Novel Approaches to Apoptosis-Inducing Therapies.

Induction of apoptotic programmed cell death is one of the underlying principles of most current cancer therapies. In this review, we discuss the limitations and drawbacks of this approach and identify three distinct, but overlapping strategies to avoid these difficulties and further enhance the efficacy of apoptosis-inducing therapies. We postulate that the application of multi-targeted small molecule inhibitor cocktails will reduce the risk of the cancer cell populations developing resistance towards therapy. Following from these considerations regarding population genetics and ecology, we advocate the reconsideration of therapeutic end points to maximise the benefits, in terms of quantity and quality of life, for the patients. Finally, combining both previous points, we also suggest an altered focus on the cellular and molecular targets of therapy, i.e. targeting the (cancer cells') interaction with the tumour microenvironment.

Levosimendan: mechanistic insight and its diverse future aspects in cardiac care.

Inotropic agents are generally recommended to use in patients with acute decompensated heart failure (HF) with reduced ejection fraction (HFrEF) concurrent to end-organ dysfunction. However, due to certain pharmacological limitations like developing life threatening arrhythmia and tolerance, cannot be employed as much as needed. Meanwhile, Calcium ion (Ca2+) sensitisers exhibits their inotropic action by increasing the sensitivity of the cardiomyocyte to intracellular Ca2+ ion and have been reported as emerging therapeutic alternative in HF cases. Levosimendan (LEVO) is an inodilator and with its unique pharmacology justifying its use in a wide range of cardiac alterations in HF particularly in undergoing cardiac surgery. It is also reported to be better than classical inotropes in maintaining cardiac mechanical efficacy and reducing congestion in acute HF with hypotension. This review paper was designed to compile various evidence about basic pharmacology and potential clinical aspects of LEVO in cardiac surgery and other HF associated alterations. This will benefit directly to the researcher in initiating research and to fill the gaps in the area of thrust.

High density lipoprotein nanoparticle as delivery system for radio-sensitising miRNA: An investigation in 2D/3D head and neck cancer models.

Radiotherapy is one of the main treatment options for head and neck cancer patients. However, its clinical efficacy is hindered by both radiation induced side effects and radio-resistance. Radio-sensitising approaches with acceptable toxicity are being actively investigated. Among these, RNA therapeutics have great potentials as radio-sensitisers owing to their ability to target pathways specific to radio-resistance. However, their clinical translation is challenging due to delivery issues. Herein, we report the application of high-density lipoprotein nanoparticle (HDL NPs) as a biocompatible delivery system for a well-established radio-sensitising RNA, miR-34a. A simple/fast microfluidic based technique was used to prepare miR-34a-HDL NPs. Profiling of the radiation response in the UM-SCC-1 head and neck cancer cell line confirmed reduced metabolic activity and increased radiation induced apoptosis upon treatment with miR-34a-HDL NPs. The radio-sensitising properties of miR-34a-HDL NPs were further confirmed in a more biologically relevant co-culture spheroid model of head and neck cancer. Increased apoptotic activity and disrupted cell cycle were induced by miR-34a delivered by HDL NPs. The enhanced radio-biologic effects observed in both 2D and 3D models confirmed the utility of HDL NPs as an efficient delivery system for radio-sensitising RNA.

Effects of solubility characteristics of sensitiser and pH on the photooxidation of oil in tuna oil-added acidic O/W emulsions.

The effects of sensitisers and pH on the oil oxidation of acidic O/W emulsions were studied under light by measuring hydroperoxide content and headspace oxygen consumption in the emulsions. The emulsions consisted of canola and tuna oil (2:1w/w, 32%), diluted acetic acid (64%), egg yolk powder (4%), chlorophyll b or erythrosine (5µM), and/or diazabicyclooctane (DABCO) or sodium azide (0.5M). The emulsion pH values were 2.67, 3.68, and 6.27. Chlorophyll increased oil oxidation in the emulsion under light via singlet oxygen production while erythrosine did not. DABCO significantly decreased photooxidation of the oil containing chlorophyll, suggesting singlet oxygen involvement. However, sodium azide increased photooxidation of the oil containing chlorophyll possibly via azide radical production under acidic conditions. The oil photooxidation was higher in the emulsion containing chlorophyll at pH 6.27 than at pH 2.67 or 3.68, primarily by singlet oxygen and secondarily by free radicals produced from hydroperoxide decomposition.

Effect of a single dose of pimobendan on right ventricular and right atrial function in 11 healthy cats.

OBJECTIVES: The objective of this study was to investigate the effect of pimobendan on echocardiographic parameters of right ventricular and atrial function in healthy cats. ANIMALS: Eleven privately owned, healthy adult cats. MATERIAL AND METHODS: Each cat underwent five echocardiographic examinations: the first and second examinations were performed 1 h apart on day 0. On day 1, the third examination served as baseline, whereas the fourth and fifth examinations were performed one and 6 h after administration of a single oral dose of pimobendan (1.25 mg/cat), respectively. Parameters of right ventricular and atrial morphology and function were collected and compared among time points. RESULTS: Pimobendan administration produced a change in some echocardiographic variables. Specifically, heart rate, right ventricular fractional shortening and peak velocity of systolic lateral tricuspid annular motion increased (P = 0.032, P = 0.002 and P < 0.001, respectively), whereas right ventricular end-systolic internal diameter and right atrial maximum and minimum internal diameters decreased (P = 0.004, P = 0.025 and P = 0.01, respectively). Right ventricular fractional area change and tricuspid annular plane systolic excursion did not change. CONCLUSIONS: This novel study showed that pimobendan had positive effects on right ventricular and right atrial function in healthy cats. Further studies are needed to determine whether pimobendan has similar effects in cats with cardiac diseases.

Crystal structure of benzyl 2-naphthyl ether, a sensitiser for thermal paper.

The title compound [systematic name: 2-(benz-yloxy)naphthalene], C17H14O, which is used as a sensitiser for thermal paper, has a twisted conformation with a dihedral angle of 48.71 (12)° between the phenyl ring and the naphthyl ring system. In the crystal, one mol-ecule inter-acts with six neighbouring mol-ecules via inter-molecular C-H⋯π inter-actions to form a herringbone mol-ecular arrangement.

Molecular Engineering of Zinc-Porphyrin Sensitisers for p-Type Dye-Sensitised Solar Cells.

Design of novel efficient light-harvesters for p-type dye-sensitised solar cells (DSSCs) is indispensable for further advances in this photovoltaic technology. Herein, a novel D-π-A (D=donor, π=π-conjugated linker, A=acceptor) sensitiser, ZnP1, featuring an electron acceptor, perylenemonoimide (PMI), connected to an electron donor, di(p-carboxyphenyl)amine (DCPA), through fluorene and a zinc(II) porphyrin with alkyl chains as a π-conjugated bridge is introduced. Spectroscopic and electrochemical characterisation of this dye along with a newly synthesised PMI-free reference dye ZnP0 has been undertaken to demonstrate strong electron coupling between the DCPA donor and PMI acceptor subunits through the porphyrin ring in ZnP1, which redshifts the light absorption onset to the near-IR region. When integrated into p-DSSCs based on a mesoporous nickel(II) oxide semiconductor electrode and a tris(acetylacetonato) iron(III/II) redox mediator, ZnP1 exhibits an onset of the incident photon-to-current conversion efficiency at 800 nm and a power conversion efficiency of up to 0.92 % under simulated 100 mW cm-2 AM 1.5 G irradiation. This is the highest efficiency of the porphyrin-based p-DSSCs hitherto reported.

The chitosan - Porphyrazine hybrid materials and their photochemical properties.

Three magnesium sulfanyl porphyrazines differing in the size of peripheral substituents (3,5-dimethoxybenzylsulfanyl, (3,5-dimethoxybenzyloxy)benzylsulfanyl, 3,5-bis[(3,5-bis[(3,5-dimethoxybenzyloxy)benzyloxy]benzylsulfanyl) were exposed to visible and ultraviolet radiation (UV A + B + C) in order to determine their photochemical properties. The course of photochemical reactions in dimethylformamide solutions and the ability of the systems to generate singlet oxygen were studied by UV-Vis spectroscopy, which additionally gave information on aggregation processes. The porphyrazines were found to be stable upon visible light irradiation conditions, but when exposed to high energy UV radiation, the efficient photodegradation of these macrocycles was observed. Therefore, these three magnesium sulfanyl porphyrazines were incorporated into chitosan matrix. The obtained thin films of chitosan doped with porphyrazines were subjected to polychromatic UV-radiation and studied by spectroscopic methods (UV-Vis, FTIR), scanning electron microscopy (SEM) and atomic force microscopy (AFM). Application of chitosan as a polymer matrix for porphyrazines was found to be successful method that effectively stopped the unwelcome degradation of macrocycles, thus worth considering for their photoprotection. In addition, the surface properties of the hybrid material were determined by contact angle measurements and calculation of surface free energy. Intermolecular interactions between these novel porphyrazines and chitosan were detected. The mechanism of photochemical reactions occurring in studied systems has been discussed.

Sonodynamic inactivation of Gram-positive and Gram-negative bacteria using a Rose Bengal-antimicrobial peptide conjugate.

Combating antimicrobial resistance is one of the most serious public health challenges facing society today. The development of new antibiotics or alternative techniques that can help combat antimicrobial resistance is being prioritised by many governments and stakeholders across the globe. Antimicrobial photodynamic therapy is one such technique that has received considerable attention but is limited by the inability of light to penetrate through human tissue, reducing its effectiveness when used to treat deep-seated infections. The related technique sonodynamic therapy (SDT) has the potential to overcome this limitation given the ability of low-intensity ultrasound to penetrate human tissue. In this study, a Rose Bengal-antimicrobial peptide conjugate was prepared for use in antimicrobial SDT (ASDT). When Staphylococcus aureus and Pseudomonas aeruginosa planktonic cultures were treated with the conjugate and subsequently exposed to ultrasound, 5 log and 7 log reductions, respectively, in bacterial numbers were observed. The conjugate also displayed improved uptake by bacterial cells compared with a mammalian cell line (P ≤ 0.01), whilst pre-treatment of a P. aeruginosa biofilm with ultrasound resulted in a 2.6-fold improvement in sensitiser diffusion (P ≤ 0.01). A preliminary in vivo experiment involving ASDT treatment of P. aeruginosa-infected wounds in mice demonstrated that ultrasound irradiation of conjugate-treated wounds affects a substantial reduction in bacterial burden. Combined, the results obtained from this study highlight ASDT as a targeted broad-spectrum novel modality with potential for the treatment of deep-seated bacterial infections.

In vitro potency, in vitro and in vivo efficacy of liposomal alendronate in combination with γδ T cell immunotherapy in mice.

Nitrogen-containing bisphosphonates (N-BP), including zoledronic acid (ZOL) and alendronate (ALD), have been proposed as sensitisers in γδ T cell immunotherapy in pre-clinical and clinical studies. Therapeutic efficacy of N-BPs is hampered by their rapid renal excretion and high affinity for bone. Liposomal formulations of N-BP have been proposed to improve accumulation in solid tumours. Liposomal ALD (L-ALD) has been suggested as a suitable alternative to liposomal ZOL (L-ZOL), due to unexpected mice death experienced in pre-clinical studies with the latter. Only one study so far has proven the therapeutic efficacy of L-ALD, in combination with γδ T cell immunotherapy, after intraperitoneal administration of γδ T cell resulting in delayed growth of ovarian cancer in mice. This study aims to assess the in vitro efficacy of L-ALD, in combination with γδ T cell immunotherapy, in a range of cancerous cell lines, using L-ZOL as a comparator. The therapeutic efficacy was tested in a pseudo-metastatic lung mouse model, following intravenous injection of γδ T cell, L-ALD or the combination. In vivo biocompatibility and organ biodistribution studies of L-N-BPs were undertaken simultaneously. Higher concentrations of L-ALD (40-60µM) than L-ZOL (3-10µM) were required to produce a comparative reduction in cell viability in vitro, when used in combination with γδ T cells. Significant inhibition of tumour growth was observed after treatment with both L-ALD and γδ T cells in pseudo-metastatic lung melanoma tumour-bearing mice after tail vein injection of both treatments, suggesting that therapeutically relevant concentrations of L-ALD and γδ T cell could be achieved in the tumour sites, resulting in significant delay in tumour growth.