Melatonin-related signaling pathways and their regulatory effects in aging organisms.

Melatonin is a tryptophan-derived ancestral molecule evolved in bacteria. According to the endosymbiotic theory, eukaryotic cells received mitochondria, plastids, and other organelles from bacteria by internalization. After the endosymbiosis, bacteria evolved into organelles and retained their ability of producing melatonin. Melatonin is a small, evolutionarily conserved indole with multiple receptor-mediated, receptor-dependent, and independent actions. Melatonin's initial function was likely a radical scavenger in bacteria that's why there was high intensity of free radicals on primitive atmosphere in the ancient times, and hormetic functions of melatonin, which are effecting through the level of gene expression via prooxidant and antioxidant redox pathways, are developed in throughout the eukaryotic evolution. In the earlier stages of life, endosymbiotic events between mitochondria and other downstream organelles continue with mutual benefits. However, this interaction gradually deteriorates as a result of the imperfection of both mitochondrial and extramitochondrial endosymbiotic crosstalk with the advancing age of eukaryotic organisms. Throughout the aging process melatonin levels tend to reduce and as a manifestation of this, many symptoms in organisms' homeostasis, such as deterioration in adjustment of cellular clocks, are commonly seen. In addition, due to deterioration in mitochondrial integrity and functions, immunity decreases, and lower levels of melatonin renders older individuals to be more susceptible to impaired redox modulation and age-related diseases. Our aim in this paper is to focus on the several redox modulation mechanisms in which melatonin signaling has a central role, to discuss melatonin's gerontological aspects and to provide new research ideas with researchers.

Precision-cut liver slices as a model for assess hepatic cellular response of chitosan-glutathione nanoparticles on cultures treated with zilpaterol and clenbuterol.

Zilpaterol and clenbuterol are two ß-adrenergic agonist drugs used in animal production. Both drugs have anabolic effects with advantages on carcass yield. Meanwhile, zilpaterol is approved for animal feed in authorized countries. Clenbuterol is a banned substance due to the risk of toxicity; however, it is still being used in unknown dose levels in many farm species. Therefore, the use and abuse of these substances should be closely monitored, considering the clenbuterol ability and the not proved yet of zilpaterol to produce reactive oxygen and nitrogen species. Regarding glutathione which is the main intracellular antioxidant plays detoxification functions on liver metabolism; in this work, it is our interest to know the capacity of chitosan-glutathione nanoparticles (CS/GSH-NP) as a complementary source of exogenous GSH to modify the oxide-reduction status on bovine precision-cut liver slice cultures (PCLS) exposed to clenbuterol and zilpaterol. A single drug assay was performed in first instance by adding clenbuterol, zilpaterol, chitosan nanoparticles (CS-NP), and CS/GSH-NP. Then combinate drug assay was carried out by testing clenbuterol and zilpaterol combined with CS-NP or CS/GSH-NP. The results showed that both ß-adrenergic agonists modify in a dose-dependent manner in oxide-reduction response through ROS generation. The activity or content of glutathione peroxidase activity, intracellular GSH, gamma glutamyl-transpeptidase, aspartate aminotrasnferase and alanine aminotrasnferase were modified. The exogenous GSH delivered by nanoparticles could be used to modulate these markers.

Lutein inhibits breast cancer cell growth by suppressing antioxidant and cell survival signals and induces apoptosis.

Reduced risk of breast cancer upon intake of lutein-rich food supplements creates an interest to investigate the molecular mechanism underlying the growth inhibitory potential of lutein in MCF-7 and MDA-MB-231 cells. Lutein purified from Spinacia oleracea was identified by high-performance liquid chromatography and liquid chromatography-mass spectrometry. The cell viability was measured by water-soluble tetrazolium-1 assay. The intracellular reactive oxygen species level was examined by 2',7'-dichlorofluorescein assay. The protein expression of the markers of antioxidant defense, cell survival, and apoptosis was analyzed by western blot analysis. The induction of apoptosis by lutein was measured by 4',6-diamidino-2-phenylindole staining and caspase-3 activity assay. The purified lutein inhibited the viability of MCF-7 and MDA-MB-231 cells. The growth inhibitory effect of lutein was associated with suppressed protein expression of superoxide dismutase-2 and heme oxygenase-1, and its transcription factor nuclear factor erythroid 2-related factor-2. Lutein treatment subsequently blocked the expression of intracellular cell survival proteins, phosphorylated protein kinase B, phosphorylated extracellular-regulated kinase 1/2, and nuclear factor-kB. Suppression of antioxidant defense and cell survival markers by lutein was further linked to apoptosis induction with elevated caspase-3 activity and downregulated expression of Bcl-2 and poly-ADP ribose polymerase. Our results emphasize a significant role of lutein as an effective inhibitor of human breast cancer cell growth that activates cell death partly through the modulation of antioxidant defense response-linked cell survival signaling markers.

Redox-responsive micelles from disulfide bond-bridged hyaluronic acid-tocopherol succinate for the treatment of melanoma.

Nanotechnology-based chemotherapy is efficient in cancer treatment due to the targeted delivery of small molecules via nano-carriers, which are usually regarded as "inert". However, nano-materials are more preferred as carriers since many cause synergistic anti-tumor effects along with the drug cargo. In this study, a "bioactive" tocopherol succinate (TOS) was grafted to hyaluronic acid (HA) via of disulfide bonds to obtain HA-ss-TOS conjugates which can assemble into nano-micelles but dissociate when exposed to reducing environments in vitro and in vivo. Moreover, paclitaxel-loaded HA-ss-TOS micelles (HA-ss-TOS-PTX) can be efficiently taken up by B16F10 cells overexpressing CD 44, thereafter exhibiting enhanced cytotoxicity. The in vivo imaging study here revealed much greater tumor accumulation of Dir-labeled HA-ss-TOS compared to the free Dir group. In vivo antitumor activities further ensured that the PTX-loaded HA-ss-TOS micelles provided superior antineoplastic responses versus PTX-loaded HA-TOS micelles and Taxol. Moreover, the subcellular dissociated TOS from HA-ss-TOS showed synergistic effects with PTX. These experimental results revealed that reduction-responsive PTX-loaded polymeric nano-micelles with multi-functional properties hold great potential for anti-tumor treatment and, thus, should be further studied.

Hydrophobic Cysteine Poly(disulfide)-based Redox-Hypersensitive Nanoparticle Platform for Cancer Theranostics.

Selective tumor targeting and drug delivery are critical for cancer treatment. Stimulus-sensitive nanoparticle (NP) systems have been designed to specifically respond to significant abnormalities in the tumor microenvironment, which could dramatically improve therapeutic performance in terms of enhanced efficiency, targetability, and reduced side-effects. We report the development of a novel L-cysteine-based poly (disulfide amide) (Cys-PDSA) family for fabricating redox-triggered NPs, with high hydrophobic drug loading capacity (up to 25 wt% docetaxel) and tunable properties. The polymers are synthesized through one-step rapid polycondensation of two nontoxic building blocks: L-cystine ester and versatile fatty diacids, which make the polymer redox responsive and give it a tunable polymer structure, respectively. Alterations to the diacid structure could rationally tune the physicochemical properties of the polymers and the corresponding NPs, leading to the control of NP size, hydrophobicity, degradation rate, redox response, and secondary self-assembly after NP reductive dissociation. In vitro and in vivo results demonstrate these NPs' excellent biocompatibility, high selectivity of redox-triggered drug release, and significant anticancer performance. This system provides a promising strategy for advanced anticancer theranostic applications.

Novel free-paclitaxel-loaded redox-responsive nanoparticles based on a disulfide-linked poly(ethylene glycol)-drug conjugate for intracellular drug delivery: synthesis, characterization, and antitumor activity in vitro and in vivo.

To address the obstacles facing cancer chemotherapeutics, including toxicity, side effects, water insolubility, and lack of tumor selectivity, a novel stimuli-responsive drug-delivery system was developed based on paclitaxel-loaded poly(ethylene glycol)-disulfide-paclitaxel conjugate nanoparticles (PEG-SS-PTX/PTX NPs). The formulation emphasizes several benefits, including polymer-drug conjugates/prodrugs, self-assembled NPs, high drug content, redox responsiveness, and programmed drug release. The PTX-loaded, self-assembled NPs, with a uniform size of 103 nm, characterized by DLS, TEM, XRD, DSC, and (1)H NMR, exhibited excellent drug-loading capacity (15.7%) and entrapment efficiency (93.3%). PEG-SS-PTX/PTX NPs were relatively stable under normal conditions but disassembled quickly under reductive conditions, as indicated by their triggered-aggregation phenomena and drug-release profile in the presence of dithiothreitol (DTT), a reducing agent. Additionally, by taking advantage of the difference in the drug-release rates between physically loaded and chemically conjugated drugs, a programmed drug-release phenomenon was observed, which was attributed to a higher concentration and longer action time of the drugs. The influence of PEG-SS-PTX/PTX NPs on in vitro cytotoxicity, cell cycle progression, and cellular apoptosis was determined in the MCF-7 cell line, and the NPs demonstrated a superior anti-proliferative activity associated with PTX-induced cell cycle arrest in G2/M phase and apoptosis compared to their nonresponsive counterparts. Moreover, the redox-responsive NPs were more efficacious than both free PTX and the non-redox-responsive formulation at equivalent doses of PTX in a breast cancer xenograft mouse model. This redox-responsive PTX drug delivery system is promising and can be explored for use in effective intracellular drug delivery.

Liver-Targeted Nanoparticles Loaded with Cannabidiol Based on Redox Response for Effective Alleviation of Acute Liver Injury.

The purpose of this work was to construct liver-targeted nanoparticles based on the redox response to effectively deliver cannabidiol (CBD) for the prevention of acute liver injury (ALI). CBD-loaded nanoparticles (CBD NPs) with a particle size of 126.5 ± 1.56 nm were prepared using the polymer DA-PP-LA obtained by grafting pullulan polysaccharide with deoxycholic acid (DA) and α-lipoic acid (α-LA). CBD NPs showed typical redox-response release behavior. Interestingly, CBD NPs exhibited admirable liver targeting ability, significantly accumulated in the liver, and effectively promoted the internalization of CBD in liver cells, thus effectively reducing the H2O2-induced oxidative damage of HepG2 cells and avoiding apoptosis. More importantly, CBD NPs effectively prevented CCl4-induced ALI by protecting liver function, ameliorating oxidative stress levels, inhibiting the production of inflammatory factors, and protecting the liver from histological damage. This study provides a promising strategy for achieving targeted delivery of CBD NPs in the liver, thereby effectively preventing ALI.

Engineered exosomes with enhanced stability and delivery efficiency for glioblastoma therapy.

Due to the blood-brain barrier (BBB), the application of chemical drugs for glioblastoma treatment is severely limited. Recently, exosomes have been widely applied for drug delivery to the brain. However, the differences in brain targeting efficiency among exosomes derived from different cell sources, as well as the premature drug leakage during circulation, still limit the therapeutic efficacy. Here, we designed a functional oligopeptide-modified exosome loaded with doxorubicin (Pep2-Exos-DOX) for glioblastoma treatment. BV2 mouse microglial cell line was selected as the exosome source due to the favorable BBB penetration. To avoid drug release in the circulation, a redox-response oligopeptide was designed for incorporation into the membranes of exosomes to lock the drug during circulation. The enrichment of the drug in glioblastoma was confirmed. Pharmacodynamic evaluation showed Pep2-Exos-DOX possessed significant anti-cancer activity against glioblastoma as well as relative biosafety. This exosome-based drug delivery system modified with redox-response oligopeptides provides us a novel strategy for brain diseases treatment.

ROS-responsive charge reversal mesoporous silica nanoparticles as promising drug delivery system for neovascular retinal diseases.

Intravitreal injection of biodegradable implant drug carriers shows promise in reducing the injection frequency for neovascular retinal diseases. However, current intravitreal ocular devices have limitations in adjusting drug release rates for individual patients, thereby affecting treatment effectiveness. Accordingly, we developed mesoporous silica nanoparticles (MSNs) featuring a surface that reverse its charge in response to reactive oxygen species (ROS) for efficient delivery of humanin peptide (HN) to retinal epithelial cells (ARPE-19). The MSN core, designed with a pore size of 2.8 nm, ensures a high HN loading capacity 64.4% (w/w). We fine-tuned the external surface of the MSNs by incorporating 20% Acetyl-L-arginine (Ar) to create a partial positive charge, while 80% conjugated thioketal (TK) methoxy polyethylene glycol (mPEG) act as ROS gatekeeper. Ex vivo experiments using bovine eyes revealed the immobilization of Ar-MSNs-TK-PEG (mean zeta potential: 2 mV) in the negatively charged vitreous. However, oxidative stress reversed the surface charge to -25 mV by mPEG loss, facilitating the diffusion of the nanoparticles impeded with HN. In vitro studies showed that ARPE-19 cells effectively internalize HN-loaded Ar-MSNs-TK, subsequently releasing the peptide, which offered protection against oxidative stress-induced apoptosis, as evidenced by reduced TUNEL and caspase3 activation. The inhibition of retinal neovascularization was further validated in an in vivo oxygen-induced retinopathy (OIR) mouse model.

Rapid redox-response featured visual ascorbic acid sensor based on simple-assembled europium metal-organic framework.

A facile, fast and visible sensing platform for ascorbic acid (AA) detection has been developed based on self-assembled hydrangea-like europium metal-organic framework (HL-EuMOF). HL-EuMOF was synthesized through a simple one-step mixing process with Eu3+ and 1, 10-phenanthroline-2, 9-dicarboxylic acid at room temperature, which exhibited excellent properties including strong red fluorescence, long decay lifetime (548.623 µs) and good luminescent stability. Based on the specific redox reaction between Fe3+ and AA, the HL-EuMOF@Fe3+ was fabricated with "turn-off" response for AA, where the resulting Fe2+ displayed effective fluorescence quenching ability toward HL-EuMOF. The sensor demonstrated low detection limit (31.94 nM), rapid response time (30 s) and high selectivity. Integration of smartphone-assisted RGB analysis with HL-EuMOF@Fe3+ permitted convenient and visible quantitative determination of AA level. This approach also presented good detection performances in complex human serum and beverage samples, which could provide a valuable tool for AA detection in biomedical research and food industry.

Mitochondria-associated cellular senescence mechanisms: Biochemical and pharmacological perspectives.

Initially, endosymbiotic relation of mitochondria and other cellular compartments had been continued mutually. However, that evolutionary adaptation impaired because of the deterioration of endosymbiotic crosstalk due to aging and several pathological consequences in cellular redox status are seen, such as deterioration in redox integrity of mitochondria, interfered inter-organelle redox signaling and inefficient antioxidant response element mediated gene expression. Although the dysfunction of mitochondria is known to be a classical pattern of senescence, it is unresolved that why dysfunctional mitochondria is the core of senescence-associated secretory phenotype (SASP). Redox impairment and SASP-related disease development are generally together with weaken immunity. Impaired mitochondrial redox integrity and its ineffectiveness in immunity control render elders to be more prone to age-related diseases. As senotherapeutic agents, senolytics remove senescent cells whilst senomorphics/senostatics inhibits the secretion of SASP. Senotherapeutics and the novel approaches for ameliorating SASP-related unfavorable effects are recently thought to be promising ways as mitochondria-targeted gerotherapeutic options.

Allicin-Loaded Intelligent Hydrogel Coating Improving Vascular Implant Performance.

Coronary atherosclerosis is closely related to inflammation and oxidative stress. Owing to poor biocompatibility, lack of personalized treatment, and late toxic side effects, traditional drug-eluting stent intervention, releasing antiproliferative drugs, can delay endothelial repair and cause late thrombosis. The inflammation caused by atherosclerosis results in an acidic microenvironment and oxidative stress, which can be considered as triggers for precise and intelligent treatment. Here, we used catechol hyaluronic acid (C-HA) and cystamine (Cys) to prepare C-HA-Cys hydrogel coatings by amide reaction. The H2S-releasing donor allicin was loaded in the hydrogel to form an intelligent biomimetic coating. The disulfide bond of Cys made the cross-linked network redox-responsive to the inflammation and oxidative stress in the microenvironment by releasing the drug and H2S intelligently to combat the side effects of stent implantation. This study evaluated the hemocompatibility, anti-inflammatory capacity, vascular wall cytocompatibility, and in vivo histocompatibility of this intelligent hydrogel coating. Furthermore, the effect of H2S released from the coating on atherosclerosis-related signaling pathways such as CD31 and cystathionine γ-lyase (CSE), CD36, and ACAT-1 was investigated. Our results indicate that the C-HA-Cys-Allicin hydrogel coating could be manufactured on the surface of vascular interventional devices to achieve a precise response to the microenvironment of the lesion to release drug, which can attain the purpose of prevention of in-stent restenosis and ensure the effectiveness and safety of the application of interventional devices.

New Insights into Dyskerin-CypA Interaction: Implications for X-Linked Dyskeratosis Congenita and Beyond.

The highly conserved family of cyclophilins comprises multifunctional chaperones that interact with proteins and RNAs, facilitating the dynamic assembly of multimolecular complexes involved in various cellular processes. Cyclophilin A (CypA), the predominant member of this family, exhibits peptidyl-prolyl cis-trans isomerase activity. This enzymatic function aids with the folding and activation of protein structures and often serves as a molecular regulatory switch for large multimolecular complexes, ensuring appropriate inter- and intra-molecular interactions. Here, we investigated the involvement of CypA in the nucleus, where it plays a crucial role in supporting the assembly and trafficking of heterogeneous ribonucleoproteins (RNPs). We reveal that CypA is enriched in the nucleolus, where it colocalizes with the pseudouridine synthase dyskerin, the catalytic component of the multifunctional H/ACA RNPs involved in the modification of cellular RNAs and telomere stability. We show that dyskerin, whose mutations cause the X-linked dyskeratosis (X-DC) and the Hoyeraal-Hreidarsson congenital ribosomopathies, can directly interact with CypA. These findings, together with the remark that substitution of four dyskerin prolines are known to cause X-DC pathogenic mutations, lead us to indicate this protein as a CypA client. The data presented here suggest that this chaperone can modulate dyskerin activity influencing all its partecipated RNPs.

Intelligent hydrogel with both redox and thermo-response based on cellulose nanofiber for controlled drug delivery.

The purpose of this study is to develop a hydrogel with temperature and redox response to control drug delivery. However, the strength of temperature sensitive N-isopropylacrylamide (NIPAM) hydrogel is weak. Therefore, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) oxidized cellulose nanofiber (CNF) is introduced to improve this problem. The compressive strength of hydrogels increased by 360% after CNF addition. Meanwhile, N,N'-bis(acryloyl)cystamine (BACy) is introduced into the hydrogels as a cross-linker, imparting redox responsive properties to the hydrogels. Tumor therapeutic drugs are used as model drugs for in vitro release studies. The drug release rate of hydrogel is regulated by temperature and reducing environment. The maximum cumulative release rate of doxorubicin (DOX) is 39.56%, and the Berberine (BBR) is 99.50% after 60 h. The swelling and transparency of hydrogels showed dramatic changes in the range of 30-40 °C. Cytotoxicity experiments demonstrated that the hydrogel had almost no cytotoxicity.

Glycogen-based pH and redox sensitive nanoparticles with ginsenoside Rh2 for effective treatment of ulcerative colitis.

The purpose of this study is to construct a pH and redox sensitive nanoparticle to effectively deliver ginsenoside Rh2 for the treatment of ulcerative colitis (UC). Herein, glycogen was modified by urocanic acid and α-lipoic acid (α-LA) to obtain an amphiphilic polymer (LA-UaGly). Such polymer LA-UaGly could self-assemble to form nanoparticles (Blank NPs) in water with excellent stability, which could also successfully encapsulated ginsenoside Rh2 to form Rh2 nanoparticles (Rh2 NPs) with encapsulation efficiency of 74.36 ± 0.34%. DLS analysis indicated Rh2 NPs were spherical with a particle size of 128.9 ± 0.3 nm. As expected, Rh2 NPs exhibited typical pH and redox dual response release behaviour as well as the excellent in vivo safety. In vitro tests showed that Rh2 NPs could effectively internalize and release Rh2 into RAW264.7 cells, and protect cells from apoptosis (p < 0.05). More interestingly, Rh2 NPs exhibited strong anti-inflammatory activity via significantly inhibiting the overproduction of nitric oxide (NO) and inflammatory cytokines (TNF-α, IL-1ß and IL-6) (p < 0.05). In vivo experiments suggested that Rh2 NPs significantly ameliorated the weight loss, colon length, disease activity index (DAI) score, and myeloperoxidase (MPO) activity in mice caused by dextran sulfate sodium salt (DSS) (p < 0.05). Simultaneously, pathological analysis proved that Rh2 NPs could significantly reduce histological damage and inflammatory infiltration in mice. Rh2 NPs could also effectively regulate the intestinal flora of mice by improving the species uniformity and abundance of the intestinal flora of mice and restoring the species diversity of the intestinal flora. In addition, both in vivo and in vitro experiments proved that Rh2 NPs had stronger anti-inflammatory activity than Rh2. This study provides a promising strategy for the effective treatment of UC.

Adaptive Response of Thermophiles to Redox Stress and Their Role in the Process of dye Degradation From Textile Industry Wastewater.

Release of dye-containing textile wastewater into the environment causes severe pollution with serious consequences on aquatic life. Bioremediation of dyes using thermophilic microorganisms has recently attracted attention over conventional treatment techniques. Thermophiles have the natural ability to survive under extreme environmental conditions, including high dye concentration, because they possess stress response adaptation and regulation mechanisms. Therefore, dye detoxification by thermophiles could offer enormous opportunities for bioremediation at elevated temperatures. In addition, the processes of degradation generate reactive oxygen species (ROS) and subject cells to oxidative stress. However, thermophiles exhibit better adaptation to resist the effects of oxidative stress. Some of the major adaptation mechanisms of thermophiles include macromolecule repair system; enzymes such as superoxide dismutase, catalase, and glutathione peroxidase; and non-enzymatic antioxidants like extracellular polymeric substance (EPSs), polyhydroxyalkanoates (PHAs), etc. In addition, different bacteria also possess enzymes that are directly involved in dye degradation such as azoreductase, laccase, and peroxidase. Therefore, through these processes, dyes are first degraded into smaller intermediate products finally releasing products that are non-toxic or of low toxicity. In this review, we discuss the sources of oxidative stress in thermophiles, the adaptive response of thermophiles to redox stress and their roles in dye removal, and the regulation and crosstalk between responses to oxidative stress.

Apoptosis-Sensing Xenograft Zebrafish Tumor Model for Anticancer Evaluation of Redox-Responsive Cross-Linked Pluronic Micelles.

A suitable animal model for preclinical screening and evaluation in vivo could vastly increase the efficiency and success rate of nanomedicine development. Compared with rodents, the transparency of the zebrafish model offers unique advantages of real-time and high-resolution imaging of the whole body and cellular levels in vivo. In this research, we established an apoptosis-sensing xenograft zebrafish tumor model to evaluate the anti-cancer effects of redox-responsive cross-linked Pluronic polymeric micelles (CPPMs) visually and accurately. First, doxorubicin (Dox)-loaded CPPMs were fabricated and characterized with glutathione (GSH)-responsive drug release. Then, the B16F10 xenograft zebrafish tumor model was established to mimic the tumor microenvironment with angiogenesis and high GSH generation for redox-responsive tumor-targeting evaluation in vivo. The high GSH generation was first verified in the xenograft zebrafish tumor model. Compared with ordinary Pluronic polymeric micelles, Dox CPPMs had a much higher accumulation in zebrafish tumor sites. Finally, the apoptosis-sensing B16F10-C3 xenograft zebrafish tumor model was established for visual, rapid, effective, and noninvasive assessment of anti-cancer effects at the cellular level in vivo. The Dox CPPMs significantly inhibited the proliferation of cancer cells and induced apoptosis in the B16F10-C3 xenograft zebrafish tumor model. Therefore, the redox-responsive cross-linked Pluronic micelles showed effective anti-cancer therapy in the xenograft zebrafish tumor model. This xenograft zebrafish tumor model is available for rapid screening and assessment of anti-cancer effects in preclinical studies.

Functional resveratrol-biodegradable manganese doped silica nanoparticles for the spinal cord injury treatment.

Spinal cord injury (SCI) causes secondary injury, accompanied by pathological changes such as oxidative stress, inflammation and neuronal apoptosis. This leads to permanent disabilities such as paralysis and loss of movement or sensation. Due to the ineffectiveness of drugs passing through the blood spinal cord barrier (BSCB), there is currently no effective treatment for SCI. The aim of this experiment was to design plasma complex component functionalized manganese-doped silica nanoparticles (PMMSN) with a redox response as a targeted drug carrier for resveratrol (RES), which effectively transports insoluble drugs to cross the BSCB. RES was adsorbed into PMMSN with a particle size of approximately 110 â€‹nm by the adsorption method, and the drug loading reached 32.61 â€‹± â€‹3.38%. The RES release results for the loaded sample (PMMSN-RES) showed that the PMMSN-RES exhibited a release slowly effect. In vitro and vivo experiments demonstrated that PMMSN-RES decreased reactive oxygen species (ROS) and malondialdehyde (MDA), increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, reduced the expression of inflammatory (TNF-α, IL-1ß and IL-6) and apoptotic cytokines (cleaved caspase-3) in spinal cord tissue after SCI. In summary, PMMSN-RES may be a potential pharmaceutical preparation for the treatment of SCI by reducing neuronal apoptosis and inhibiting inflammation caused by reducing oxidative stress to promote the recovery of mouse motor function.

Engineering Paclitaxel Prodrug Nanoparticles via Redox-Activatable Linkage and Effective Carriers for Enhanced Chemotherapy.

The current clinical performance of chemotherapy is far from satisfactory, greatly limited by insufficient delivery efficacy and serious systemic side effects. Dimeric prodrug systems are emerging as valuable strategies for boosting the antitumor outcome. Here, dimeric paclitaxel prodrugs were synthesized with different bridged linkers, and the formed prodrug nanoparticles possessed excellent colloidal stability and ultrahigh drug content. The diselenide bond containing paclitaxel prodrugs could respond to a redox-heterogeneous intracellular microenvironment for on-demand drug release and subsequently show a selective cytotoxicity toward tumor cells against normal cells. Furthermore, the optimal carrier materials were screened out according to their contribution on stability, endocytosis, cytotoxicity, biodistribution, and antitumor efficacy. Compared with DSPE-PEG, human serum albumin, and Fe-tannic acid-based complex, F127 anchored dimeric paclitaxel nanoformulations exhibited preferential tumor accumulation and potent anticancer effect. Our present work provides deep insight into the development of advanced nanoformulations with comprehensive advantages for enhancing cancer therapy.

Novel AIEgen-Functionalized Diselenide-Crosslinked Polymer Gels as Fluorescent Probes and Drug Release Carriers.

Stimuli-responsive functional gels have shown significant potential for application in biosensing and drug release systems. In this study, aggregation-induced emission luminogen (AIEgen)-functionalized, diselenide-crosslinked polymer gels were synthesized via free radical copolymerization. A series of polymer gels with different crosslink densities or tetraphenylethylene (TPE) contents were synthesized. The diselenide crosslinker in the gels could be fragmented in the presence of H2O2 or dithiothreitol (DTT) due to its redox-responsive property. Thus, the TPE-containing polymer chains were released into the aqueous solution. As a result, the aqueous solution exhibited enhanced fluorescence emission due to the strong hydrophobicity of TPE. The degradation of polymer gels and fluorescence enhancement in an aqueous solution under different H2O2 or DTT concentrations were studied. Furthermore, the polymer gels could be used as drug carriers, suggesting a visual drug release process under the action of external redox agents. The AIEgen-functionalized, diselenide-crosslinked polymer gels hold great potential in the biomedical area for biosensing and controlled drug delivery.