Challenges and opportunities in the development of metal-based anticancer theranostic agents

Around 10 million fatalities were recorded worldwide in 2020 due to cancer and statistical projections estimate the number to increase by 60% in 2040. With such a substantial rise in the global cancer burden, the disease will continue to impose a huge socio-economic burden on society. Currently, the most widely used clinical treatment modality is cytotoxic chemotherapy using platinum drugs which is used to treat variety of cancers. Despite its clinical success, critical challenges like resistance, off-target side effects and cancer variability often reduce its overall therapeutic efficiency. These challenges require faster diagnosis, simultaneous therapy and a more personalized approach toward cancer management. To this end, small-molecule ‘theranostic’ agents have presented a viable solution combining diagnosis and therapy into a single platform. In this review, we present a summary of recent efforts in the design and optimization of metal-based small-molecule ‘theranostic’ anticancer agents. Importantly, we highlight the advantages of a theranostic candidate over the purely therapeutic or diagnostic agent in terms of evaluation of its biological properties.     

How does landscape context contribute to effects of habitat fragmentation on diversity and population density of butterflies?

Aim Studies on habitat fragmentation of insect communities mostly ignore the impact of the surrounding landscape matrix and treat all species equally. In our study, on habitat fragmentation and the importance of landscape context, we expected that habitat specialists are more affected by area and isolation, and habitat generalists more by landscape context. Location and methods The study was conducted in the vicinity of the city of Göttingen in Germany in the year 2000. We analysed butterfly communities by transect counts on thirty‐two calcareous grasslands differing in size (0.03–5.14 ha), isolation index (2100–86,000/edge‐to‐edge distance 55–1894 m), and landscape diversity (Shannon–Wiener: 0.09–1.56), which is correlated to percentage grassland in the landscape. Results A total of 15,185 butterfly specimens belonging to fifty‐four species are recorded. In multiple regression analysis, the number of habitat specialist (n = 20) and habitat generalist (n = 34) butterfly species increased with habitat area, but z‐values (slopes) of the species–area relationships for specialists (z = 0.399) were significantly steeper compared with generalists (z = 0.096). Generalists, but not specialists, showed a marginally significant increase with landscape diversity. Effects of landscape diversity were scale‐dependent and significant only at the smallest scale (landscape context within a 250 m radius around the habitat). Habitat isolation was not related to specialist and generalist species numbers. In multiple regression analysis the density of specialists increased significantly with habitat area, whereas generalist density increased only marginally. Habitat isolation and landscape diversity did not show any effects. Main conclusions Habitat area was the most important predictor of butterfly community structure and influenced habitat specialists more than habitat generalists. In contrast to our expectations, habitat isolation had no effect as most butterflies could cope with the degree of isolation in our study region. Landscape diversity appeared to be important for generalist butterflies only.     

Geographical range size of tropical plants influences their response to anthropogenic activities

Biodiversity patterns may be influenced by the species geographical range sizes, but this is rarely shown. We used a highly replicated and large-scale study in coastal Ecuador to determine for the first time the importance of latitudinal range size of plant species in their response to land-use activities. We examined herbaceous plant communities of five land-use types with decreasing anthropogenic disturbance (from the most intervened rice and pasture to the less intervened managed agroforest, abandoned agroforest, and forest) in a low and a high impact human-dominated landscape. All species were classified in four latitudinal range size quartiles, from the 25% species with the narrowest to the 25% with the widest range size. We found notable differences between patterns of total species richness and those of individual range size quartiles. Whereas total species richness was higher in more intervened land-use types, percentages of narrow-ranged species were significantly higher in less intervened land-use types. In contrast, percentages of wide-ranging species were higher in more intervened land-use types. Hence, responses of plant species to human activities were influenced by traits that determine their range sizes. An analysis of floristic similarity between land-use types revealed that narrow-ranged species were mainly preserved in forest fragments, but the other land-use types supported many unique narrow-ranged species and therefore made an important contribution to their preservation at the landscape level. Conservation efforts should combine protection of natural habitats with strategies to maintain a diversity of low-intensity land-use types, looking for win-win solutions or trade-offs between biodiversity conservation and human welfare in human-dominated landscapes.     

Lidocaine-loaded fish scale-nanocellulose biopolymer composite microneedles

Microneedle (MN) technology has emerged as an effective drug delivery system, and it has tremendous potential as a patient friendly substitute for conventional methods for transdermal drug delivery (TDD). In this paper, we report on the preparation of lidocaine-loaded biodegradable microneedles, which are manufactured from fish scale-derived collagen. Lidocaine, a common tissue numbing anaesthetic, is loaded in these microneedles with an aim of delivering the drug with controlled skin permeation. Evaluation of lidocaine permeation in porcine skin has been successfully performed using Franz diffusion cell (FDC) which has shown that the drug permeation rate increases from 2.5 to 7.5% w/w after 36 h and pseudo steady state profile is observed from 5.0 to 10.0% w/w lidocaine-loaded microneedle. Swelling experiments have suggested that the microneedles have negligible swellability which implies that the patch would stick to the tissue when inserted. The experiments on MN dissolution have depicted that the lidocaine loaded in the patch is lower than the theoretical loading, which is expected as there can be losses of the drug during initial process manufacture.     

Key physiological parameters dictate triggering of activity-dependent bulk endocytosis in hippocampal synapses

To maintain neurotransmission in central neurons, several mechanisms are employed to retrieve synaptically exocytosed membrane. The two major modes of synaptic vesicle (SV) retrieval are clathrin-mediated endocytosis and activity-dependent bulk endocytosis (ADBE). ADBE is the dominant SV retrieval mode during intense stimulation, however the precise physiological conditions that trigger this mode are not resolved. To determine these parameters we manipulated rat hippocampal neurons using a wide spectrum of stimuli by varying both the pattern and duration of stimulation. Using live-cell fluorescence imaging and electron microscopy approaches, we established that stimulation frequency, rather than the stimulation load, was critical in the triggering of ADBE. Thus two hundred action potentials, when delivered at high frequency, were sufficient to induce near maximal bulk formation. Furthermore we observed a strong correlation between SV pool size and ability to perform ADBE. We also identified that inhibitory nerve terminals were more likely to utilize ADBE and had a larger SV recycling pool. Thus ADBE in hippocampal synaptic terminals is tightly coupled to stimulation frequency and is more likely to occur in terminals with large SV pools. These results implicate ADBE as a key modulator of both hippocampal neurotransmission and plasticity.     

The relationship between adrenal vascular events and steroid secretion: the role of mast cells and endothelin.

The actions of ACTH on the adrenal cortex are known to be 2-fold. In addition to increased steroidogenesis, ACTH also causes marked vasodilation, reflected by an increased rate of blood flow through the gland. Our studies, using the in situ isolated perfused rat adrenal preparation, have shown that zona fasciculata function and corticosterone secretion are closely related to vascular events, with an increase in perfusion medium flow rate causing an increase in corticosterone secretion, in the absence of any known stimulant. These observations give rise to two important questions: how does ACTH stimulate blood flow; and how does increased blood (or perfusion medium) flow stimulate steroidogenesis? Addressing the first question, we have recently identified mast cells in the adrenal capsule, and shown that Compound 48/80, a mast cell degranulator, mimics the actions of ACTH on adrenal blood flow and corticosterone secretion. We have also demonstrated an inhibition of the adrenal vascular response to ACTH in the presence of disodium cromoglycate, which prevents mast cell degranulation. We conclude, therefore, that ACTH stimulates adrenal blood flow by its actions on mast cells in the adrenal capsule. Addressing the second question, we looked at the role of endothelin in the rat adrenal cortex. Endothelin 1, 2 and 3 caused significant stimulation of steroid secretion by collagenase dispersed cells from both the zona glomerulosa and the zona fasciculata. A sensitive response was seen, with significant stimulation at an endothelin concentration of 10(-13) mol/l or lower. Endothelin secretion by the in situ isolated perfused rat adrenal gland was measured using the Amersham assay kit. Administration of ACTH (300 fmol) caused an increase in the rate of immunoreactive endothelin secretion, from an average of 28.7 +/- 2.6 to 52.6 +/- 6 fmol/10 min (P less than 0.01, n = 5). An increase in immunoreactive endothelin secretion was also seen in response to histamine, an adrenal vasodilator, which stimulates corticosterone secretion in the intact gland, but has no effect on collagenase-dispersed cells. From these data we conclude that endothelin may mediate the effects of vasodilation on corticosterone secretion, and this mechanism may explain some of the differences in response characteristics between the intact gland and dispersed cells.     

Relative importance of resource quantity, isolation and habitat quality for landscape distribution of a monophagous butterfly

Fragmentation of food resources is a major cause of species extinction. We tested the effects of habitat area, isolation and quality for the occurrence and population density of the endangered butterfly Polyommatus coridon . Polyommatus coridon larvae are monophagous on the plant Hippocrepis comosa, and both species are specialised on calcareous grassland, which is an endangered and highly fragmented habitat type in Germany.
In 2001 we surveyed all known calcareous grasslands (n=298) around the city of Göttingen (Germany) to map the population size of H. comosa in these habitats. Further, habitat isolation (between-patch distance: 70–7220 m) and habitat quality (cover of flowering plants, height of herb layer, percent bare ground, cover of shrub layer, wind protection, inclination) were quantified. Hippocrepis comosa occurred on only 124 fragments, which were then surveyed by 20 min transect counts for adult P. coridon in 2001 and 2002.
Occurrence and population density of P. coridon were largely determined by the population size of its larval food plant, which was correlated with grassland area. Effects of habitat isolation and habitat quality on P. coridon populations contributed only little to the explanation.
In conclusion, this monophagous habitat specialist depended on large habitats with large food plant populations to exist in viable populations. Habitat isolation and quality appear to contribute to occurrence and density patterns only in landscapes where these factors shift towards extremes, therefore general recommendations for conservation programs are difficult as they depend on regional distinctions.     

Rain forest promotes trophic interactions and diversity of trap-nesting Hymenoptera in adjacent agroforestry

1. Human alteration of natural ecosystems to agroecosystems continues to accelerate in tropical countries. The resulting world-wide decline of rain forest causes a mosaic landscape, comprising simple and complex agroecosystems and patchily distributed rain forest fragments of different quality. Landscape context and agricultural management can be expected to affect both species diversity and ecosystem services by trophic interactions. 2. In Central Sulawesi, Indonesia, 24 agroforestry systems, differing in the distance to the nearest natural forest (0-1415 m), light intensity (37.5-899.6 W/m(-2)) and number of vascular plant species (7-40 species) were studied. Ten standardized trap nests for bees and wasps, made from reed and knotweed internodes, were exposed in each study site. Occupied nests were collected every month, over a period totalling 15 months. 3. A total of 13,617 brood cells were reared to produce adults of 14 trap-nesting species and 25 natural enemy species, which were mostly parasitoids. The total number of species was affected negatively by increasing distance from forest and increased with light intensity of agroforestry systems. The parasitoids in particular appeared to benefit from nearby forests. Over a 500-m distance, the number of parasitoid species decreased from eight to five, and parasitism rates from 12% to 4%. 4. The results show that diversity and parasitism, as a higher trophic interaction and ecosystem service, are enhanced by (i) improved connectivity of agroecosystems with natural habitats such as agroforestry adjacent to rain forest and (ii) management practices to increase light availability in agroforestry, which also enhances richness of flowering plants in the understorey.