Acid-Responsive Nanoporphyrin Evolution for Near-Infrared Fluorescence-Guided Photo-Ablation of Biofilm.

Combating biofilm infections remains a challenge due to the shield and acidic conditions. Herein, an acid-responsive nanoporphyrin (PN3-NP) based on the self-assembly of a water-soluble porphyrin derivative (PN3) is constructed. Additional kinetic control sites formed by the conjugation of the spermine molecules to a porphyrin macrocycle make PN3 self-assemble into stable nanoparticles (PN3-NP) in the physiological environment. Noteworthily, near-infrared (NIR) fluorescence monitoring and synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) effects of PN3-NP can be triggered by the acidity in biofilms, accompanied by intelligent transformation into dot-like nanospheres. Thus, damage to normal tissue is effectively avoided and accurate diagnosis and treatment of biofilms is achieved successfully. The good results of fluorescence imaging-guided photo-ablation of antibiotic-resistant strains methicillin-resistant Staphylococcus aureus (MRSA) biofilms verify that PN3-NP is a promising alternative to antibiotics. Meanwhile, this strategy also opens new horizons to engineer smart nano-photosensitizer for accurate diagnosis and treatment of biofilms.

Activation of apoptosis by rationally constructing NIR amphiphilic AIEgens: surmounting the shackle of mitochondrial membrane potential for amplified tumor ablation.

In recent years, the use of aggregation-induced emission luminogens (AIEgens) for biological imaging and phototherapy has become an area of intense research. However, most traditional AIEgens suffer from undesired aggregation in aqueous media with "always on" fluorescence, or their targeting effects cannot be maintained accurately in live cells with the microenvironment changes. These drawbacks seriously impede their application in the fields of bio-imaging and antitumor therapy, which require a high signal-to-noise ratio. Herein, we propose a molecular design strategy to tune the dispersity of AIEgens in both lipophilic and hydrophilic systems to obtain the novel near-infrared (NIR, ∼737 nm) amphiphilic AIE photosensitizer (named TPA-S-TPP) with two positive charges as well as a triplet lifetime of 11.43 µs. The synergistic effects of lipophilicity, electrostatic interaction, and structure-anchoring enable the wider dynamic range of AIEgen TPA-S-TPP for mitochondrial targeting with tolerance to the changes of mitochondrial membrane potential (ΔΨ m). Intriguingly, TPA-S-TPP was difficult for normal cells to be taken up, indicative of low inherent toxicity for normal cells and tissues. Deeper insight into the changes of mitochondrial membrane potential and cleaved caspase 3 levels further revealed the mechanism of tumor cell apoptosis activated by AIEgen TPA-S-TPP under light irradiation. With its advantages of low dark toxicity and good biocompatibility, acting as an efficient theranostic agent, TPA-S-TPP was successfully applied to kill cancer cells and to efficiently inhibit tumor growth in mice. This study will provide a new avenue for researchers to design more ideal amphiphilic AIE photosensitizers with NIR fluorescence.

Effect of Dysphagia Rehabilitation Using Kinesiology Taping on Oropharyngeal Muscle Hypertrophy in Post-Stroke Patients: A Double Blind Randomized Placebo-Controlled Trial.

BACKGROUND: It has recently been shown that suprahyoid muscle exercise using kinesiology taping (KT) increases the activation of the suprahyoid muscle in healthy adults, suggesting a potential therapeutic clinical exercise for dysphagia rehabilitation. This study investigated the effect of dysphagia rehabilitation using KT in stroke patients with dysphagia. METHODS: Thirty subjects in South Korea were enrolled in this prospective placebo-controlled double-blind study. Participants were randomly assigned to the experimental and sham groups. In the experimental group, the tape was attached to the hyolaryngeal complex, pulled downward with approximately 70% tension, and then attached to the sternum and the clavicle bilaterally. In the sham group, the tape was applied similarly but without the tension. Both groups performed voluntary swallowing 50 times (10 times swallowing per set, times 5 sets) a day for 4 weeks with KT applied. Outcome measures were assessed using portable ultrasound equipment. The parameter measured was the change in thickness of the tongue muscle, mylohyoid muscle, and the anterior belly of the digastric muscle. RESULTS: The experimental group showed statistically significant changes in the thickness of the tongue muscle, mylohyoid muscle, and anterior belly of the digastric muscle than the sham group (p = 0.007, 0.002, and 0.001). CONCLUSION: Dysphagia rehabilitation using KT is a technique that may promote oropharyngeal muscle thickness in patients with dysphagia after stroke.

The effect of neuromuscular electrical stimulation with different electrode positions on swallowing in stroke patients with oropharyngeal dysphagia: A randomized trial.

OBJECTIVE: To examine the effects of neuromuscular electrical stimulation (NMES) on oropharyngeal swallowing function according to 2 types of placement, acting as assistance and as resistance, in stroke patients with dysphagia. METHODS: Thirty-eight stroke patients with dysphasia were randomly assigned to the suprahyoid group (SMG), or infrahyoid muscle group (IMG); 26 patients completed the intervention and were included in the analysis. In the SMG, the electrodes were placed on the region between the jaw and the hyoid bone, whereas in the IMG, the electrodes were placed on the region below the hyoid for the targeted infrahyoid muscles. Both groups received NMES for 30 min/d, 5 d/wk, for 4 weeks and conventional dysphagia therapy. Swallowing function was measured using the Videofluoroscopic Dysphagia Scale and Penetration-Aspiration Scale based on videofluoroscopic swallowing study. Oral dietary intake was measured using the Functional Oral Intake Scale. RESULTS: Both groups showed significant improvements in oropharyngeal function and level of functional oral intake, but there was no significant difference between the two groups. However, the SMG showed a more reduced penetration-aspiration, compared with the IMG. CONCLUSIONS: Altogether, these data demonstrate that 2 types of NMES placements have a similar effect on improving swallowing function and oral diet intake in patients with dysphagia.

Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson's Disease.

The motor and nonmotor symptoms of Parkinson's disease (PD) correlate with the formation and propagation of aberrant α-synuclein aggregation. This protein accumulation is a pathological hallmark of the disease. Our group recently showed that peucedanocoumarin III (PCIII) possesses the ability to disaggregate ß sheet aggregate structures, including α-synuclein fibrils. This finding suggests that PCIII could be a therapeutic lead compound in PD treatment. However, the translational value of PCIII and its safety information have never been explored in relevant animal models of PD. Therefore, we first designed and validated a sequence of chemical reactions for the large scale organic synthesis of pure PCIII in a racemic mixture. The synthetic PCIII racemate facilitated clearance of repeated ß sheet aggregate (ß23), and prevented ß23-induced cell toxicity to a similar extent to that of purified PCIII. Given these properties, the synthetic PCIII's neuroprotective function was assessed in 6-hydroxydopamine (6-OHDA)-induced PD mouse models. The PCIII treatment (1 mg/kg/day) in a 6-OHDA-induced PD mouse model markedly suppressed Lewy-like inclusions and prevented dopaminergic neuron loss. To evaluate the safety profiles of PCIII, high dose PCIII (10 mg/kg/day) was administered intraperitoneally to two-month-old mice. Following 7 days of PCIII treatment, PCIII distributed to various tissues, with substantial penetration into brains. The mice that were treated with high dose PCIII had no structural abnormalities in the major organs or neuroinflammation. In addition, high dose PCIII (10 mg/kg/day) in mice had no adverse impact on motor function. These findings suggest that PCIII has a relatively high therapeutic index. Given the favorable safety features of PCIII and neuroprotective function in the PD mouse model, it may become a promising disease-modifying therapy in PD to regulate pathogenic α-synuclein aggregation.

Obovatol Induces Apoptosis in Non-small Cell Lung Cancer Cells via C/EBP Homologous Protein Activation.

Although obovatol, a phenolic compound from the bark of Magnolia obovata, was known to have antioxidant, neuroprotective, antiinflammatory, antithrombotic and antitumour effects, its underlying antitumour mechanism is poorly understood so far. Thus, in the present study, the antitumour molecular mechanism of obovatol was investigated in non-small cell lung cancer cells (NSCLCs). Obovatol exerted cytotoxicity in A549 and H460 NSCLCs, but not in BEAS-2B cells. Also, obovatol increased sub-G1 accumulation and early and late apoptotic portion in A549 and H460 NSCLCs. Consistently, obovatol cleaved PARP, activated caspase 9/3 and Bax and attenuated the expression of cyclin D1 in A549 and H460 NSCLCs. Interestingly, obovatol upregulated the expression of endoplasmic reticulum stress proteins such as C/EBP homologous protein (CHOP), IRE1α, ATF4 and p-elF2 in A549 and H460 NSCLCs. Conversely, depletion of CHOP blocked the apoptotic activity of obovatol to increase sub-G1 accumulation in A549 and H460 NSCLCs. Overall, our findings support scientific evidences that obovatol induces apoptosis via CHOP activation in A549 and H460 NSCLCs. Copyright © 2016 John Wiley & Sons, Ltd.

Copper-zinc superoxide dismutase-deficient mice show increased susceptibility to experimental autoimmune encephalomyelitis induced with myelin oligodendrocyte glycoprotein 35-55.

In this report, we have addressed the role of copper-zinc superoxide dismutase (SOD1) deficiency in the mediation of central nervous system autoimmunity. We demonstrate that SOD1-deficient C57Bl/6 mice develop more severe autoimmune encephalomyelitis induced with myelin oligodendrocyte glycoprotein (MOG) 35-55, compared with wild type mice. This alteration in the disease phenotype was not due to aberrant expansion of MOG-specific T cells nor their ability to produce inflammatory cytokines; rather lymphocytes generated in SOD1-deficient mice were more prone to spontaneous cell death when compared with their wild type littermate controls. The data point to a role for SOD1 in the maintenance of self-tolerance leading to the suppression of autoimmune responses.

Design, synthesis, and biological evaluation of 3,4,5-trimethoxyphenyl acrylamides as antinarcotic agents.

The synthesis and biological evaluation of 3,4,5-trimethoxyphenyl acrylamides 1a-f as novel antinarcotic agents are described. The molecules were prepared by the Wittig reaction, followed by a coupling reaction between 3,4,5-trimethoxycinnamic acid (9) and aliphatic amines, which resulted in good yields. When tested for biological activity, compounds 1d-f exhibited strong inhibitory effects on the morphine withdrawal syndrome in mice due to their high binding affinities with serotonergic 5-HT1A receptors.