grant(CBET 0943343)to V.P
文摘Neuroglial cells are homeostatic neural cells. Generally, they are electrically non-excitable and their activation is associated with the generation of complex intracellular Ca^2＋ signals that define the ＂Ca^2＋ excitability＂ of glia. In mammalian glial cells the major source of Ca^2＋ for this excitability is the lumen of the endoplasmic reticulum （ER）, which is ultimately （re）filled from the extracellular space. This occurs via store-operated Ca^2＋ entry （SOCE） which is supported by a specific signaling system connecting the ER with plasmalemmal Ca^2＋ entry. Here, emptying of the ER Ca^2＋ store is necessary and sufficient for the activation of SOCE, and without Ca^2＋ influx via SOCE the ER store cannot be refilled. The molecular arrangements underlying SOCE are relatively complex and include plasmalemmal channels, ER Ca^2＋ sensors, such as stromal interaction molecule, and possibly ER Ca^2＋ pumps （of the SERCA type）. There are at least two sets of plasmalemmal channels mediating SOCE, the Ca2＊-release activated channels, Orai, and transient receptor potential （TRP） channels. The molecular identity of neuroglial SOCE has not been yet identified unequivocally. However, it seems that Orai is predominantly expressed in microglia, whereas astrocytes and oligodendrocytes rely more on TRP channels to produce SOCE. In physiological conditions the SOCE pathway is instrumental for the sustained phase of the Ca^2＋ signal observed following stimulation of metabotropic receptors on glial cells.
基金supported in part by The Evelyn F.McKnight Brain Institute.
文摘Unfortunately,ag ing is not a reversible phenomenon and the processes of senescence are unavoidable.However,the biological effects of aging may be turned back,and with those,it can be reduced risk of all age-related illnesses,such as cardiovascular diseases,cancer,diabetes,and neurodegenerative diseases,including Alzheimer’s disease(AD),and Parkinson’s diseases(PD).In the latest decades,scientists worldwide therefore have developed several strategies,either natural or pharmacological,to counteract aging phenomena,with the final goal to improve human life expectancy.The main scientific rationale beyond these strategies focuses on the opportunity to reduce chronic low-grade inflammation(inflammaging),the increase in oxidative stress damage,and the impairment in the immune system,all typical mechanisms of senescence(Verdaguer et al.,2012).
文摘Given the interdependence of multiple factors in age-related vestibular loss (e.g., balance, vision,cognition), it is important to examine the individual contributions of these factors with ARVL. While therelationship between the vestibular and visual systems has been well studied (Bronstein et al., 2015),little is known about the association of the peripheral vestibular system with neurodegenerative disorders (Cronin et al., 2017). Further, emerging research developments implicate the vestibular system asan opportunity for examining brain function beyond balance, and into other areas, such as cognition andpsychological functioning. Additionally, the bidirectional impact of psychological functioning is understudied in ARVL. Recognition of ARVL as part of a multifaceted aging process will help guide thedevelopment of integrated interventions for patients who remain at risk for decline. In this review, wewill discuss a wide variety of characteristics of the peripheral vestibular system and ARVL, how it relatesto neurodegenerative diseases, and correlations between ARVL and balance, vision, cognitive, and psychological dysfunction. We also discuss clinical implications as well as future directions for research, withan emphasis on improving care for patients with ARVL.
基金supported by grants from the National Institute on Aging(AG057780 to SMC)and by Cognition Therapeutics,Inc.
文摘Trial Registration:May 11th,2018 ClinicalTrials.gov Identifier:NCT03522129 https://clini caltr ials.gov/ct2/show/NCT03522129.Investigational therapies for Alzheimer’s disease(AD)target a wide range of mechanisms,yet promising dis-ease-modifying therapies remain a huge unmet need.Much evidence indicates that the oligomeric form of amyloid-beta(Aβ)is a toxic species contributing to AD through synaptic damage and neuronal toxicity[1].
文摘Nowadays,it is a truism that chemists,bioengineers and others must be schooled in cell and molecular biology,including knowledge of the cellular,elemental and molecular building blocks of living systems.Inspired by exquisite and efficient biomolecular machines in living cells,such as ATPases that catalyze the decomposition of ATP into ADP and free phosphate ion,researchers representing multiple disciplines are actively engaged in developing artificial nanostructures with well-defined geometry and nanoscale addressability.A successful outcome of these studies could lead to the development and clinical application of smart molecular machines for the drug delivery of theranostics in vivo.
基金The authors are grateful to Dr. Kathryn Williams for her critical comments during the preparation of this manuscript. This work is supported by grants awarded by the National Institutes of Health （No. GM079359 and CA133086）. This work is also supported by the National Basic Research Program of China （No. 2011CB911000）, National Natural Science Foundation of China （Nos. 21221003 and 21327009） and China National Instrumentation Program （No. 2011YQ03012412）.
文摘Ultrathin two-dimensional （2D） porous Zn（OH）2 nanosheets （PNs） were fabricated by means of one-dimensional Cu nanowires as backbones. The PNs have thickness of approximately 3.8 nm and pore size of 4-10 nm. To form ＂smart＂ porous nanosheets, DNA aptamers were covalently conjugated to the surface of PNs. These ultrathin nanosheets show good biocompatibility, effident cellular uptaker and promising pH-stimulated drug release.
