Therapeutic proteins have increased dramatically in both number and frequency of use in recent years, primarily owing to advances in protein engineering. Protein therapy provides the advantages of ...high potency and specificity, as well as low oncogenic risks. To date, due to their inability to cross the plasma membrane into the intracellular space of mammalian cells, most therapeutic proteins can only target secreted modulators or extracellular receptors. The full potential of protein therapy is, however, being gradually realized by the development of various strategies capable of intracellular protein delivery. Notwithstanding, most of these strategies suffer from severe endosomal trapping, resulting in very low protein delivery efficiency. In this Perspective, we discuss various methods to directly transport proteins into the cell cytoplasm, thus bypassing the problems associated with endocytosis.
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IJS, KILJ, NUK, PNG, UL, UM
We consider the fidelity of the vector meson dominance (VMD) assumption as an instrument for relating the electromagnetic vector-meson production reaction
e
+
p
→
e
′
+
V
+
p
to the purely hadronic ...process
V
+
p
→
V
+
p
. Analyses of the photon vacuum polarisation and the photon-quark vertex reveal that such a VMD
Ansatz
might be reasonable for light vector-mesons. However, when the vector-mesons are described by momentum-dependent bound-state amplitudes, VMD fails for heavy vector-mesons: it cannot be used reliably to estimate either a photon-to-vector-meson transition strength or the momentum dependence of those integrands that would arise in calculations of the different reaction amplitudes. Consequently, for processes involving heavy mesons, the veracity of both cross-section estimates and conclusions based on the VMD assumption should be reviewed, e.g., those relating to hidden-charm pentaquark production and the origin of the proton mass.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background and purpose
Previous studies suggested that the overall burden of prior infections contributes to cardiovascular diseases and stroke. In the present study, the association between ...infectious burden (IB) and Alzheimer's disease (AD) was examined.
Methods
Antibody titers to common infectious pathogens including cytomegalovirus (CMV), herpes simplex virus type 1 (HSV‐1), Borrelia burgdorferi, Chlamydophila pneumoniae and Helicobacter pylori were measured by enzyme‐linked immunosorbent assay in 128 AD patients and 135 healthy controls. IB was defined as a composite serological measure of exposure to these common pathogens.
Results
Seropositivities toward zero−two, three and four−five of these pathogens were found in 44%, 40% and 16% of healthy controls but in 20%, 44% and 36% of AD patients, respectively. IB, bacterial burden and viral burden were independently associated with AD after adjusting for age, gender, education, APOE genotype and various comorbidities. Mini‐Mental State Examination scores were negatively correlated with IB in all cases. Serum beta‐amyloid protein (Aβ) levels (i.e. Aβ40, Aβ42 and total Aβ) and inflammatory cytokines (i.e. interferon‐γ, tumor necrosis factor α, interleukin‐1β and interleukin‐6) in individuals exposed to four−five infectious pathogens were significantly higher than those exposed to zero−two or three pathogens.
Conclusions
IB consisting of CMV, HSV‐1, B. burgdorferi, C. pneumoniae and H. pylori is associated with AD. This study supports the role of infection/inflammation in the etiopathogenesis of AD.
Click here to view the accompanying paper in this issue. Videocasts of this article are available in: English: http://player.polyv.net/videos/player.swf?vid=f6ee5715d9808c7a481b7ae727da00dd_f Mandarin: http://player.polyv.net/videos/f6ee5715d98ae743a9b0509d0900c91f_f.swf
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Protein/antibody therapeutics have exhibited the advantages of high specificity and activity even at an extremely low concentration compared to small molecule drugs. However, they are accompanied by ...unfavorable physicochemical properties such as fragile tertiary structure, large molecular size, and poor penetration of the membrane, and thus the clinical use of protein drugs is hindered by inefficient delivery of proteins into the host cells. To overcome the challenges associated with protein therapeutics and enhance their biopharmaceutical applications, various protein‐loaded nanocarriers with desired functions, such as lipid nanocapsules, polymeric nanoparticles, inorganic nanoparticles, and peptides, are developed. In this review, the different strategies for intracellular delivery of proteins are comprehensively summarized. Their designed routes, mechanisms of action, and potential therapeutics in live cells or in vivo are discussed in detail. Furthermore, the perspective on the new generation of delivery systems toward the emerging area of protein‐based therapeutics is presented as well.
Intracellular protein delivery is a powerful tool for a wide array of therapeutic purposes. Various nanoparticle‐based systems for intracellular delivery of proteins are comprehensively summarized. Their designed routes, action mechanisms, and potential therapeutics are discussed in detail. Furthermore, the perspective of new generation delivery systems toward the emerging area of protein‐based therapeutics is presented.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Mitochondria are the powerhouse of cells. They are vital organelles that maintain cellular function and metabolism. Dysfunction of mitochondria results in various diseases with a great diversity of ...clinical appearances. In the past, strategies have been developed for fabricating subcellular‐targeting drug‐delivery nanocarriers, enabling cellular internalization and subsequent organelle localization. Of late, innovative strategies have emerged for the smart design of multifunctional nanocarriers. Hierarchical targeting enables nanocarriers to evade and overcome various barriers encountered upon in vivo administration to reach the organelle with good bioavailability. Stimuli‐responsive nanocarriers allow controlled release of therapeutics to occur at the desired target site. Synergistic therapy can be achieved using a combination of approaches such as chemotherapy, gene and phototherapy. In this Review, we survey the field for recent developments and strategies used in the smart design of nanocarriers for mitochondria‐targeted therapeutics. Existing challenges and unexplored therapeutic opportunities are also highlighted and discussed to inspire the next generation of mitochondrial‐targeting nanotherapeutics.
Smart design of nanotherapeutics: Mitochondria play pivotal roles in regulating cell survival and death. They have become important targets in organelle‐targeted therapy. This Review highlights a collection of the latest advances in the design strategies of multifunctional mitochondria‐targeted nanotherapeutics.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cancer has been one of the most common life‐threatening diseases for a long time. Traditional cancer therapies such as surgery, chemotherapy (CT), and radiotherapy (RT) have limited effects due to ...drug resistance, unsatisfactory treatment efficiency, and side effects. In recent years, photodynamic therapy (PDT), photothermal therapy (PTT), and chemodynamic therapy (CDT) have been utilized for cancer treatment owing to their high selectivity, minor resistance, and minimal toxicity. Accumulating evidence has demonstrated that selective delivery of drugs to specific subcellular organelles can significantly enhance the efficiency of cancer therapy. Mitochondria‐targeting therapeutic strategies are promising for cancer therapy, which is attributed to the essential role of mitochondria in the regulation of cancer cell apoptosis, metabolism, and more vulnerable to hyperthermia and oxidative damage. Herein, the rational design, functionalization, and applications of diverse mitochondria‐targeting units, involving organic phosphine/sulfur salts, quaternary ammonium (QA) salts, peptides, transition‐metal complexes, guanidinium or bisguanidinium, as well as mitochondria‐targeting cancer therapies including PDT, PTT, CDT, and others are summarized. This review aims to furnish researchers with deep insights and hints in the design and applications of novel mitochondria‐targeting agents for cancer therapy.
The concept of “Mito‐Bomb Tumor Therapy” is proposed from an interdisciplinary perspective of “biology–chemistry–materials,” and the biological functions of mitochondria, mitochondria‐targeting functional units, and various cancer treatment strategies that target mitochondria, including but not limited to photothermal therapy, photodynamic therapy, and chemodynamic therapy are summarized in detail.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Mitochondria are key organelles in mammalian cells whose dysfunction is linked to various diseases. Drugs targeting mitochondrial proteins provide a highly promising strategy for potential ...therapeutics. Methods for the delivery of small‐molecule drugs to the mitochondria are available, but these are not suitable for macromolecules, such as proteins. Herein, we report the delivery of native proteins and antibodies to the mitochondria using biodegradable silica nanoparticles (BS–NPs). The modification of the nanoparticle surface with triphenylphosphonium (TPP) and cell‐penetrating poly(disulfide)s (CPD) facilitated their rapid intracellular uptake with minimal endolysosomal trapping, providing sufficient time for effective mitochondrial localization followed by glutathione‐triggered biodegradation and of native, functional proteins into the mitochondria.
Selective delivery: Biodegradable silica nanoparticles, decorated with cell‐penetrating poly(disulfide)s and triphenylphosphonium, which enables their transport into the mitochondria, degrade upon encountering glutathione in the mitochondria, thereby releasing encapsulated proteins. This strategy could be useful for the targeted delivery of protein‐based therapeutics.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The design of drug delivery systems capable of minimal endolysosomal trapping, controlled drug release, and real‐time monitoring of drug effect is highly desirable for personalized medicine. Herein, ...by using mesoporous silica nanoparticles (MSNs) coated with cell‐penetrating poly(disulfide)s and a fluorogenic apoptosis‐detecting peptide (DEVD‐AAN), we have developed a platform that could be uptaken rapidly by mammalian cells via endocytosis‐independent pathways. Subsequent loading of these MSNs with small molecule inhibitors and antisense oligonucleotides resulted in intracellular release of these drugs, leading to combination inhibition of endogenous miR‐21 activities which was immediately detectable by the MSN surface‐coated peptide using two‐photon fluorescence microscopy.
Combine and detect: Mesoporous silica nanoparticles are coated with cell‐penetrating poly(disulfide)s and a fluorogenic apoptosis‐detecting peptide. The result is a theranostic drug delivery system for endocytosis‐independent delivery/controlled release of combination drugs for the inhibition of endogenous miR‐21 with simultaneous detection of subsequent drug effects by two‐photon fluorescence microscopy.
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Covering: 2010 to 2014.
Advances in isolation, synthesis and screening strategies have made many bioactive substances available. However, in most cases their putative biological targets remain ...unknown. Herein, we highlight recent advances in target identification of natural products and bioactive compounds by using affinity-based probes. Aided by photoaffinity labelling, this strategy can capture potential cellular targets (on and off) of a natural product or bioactive compound in live cells directly, even when the compound-target interaction is reversible with moderate affinity. The knowledge of these targets may help uncover molecular pathways and new therapeutics for currently untreatable diseases. In this highlight, we will introduce the development of various photoactivatable groups, their synthesis and applications in target identification of natural products and bioactive compounds, with a focus on work done in recent years and from our laboratory. We will further discuss the strengths and weaknesses of each group and the outlooks for this novel proteome-wide profiling strategy.
Direct capture of drug-target complexes
in situ
by using affinity-based probes allows target identification of natural products and bioactive compounds, even if the binding is reversible with moderate affinity.
Activity-based protein profiling (ABPP) is a technique that uses highly selective active-site targeted chemical probes to label and monitor the state of proteins. ABPP integrates the strengths of ...both chemical and biological disciplines. By utilizing chemically synthesized or modified bioactive molecules, ABPP is able to reveal complex physiological and pathological enzyme-substrate interactions at molecular and cellular levels. It is also able to provide critical information of the catalytic activity changes of enzymes, annotate new functions of enzymes, discover new substrates of enzymes, and allow real-time monitoring of the cellular location of enzymes. Based on the mechanism of probe-enzyme interaction, two types of probes that have been used in ABPP are activity-based probes (ABPs) and affinity-based probes (A
f
BPs). This review highlights the recent advances in the use of ABPs and A
f
BPs, and summarizes their design strategies (based on inhibitors and substrates) and detection approaches.
This review highlights the recent advances in the use of activity-based probes (ABPs) and affinity-based probes (A
f
BPs), and summarizes their design strategies (based on inhibitors and substrates) and detection approaches.
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