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.     

Attenuation of doxorubicin-induced cardiotoxicity and genotoxicity by an indole-based natural compound 3,3′-diindolylmethane (DIM) through activation of Nrf2/ARE signaling pathways and inhibiting apoptosis

The most crucial complication related to doxorubicin (DOX) therapy is nonspecific cytotoxic effect on healthy normal cells. The clinical use of this broad-spectrum chemotherapeutic agent is restricted due to development of severe form of cardiotoxicity, myelosuppression, and genotoxicity which interfere with therapeutic schedule, compromise treatment outcome and may lead to secondary malignancy. 3,3′-diindolylmethane (DIM) is a naturally occurring plant alkaloid formed by the hydrolysis of indolylmethyl glucosinolate (glucobrassicin). Therefore, the present study was undertaken to investigate the protective role of DIM against DOX-induced toxicity in mice. DOX was administered (5?mg/kg b.w., i.p.) and DIM was administered (25?mg/kg b.w., p.o.) in concomitant and 15 days pretreatment schedule. Results showed that DIM significantly attenuated DOX-induced oxidative stress in the cardiac tissues by reducing the levels of free radicals and lipid peroxidation, and by enhancing the level of glutathione (reduced) and the activity of antioxidant enzymes. The chemoprotective potential of DIM was confirmed by histopathological evaluation of heart and bone marrow niche. Moreover, DIM considerably mitigated DOX-induced clastogenicity, DNA damage, apoptosis, and myeloid hyperplasia in bone marrow niche. In addition, oral administration of DIM significantly (p?相似文献   

Gene structure,transcripts and calciotropic effects of the PTH family of peptides in <Emphasis Type=Italic>Xenopus</Emphasis> and chicken

Background  

Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) belong to a family of endocrine factors that share a highly conserved N-terminal region (amino acids 1-34) and play key roles in calcium homeostasis, bone formation and skeletal development. Recently, PTH-like peptide (PTH-L) was identified in teleost fish raising questions about the evolution of these proteins. Although PTH and PTHrP have been intensively studied in mammals their function in other vertebrates is poorly documented. Amphibians and birds occupy unique phylogenetic positions, the former at the transition of aquatic to terrestrial life and the latter at the transition to homeothermy. Moreover, both organisms have characteristics indicative of a complex system in calcium regulation. This study investigated PTH family evolution in vertebrates with special emphasis on Xenopus and chicken.     

Detection of Brugia malayi in laboratory and wild-caught Mansonioides mosquitoes (Diptera: Culicidae) using Hha I PCR assay

An Hha 1 based polymerase chain reaction (PCR) assay developed for the detection of Brugia malayi, the causative agent of Brugian lymphatic filariasis, was evaluated for its sensitivity in the laboratory and for its usefulness in measuring changes in transmission of the disease in the field. Laboratory studies showed that the new assay was highly sensitive in comparison with the standard dissection and microscopy technique. The assay can detect as little as 4 pg of parasite DNA or a single microfilaria in pools of up to 100 mosquitoes. The optimum pool size for convenience was found to be 50 mosquitoes per pool. The efficacy of PCR assay was evaluated in filariasis control programmes in operation in endemic areas of Kerala State, South India. The infection rates obtained by the Hha I PCR assay and the conventional dissection and microscopy technique were 1.2% and 1.7% respectively in operational areas and 8.3% and 4.4% respectively, in check areas, which were not significantly different (P < 0.05). Thus, the Hha I PCR assay was found to be as sensitive as the conventional technique and hence it can be used as a new epidemiological tool for assessing parasite infection in field-collected mosquitoes.     

Amelioration of dextran sulfate colitis by butyrate: role of heat shock protein 70 and NF-kappaB

Butyrate enemas have been demonstrated to ameliorate inflammation in ulcerative colitis. The mechanism of this protective effect of butyrate is not known, and this study examines the effect of butyrate on epithelial function, inducible heat shock protein 70 (HSP70) expression, and NF-kappaB activation in experimental colitis. Colitis was induced in rats by oral dextran sulfate sodium (DSS) and by butyrate or saline enemas. Mucosal barrier function was assessed by electrical resistance and [14C]mannitol permeability. HSP70 production was determined by [35S]methionine labeling, Western blot analysis, and immunohistochemistry. Activation of heat shock factors (HSFs) and NF-kappaB was evaluated by EMSA. Butyrate showed a significant protection against the decrease in cell viability, increase in mucosal permeability, and polymorphonuclear neutrophil infiltration seen in DSS colitis. Butyrate inhibited HSP70 expression in DSS colitis and also inhibited the activation of HSF and NF-kappaB. Thus butyrate enema was found to be cytoprotective in DSS colitis, an effect partly mediated by suppressing activation of HSP70 and NF-kappaB.     

Structure and Binding Interface of the Cytosolic Tails of αXβ2 Integrin

Background

Integrins are signal transducer proteins involved in a number of vital physiological processes including cell adhesion, proliferation and migration. Integrin molecules are hetero-dimers composed of two distinct subunits, α and β. In humans, 18 α and 8 β subunits are combined into 24 different integrin molecules. Each of the subunit comprises a large extracellular domain, a single pass transmembrane segment and a cytosolic tail (CT). The CTs of integrins are vital for bidirectional signal transduction and in maintaining the resting state of the receptors. A large number of intracellular proteins have been found to interact with the CTs of integrins linking integrins to the cytoskeleton.

Methodology/Principal Findings

In this work, we have investigated structure and interactions of CTs of the leukocyte specific integrin αXβ2. We determined the atomic resolution structure of a myristoylated CT of αX in perdeuterated dodecylphosphocholine (DPC) by NMR spectroscopy. Our results reveal that the 35-residue long CT of αX adopts an α-helical conformation for residues F4-N17 at the N-terminal region. The remaining residues located at the C-terminal segment of αX delineate a long loop of irregular conformations. A segment of the loop maintains packing interactions with the helical structure by an extended non-polar surface of the αX CT. Interactions between αX and β2 CTs are demonstrated by ¹⁵N-¹H HSQC NMR experiments. We find that residues constituting the polar face of the helical conformation of αX are involved in interactions with the N-terminal residues of β2 CT. A docked structure of the CT complex indicates that a network of polar and/or salt-bridge interactions may sustain the heteromeric interactions.

Conclusions/Significance

The current study provides important insights into the conservation of interactions and structures among different CTs of integrins.     

Effect of inland water salinity on growth performance and nutritional physiology in growing milkfish, Chanos chanos (Forsskal): field and laboratory studies

To investigate the effect of inland groundwater salinity on growth performance, feed conversion efficiency, nutrient retention and intestinal enzyme activity in milkfish, two experiments were conducted. In the first experiment (Expt I), a 100‐day monoculture of Chanos chanos [mean body weight (BW): 2.2 g] at different salinities (0, 10, 15, 20 and 25‰) was carried out in ponds fertilized with cowdung (about 10 000 kg ha^?1 year^?1) and poultry droppings (about 3000 kg ha^?1 year^?1). The fish were fed a compounded supplementary diet (containing 40% protein) at 5% BW day^?1. Studies have revealed that growth increased with each increase in the salinity level; the highest values in weight gain and energy assimilated were observed in ponds maintained at 25‰ salinity [weight: 322.2 g and specific growth rate (SGR): 8.3]. Highest values of condition factor (0.7) and exponential value (n) of the length–weight relationship (LWR; n = 3.25) were also observed in ponds maintained at 25‰ salinity. Dissolved oxygen (DO), biological oxygen demand (BOD), pH and nutrient release remained at the optimal level during the culture period. High values of chlorophyll a, net primary productivity (NPP), phytoplankton and zooplankton population coincided with the highest values of alkalinity and turbidity in ponds maintained at 25‰ salinity. Multivariate analysis revealed a significant positive correlation of chlorides (r = 0.91), conductivity (r = 0.89) and hardness (r = 0.96) with fish growth. Productivity indicating parameters viz. NPP (r = 0.45), nitrate (r = 0.94) and o‐PO₄ (r = 0.52) also showed a significant positive correlation with fish weight gain. In the second experiment (Expt II), milkfish (mean BW: 3.7 g) fry were exposed to different levels of salinity (0.0, 10, 15, 20, 25 and 30‰), and maintained for 90 days in the laboratory. Significantly (P < 0.05) high growth (percentage increase in BW: 183.1 and SGR: 1.2), feed conversion efficiency (64.5%) and intestinal enzyme activity (protease 5.1, amylase 4.1 and cellulolytic 3.2) were observed in the group maintained at 25 ppt salinity in comparison with other groups similarly maintained at low or high salinity levels. Carcass composition, muscle and liver glycogen levels were also significantly (P < 0.05) affected by salinity changes. The significance of these findings is discussed in this paper.     

Normal hematological indices, blood chemistry and histology and ultrastructure of pancreatic islets in the wild Indian bonnet monkeys (Macaca radiata radiata)

The present study is aimed at determining some haematological and biochemical parameters in the wild Indian bonnet monkeys as also the microscopic and ultrastructural characteristics of their pancreatic islets. Adult wild Indian bonnet monkeys (Macaca radiata radiata) of both sexes weighing between 2.5 and 4 kg were used in these experiments. Their platelet, reticulocyte and total leukocyte counts and the blood concentrations of hemoglobin and plasma proteins and the serum concentrations of aspartate amino transferase, alanine amino transferase and calcium are similar to the values reported for M. mulatta. Plasma glucose is lower when compared with reported values of M. mulatta and M. fascicularis. Insulin levels are comparable with those of M. mulatta and M. nigra. Histology of islets is similar to that of humans. Ovoid cell collections of islet cells are scattered throughout the pancreas. Ultrastructure of A, B and D cells is similar to humans. These findings suggest that this relatively underutilized macaques may be a suitable model for biomedical research.     

Effect of plant growth regulators on regeneration of plantlets from bud cultures ofCymbopogon nardus L. and the detection of essential oils from thein vitro plantlets

Cymbopogon nardus L. could be propagated via tissue culture using axillary buds as explants. The aseptic bud explants obtained using double sterilization methods produced stunted abnormal multiple shoots when they were cultured on Murashige and Skoog medium (MS) supplemented with 1.0 mg L^-1 or 2.0 mg L^-1 benzyladenine (BA). Stunted shoots that cultured on MS + 1.0 mg L^-1 BA + 1.0 mg L^-1 N⁶-isopentenyl-adenine (2iP) could induce elongation of shoots from about 60% of the stunted shoots. Normal multiple shoots could be induced at the highest (19.7 shoots per bud) from the bud explants within six weeks when cultured on proliferation medium consisted of MS supplemented with 0.3 mg L^-1 BA and 0.1 mg L^-1 indole-3-butyric acid (IBA). The separated individual shoot produced roots when transferred to basic MS solid medium. The essential oils that were contained in the mature plants namely citronellal, geraniol and citronellol were also found in thein vitro C. nardus plantlets. Citronellal was the main essential oil component in the matured plants while geraniol was the main component in thein vitro plantlets.