Combining Copper and Zinc into a Biosensor for Anti-Chemoresistance and Achieving Osteosarcoma Therapeutic Efficacy.

Due to its built-up chemoresistance after prolonged usage, the demand for replacing platinum in metal-based drugs (MBD) is rising. The first MBD approved by the FDA for cancer therapy was cisplatin in 1978. Even after nearly four and a half decades of trials, there has been no significant improvement in osteosarcoma (OS) therapy. In fact, many MBD have been developed, but the chemoresistance problem raised by platinum remains unresolved. This motivates us to elucidate the possibilities of the copper and zinc (CuZn) combination to replace platinum in MBD. Thus, the anti-chemoresistance properties of CuZn and their physiological functions for OS therapy are highlighted. Herein, we summarise their chelators, main organic solvents, and ligand functions in their structures that are involved in anti-chemoresistance properties. Through this review, it is rational to discuss their ligands' roles as biosensors in drug delivery systems. Hereafter, an in-depth understanding of their redox and photoactive function relationships is provided. The disadvantage is that the other functions of biosensors cannot be elaborated on here. As a result, this review is being developed, which is expected to intensify OS drugs with higher cure rates. Nonetheless, this advancement intends to solve the major chemoresistance obstacle towards clinical efficacy.

CuZn Complex Used in Electrical Biosensors for Drug Delivery Systems.

This paper is to discuss the potential of using CuZn in an electrical biosensor drug carrier for drug delivery systems. CuZn is the main semiconductor ingredient that has great promise as an electrochemical detector to trigger releases of active pharmaceutical ingredients (API). This CuZn biosensor is produced with a green metal of frameworks, which is an anion node in conductive polymers linked by bioactive ligands using metal-polymerisation technology. The studies of Cu, Zn, and their oxides are highlighted by their electrochemical performance as electrical biosensors to electrically trigger API. The three main problems, which are glucose oxidisation, binding affinity, and toxicity, are highlighted, and their solutions are given. Moreover, their biocompatibilities, therapeutic efficacies, and drug delivery efficiencies are discussed with details given. Our three previous investigations of CuZn found results similar to those of other authors' in terms of multiphases, polymerisation, and structure. This affirms that our research is on the right track, especially that related to green synthesis using plant extract, CuZn as a nanochip electric biosensor, and bioactive ligands to bind API, which are limited to the innermost circle of the non-enzymatic glucose sensor category.

Composing On-Program Triggers and On-Demand Stimuli into Biosensor Drug Carriers in Drug Delivery Systems for Programmable Arthritis Therapy.

Medication in arthritis therapies is complex because the inflammatory progression of rheumatoid arthritis (RA) and osteoarthritis (OA) is intertwined and influenced by one another. To address this problem, drug delivery systems (DDS) are composed of four independent exogenous triggers and four dependent endogenous stimuli that are controlled on program and induced on demand, respectively. However, the relationships between the mechanisms of endogenous stimuli and exogenous triggers with pathological alterations remain unclear, which results in a major obstacle in terms of clinical translation. Thus, the rationale for designing a guidance system for these mechanisms via their key irritant biosensors is in high demand. Many approaches have been applied, although successful clinical translations are still rare. Through this review, the status quo in historical development is highlighted in order to discuss the unsolved clinical difficulties such as infiltration, efficacy, drug clearance, and target localisation. Herein, we summarise and discuss the rational compositions of exogenous triggers and endogenous stimuli for programmable therapy. This advanced active pharmaceutical ingredient (API) implanted dose allows for several releases by remote controls for endogenous stimuli during lesion infections. This solves the multiple implantation and local toxic accumulation problems by using these flexible desired releases at the specified sites for arthritis therapies.

Structural Strength Analyses for Low Brass Filler Biomaterial with Anti-Trauma Effects in Articular Cartilage Scaffold Design.

The existing harder biomaterial does not protect the tissue cells with blunt-force trauma effects, making it a poor choice for the articular cartilage scaffold design. Despite the traditional mechanical strengths, this study aims to discover alternative structural strengths for the scaffold supports. The metallic filler polymer reinforced method was used to fabricate the test specimen, either low brass (Cu80Zn20) or titanium dioxide filler, with composition weight percentages (wt.%) of 0, 2, 5, 15, and 30 in polyester urethane adhesive. The specimens were investigated for tensile, flexural, field emission scanning electron microscopy (FESEM), and X-ray diffraction (XRD) tests. The tensile and flexural test results increased with wt.%, but there were higher values for low brass filler specimens. The tensile strength curves were extended to discover an additional tensile strength occurring before 83% wt.%. The higher flexural stress was because of the Cu solvent and Zn solute substituting each other randomly. The FESEM micrograph showed a cubo-octahedron shaped structure that was similar to the AuCu3 structure class. The XRD pattern showed two prominent peaks of 2θ of 42.6° (110) and 49.7° (200) with d-spacings of 1.138 Å and 1.010 Å, respectively, that indicated the typical face-centred cubic superlattice structure with Cu and Zn atoms. Compared to the copper, zinc, and cart brass, the low brass indicated these superlattice structures had ordered-disordered transitional states. As a result, this additional strength was created by the superlattice structure and ordered-disordered transitional states. This innovative strength has the potential to develop into an anti-trauma biomaterial for osteoarthritic patients.

Numerical Simulation Study on Relationship between the Fracture Mechanisms and Residual Membrane Stresses of Metallic Material.

The distribution and dissipation energies in fracture mechanisms were a critical challenge to derive, especially for this ultra-thin sample. The membrane failure, which is the end of the fracture mechanisms, is a result of the cone wave reflections from the backend membrane boundaries. These reflections delay the failure processes due to the shock impacts. To compare these results with the experimental work, a numerical simulation was conducted for these processes. The cylinder-shaped rigid projectile was impacted using a frictionless Lagrange solver. The target was a cartridge brass circle plate clamped at its perimeter, and its zone was refined to a ten-times higher meshing density for better analysis. The erosion and cut-off controls involved a zero-gap interaction condition and an instantaneous geometric erosion strain of 200%. Due to the maximum projectile velocity of 382 m/s having the slowest perforation, the target thickness was found to be 5.5 mm. The fracture mechanism phenomena, such as tensile, compressive, through-thickness, and growth in-plane delamination, propagating delamination, and local punch shear waves were observed. After deducting tensile and flexural strengths from the last experiment, a total residual membrane stress of 650 MPa was found. This result indicated a relationship between the fracture mechanisms and residual membrane stresses of metallic material.

Structural Characterization Analyses of Low Brass Filler Biomaterial for Hard Tissue Implanted Scaffold Applications.

A biomaterial was created for hard tissue implanted scaffolds as a translational therapeutic approach. The existing biomaterials containing titanium dioxide filler posed a risk of oxygen gas vacancy. This will block the canaliculars, leading to a limit on the nutrient fluid supply. To overcome this problem, low brass was used as an alternative filler to eliminate the gas vacancy. Low brass with composition percentages of 0%, 2%, 5%, 15%, and 30% was filled into the polyester urethane liquidusing the metallic filler polymer reinforced method. The structural characterizations of the low brass filler biomaterial were investigated by Field Emission Scanning Electron Microscopy. The results showed the surface membrane strength was higher than the side and cross-section. The composition shapes found were hexagon for polyester urethane and peanut for low brass. Low brass stabilised polyester urethane in biomaterials by the formation of two 5-ringed tetrahedral crystal structures. The average pore diameter was 308.9 nm, which is suitable for articular cartilage cells. The pore distribution was quite dispersed, and its curve had a linear relationship between area and diameter, suggestive of the sphere-shaped pores. The average porosities were different between using FESEM results of 6.04% and the calculated result of 3.28%. In conclusion, this biomaterial had a higher surface membrane strength and rather homogeneous dispersed pore structures.

Acute cold-induced thermogenesis in neonatal chicks (Gallus gallus).

Mechanisms of thermogenic responses that play a role to maintain homeothermy during an early stage of neonatal chicks on acute cold exposure are scarcely studied as hatchlings are believed to be poikilothermic. However, chicks can attain the homeothermy during their subsequent growth after hatching. To identify thermogenic responses during neonatal stages of chicks (Gallus gallus) on acute cold exposure (12 degrees C, 3h), changes in plasma corticosterone levels, thermogenesis, gene transcripts (avUCP and avPGC1alpha) in skeletal muscles (pectoralis superficialis and gastrocnemius) and mitochondrial substrate oxidation enzyme activities in dissected tissues of 1- and 4-d-old chicks were studied. Results revealed that 1-day-old neonatal chicks were particularly vulnerable to cold exposure and were hypothermic. However, 4-d-old cold-exposed chicks maintained thermostability with significantly higher plasma corticosterone levels, oxygen consumption, heat production, and increased mitochondrial substrate oxidation enzyme activities (CS and 3HADH) in different dissected tissues. Analysis of gene transcripts for avian peroxisome-proliferator-activated receptor-gamma co-activator-1alpha (avPGC1alpha) and avian uncoupling protein (avUCP) in skeletal muscles revealed no significant change between cold-sensitive (1-d-old) and cold-tolerant (4-d-old) neonatal chicks, and failed to explain the enhanced thermogenesis and tolerance to acute cold. Additionally, avPGC1alpha gene transcripts were not correlated with the increased enzyme activities of CS or 3HADH in skeletal muscle. In conclusion, these data suggest the possible role of HPA-axis in cold-tolerant neonatal chicks to modulate substrate mobilization and oxidation. The thermogenic mechanisms based in part upon the increased capacity for mitochondrial substrate oxidation in different tissues are associated with enhanced heat production to attain homeothermy and acquire tolerance to acute cold exposure during an early stage of neonatal chicks.

Olive oil-supplemented diet alleviates acute heat stress-induced mitochondrial ROS production in chicken skeletal muscle.

We have previously shown that avian uncoupling protein (avUCP) is downregulated on exposure to acute heat stress, stimulating mitochondrial reactive oxygen species (ROS) production and oxidative damage. In this study, we investigated whether upregulation of avUCP could attenuate oxidative damage caused by acute heat stress. Broiler chickens (Gallus gallus) were fed either a control diet or an olive oil-supplemented diet (6.7%), which has been shown to increase the expression of UCP3 in mammals, for 8 days and then exposed either to heat stress (34 degrees C, 12 h) or kept at a thermoneutral temperature (25 degrees C). Skeletal muscle mitochondrial ROS (measured as H(2)O(2)) production, avUCP expression, oxidative damage, mitochondrial membrane potential, and oxygen consumption were studied. We confirmed that heat stress increased mitochondrial ROS production and malondialdehyde levels and decreased the amount of avUCP. As expected, feeding birds an olive oil-supplemented diet increased the expression of avUCP in skeletal muscle mitochondria and decreased ROS production and oxidative damage. Studies on mitochondrial function showed that heat stress increased membrane potential in state 4, which was reversed by feeding birds an olive oil-supplemented diet, although no differences in basal proton leak were observed between control and heat-stressed groups. These results show that under heat stress, mitochondrial ROS production and olive oil-induced reduction of ROS production may occur due to changes in respiratory chain activity as well as avUCP expression in skeletal muscle mitochondria.

Oxidative damage in different tissues of neonatal chicks exposed to low environmental temperature.

Maintenance of body temperature in a cold environment is crucial for survival in homeotherms. However, we have previously reported that on exposure to low environmental temperature, neonatal chicks (Gallus gallus) show hypothermia, decreased behavioral activity, and absence of gene transcript enhancement of putative thermogenic proteins, as well as no change in mitochondrial substrate oxidation enzymes. Various metabolic abnormalities and/or tissue damage may also decline the thermogenic capacity of low-temperature-exposed neonatal chicks. Therefore, to investigate oxidative damage in low-temperature-exposed (20 degrees C for 12 h) neonatal chicks, we studied lipid peroxidation when compared to the control chicks kept at thermoneutral temperature (30 degrees C). Malondialdehyde (MDA), was measured in plasma, brain, heart, liver and skeletal muscle (pectoralis superficialis and gastrocnemius). Weight gain and feed consumption did not change when chicks were exposed to low-temperature as compared to that of control chicks. On low-temperature exposure, body temperature was significantly decreased and plasma non-esterified fatty acid level was 1.3-fold higher than that of control chicks. In low-temperature exposed chicks, brain and heart MDA levels were 2.1- and 1.2-fold higher, respectively, than that of control chicks. This increase in MDA levels was not observed in plasma, liver and muscle of low-temperature-exposed chicks. In conclusion, there is evidence of increased lipid peroxidation in brain and heart of neonatal chicks exposed to low-temperature. We hypothesize that this oxidative damage in brain and heart may contribute to the impaired physiological, behavioral and thermoregulatory responses that potentiate the sensitivity to cold exposure.

Managing hypertension in people of African origin with diabetes: Evaluation of adherence to NICE Guidelines.

BACKGROUND: The pathophysiology of hypertension in people of African origin differs from other ethnicities. This effect may be exacerbated in people with type 2 diabetes mellitus (T2DM), hence control of hypertension is particularly important in this population. AIMS: The primary aim was to evaluate the adherence to National Institute of Clinical Excellence (NICE) guidance (National Guidelines NG28) for hypertension management in African origin patients with T2DM. METHODS: This study was done using electronic health records at a large primary care centre based in Birmingham, UK. Strict exclusion criteria were applied to identify individuals with T2DM, African origin patients and a diagnosis of hypertension. Retrospectively participants were identified, and NICE guideline adherence was assessed using descriptive statistics. RESULTS: 78 patients were included in the study of which 28 (36%) were on the NICE recommended combination of antihypertensives, suggesting poor adherence to the guidance in primary care prescribing. The blood pressure control of 35 (44.9%) patients was suboptimal, although this group received more frequent blood pressure monitoring. Microalbuminuria remains a problem in the suboptimal group. CONCLUSION: This study provides insight into adherence to NICE guidance for managing hypertension in African origin patients with diabetes. Further work should be done to explore the effects of hypertension in this ethnic group and if there is a need for a more refined management guideline.

Homeothermy in neonatal chicks exposed to low environmental temperature with or without intracerebroventricular administration of corticotropin-releasing factor.

To determine the mechanism of sensitivity to low-temperature exposure (20 degrees C for 3h) and corticotropin-releasing factor (CRF) induced increased homeothermy, we investigated gene transcripts of putative thermogenic proteins and mitochondrial fatty acid (FA)-oxidation enzymes in neonatal chicks. The hypothalamic-pituitary-adrenal (HPA) axis in low-temperature-exposed neonatal chicks was activated by central administration of CRF. Neonatal chicks showed hypothermia on exposure to low-temperature, with no enhancement of HPA axis and gene transcripts of avian adenine nucleotide translocator, avian uncoupling protein, avian peroxisome-proliferator-activated receptor-gamma co-activator-1alpha, and mitochondrial FA transport and oxidation enzymes in vital organs. However, central administration of CRF activated the HPA axis under low environmental temperature and induced increased homeothermy that was associated with the enhancement of gene transcripts and activities of mitochondrial FA-oxidation enzymes in the liver and heart.

Central administration of corticotropin-releasing factor induces tissue specific oxidative damage in chicks.

Corticotropin-releasing factor (CRF) modulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and has a key role in mediating neuroendocrine effects which occur in response to stressful stimuli. We have recently shown that intracerebroventricular (ICV) injection of CRF in neonatal chicks increased homeothermy that was associated with enhanced gene transcripts of mitochondrial fatty acid (FA) transport and oxidation enzymes in a tissue specific manner. These observations prompted an investigation into the potential role of CRF in a state of oxidative damage in different tissues. We therefore, investigated whether CRF-induced changes in metabolism are accompanied by oxidative damage in the plasma, brain and other tissues. Neonatal chicks (Gallus gallus) with or without ICV-CRF (42 pmol) were kept at thermoneutral temperature (30 degrees C). After 3 h, malondialdehyde (MDA) was measured in the plasma, brain, heart, liver and skeletal muscle (gastrocnemius). ICV-CRF significantly decreased the weight gain and feed consumption of chicks. Plasma, heart and liver revealed significantly higher MDA levels in chicks with ICV-CRF as compared to that of control chicks, but this pattern was not observed in the brain and muscle. Gene transcripts of enzymes involved in mitochondrial FA transport and oxidation, and 3-hydroxyacyl CoA dehydrogenase and citrate synthase enzyme activities in the brain were not changed by ICV-CRF. In conclusion, central administration of CRF in neonatal chicks induces tissue specific oxidative damage: higher MDA levels were observed in the heart and liver while no such change occurred in the brain and muscle.

Sequential changes in superoxide production, anion carriers and substrate oxidation in skeletal muscle mitochondria of heat-stressed chickens.

We have shown that heat-stressed birds exhibit increased superoxide production in skeletal muscle mitochondria. To determine the precise mechanism for this effect, here we studied not only progressive, but also sequential changes in superoxide production, anion carriers and substrate oxidation in mitochondria of heat-stressed chickens. Exposure to acute heat stress (34 degrees C for 6, 12 and 18h) stimulated pectoralis muscle mitochondrial superoxide production. Heat stress-induced downregulations of avUCP gene transcripts and mitochondrial avUCP protein content were time-dependent: avUCP gene transcript was decreased after 6h, while avUCP protein content was only downregulated after 12h of heat stress. Avian adenine nucleotide translocator (avANT) gene transcripts were not changed on exposure to heat stress, suggesting that avANT may not be involved in the regulation of superoxide production in the muscle mitochondria of heat-stressed chickens. During the initial stage of acute heat stress beta-oxidation enzymes gene transcripts and activity were upregulated, with elevated plasma non-esterified fatty acid levels and increased expression of mitochondrial fatty acid transport genes. This sudden surge in mitochondrial substrate oxidation resulted in higher superoxide production: the avUCP expression at 6h after heat stress might have not been large enough to alleviate the overproduction of reactive oxygen species (ROS) even though a small amount of endogenous FFA, a potential uncoupler, might have been present in the mitochondria. Thereafter, avUCP content was downregulated while substrate oxidation returned to control levels. This downregulation of avUCP may have caused increased mitochondrial superoxide production, keeping the superoxide production high in the later stages of heat stress. These results suggest that overproduction of mitochondrial ROS in chicken skeletal muscle under the heat stress might result from enhanced substrate oxidation and downregulation of avUCP in a time-dependent manner.

Possible role of avian uncoupling protein in down-regulating mitochondrial superoxide production in skeletal muscle of fasted chickens.

Little is known about the precise physiological roles of uncoupling protein 1 (UCP1) homologs (UCP2, UCP3, avian UCP) whose levels are up-regulated during fasting. UCPs in skeletal muscle are thought to play a role in the regulation of lipids as fuel substrates, and/or in controlling the production of reactive oxygen species (ROS). The aim of this investigation, using skeletal muscle from fasted chickens, was to examine alterations in the expression of genes encoding for avian UCP and key enzymes relevant to lipid flux across the mitochondrial beta-oxidation pathway. We also clarified whether an increase in avUCP content could be associated with altered ROS production by mitochondria. Transcription levels of avUCP and CPT-I genes were increased 7.7- and 9.5-fold after a 24h fast and slightly diminished but remained about 5.0- and 7.7-fold higher than baseline levels, respectively, after 48h of fasting. In contrast, members of the beta-oxidation pathway, LCAD and 3HADH, were gradually up-regulated from 12 to 48h of fasting. This suggests that processes involved in the transfer and oxidation of fatty acids are up-regulated differently during the initial stage of fasting. Analysis of ROS production by lucigenin-derived chemiluminescence showed that the FFA-sensitive portion of carboxyatractyloside-upregulated ROS production was greater in skeletal muscle mitochondria from 24h-fasted chickens compared with control, which leads us to postulate that ROS production is potentially down-regulated by UCP. The possible involvement of a backlog of fatty acid for oxidation, observed in chickens after a 24h fast, in a transmembrane gradient of free non-oxidized fatty acids is also discussed.

The suppressive effect of dietary coenzyme Q10 on mitochondrial reactive oxygen species production and oxidative stress in chickens exposed to heat stress.

This study was conducted to determine if dietary supplementation with coenzyme Q10 (CoQ10 ), which can act as a potent antioxidant and is an obligatory cofactor of mitochondrial uncoupling protein, suppresses the heat stress (HS)-induced overproduction of mitochondrial reactive oxygen species (ROS) and oxidative damage in the skeletal muscle of birds. The carbonyl protein content of skeletal muscle was significantly higher in birds exposed to HS treatment (34°C, 12 h) than in thermoneutral birds (25°C). This increase was suppressed by CoQ10 supplementation (40 mg/kg diet). Succinate-supported mitochondrial ROS production was increased by HS treatment, and this increase was also suppressed by CoQ10 supplementation. In contrast, CoQ10 supplementation did not affect the HS-induced decrease in mitochondrial proton leak. The mitochondrial membrane potential (ΔΨ), to which HS-induced ROS production was previously shown to be sensitive, tended to be increased by HS treatment, but this rise in ΔΨ was not affected by CoQ10 supplementation. Taken together, these results suggest that dietary CoQ10 supplementation attenuates HS-induced oxidative damage to skeletal muscle, by preventing the overproduction of succinate-supported mitochondrial ROS in a manner that is independent of ΔΨ. © 2015 Japanese Society of Animal Science.