Dysregulation of calcium homeostasis in cancer and its role in chemoresistance.

Globally, cancer, as a major public health concern, poses a severe threat to people's well-being. Advanced and specialized therapies can now cure the majority of people with early-stage cancer. However, emerging resistance to traditional and novel chemotherapeutic drugs remains a serious issue in clinical medicine. Chemoresistance often leads to cancer recurrence, metastasis, and increased mortality, accounting for 90% of chemotherapy failures. Thus, it is important to understand the molecular mechanisms of chemoresistance and find novel therapeutic approaches for cancer treatment. Among the several factors responsible for chemoresistance, calcium (Ca2+) dysregulation plays a significant role in cancer progression and chemoresistance. Therefore, targeting this derailed Ca2+ signalling for cancer therapy has become an emerging research area. Of note, the Ca2+ signal and its proteins are a multifaceted and potent tool by which cells achieve specific outcomes. Depending on cell survival needs, Ca2+ is either upregulated or downregulated in both chemosensitive and chemoresistant cancer cells. Consequently, the appropriate treatment should be selected based on Ca2+ signalling dysregulation. This review discusses the role of Ca2+ in cancer cells and the targeting of Ca2+ channels, pumps, and exchangers. Furthermore, we have emphasised the role of Ca2+ in chemoresistance and therapeutic strategies. In conclusion, targeting Ca2+ signalling is a multifaceted process. Methods such as site-specific drug delivery, target-based drug-designing, and targeting two or more Ca2+ proteins simultaneously may be explored; however, further clinical studies are essential to validate Ca2+ blockers' anti-cancer efficacy.

Research and therapeutic applications of silk proteins in cancer.

Despite the availability of advanced treatments, cancer remains the second leading cause of death worldwide. This is due to the many challenges prevailing in the research field and cancer therapy. Resistance to therapy and side effects provide major hindrances to recovery from cancer. As a result, in addition to the aim of killing cancer cells, the focus should also be on reducing or preventing side effects of the treatment. To enhance the effectiveness of cancer treatment, many researchers are studying drug delivery systems based on silk proteins: fibroin and sericin. These proteins have high biocompatibility, biodegradability, and ease of modification. Consequently, many researchers have developed several formulations of silk proteins such as scaffolds, nanoparticles, and hydrogels by combining them with other materials or drugs. This review summarizes the use of silk proteins in various forms in cancer research and therapy. The use of silk proteins to study cancer cells, to deliver cancer drugs to a target site, in cancer thermal therapy, and as an anti-cancer agent is described here.

Neurotoxic mechanisms of triclosan: The antimicrobial agent emerging as a toxicant.

Several scientific studies have suggested a link between increased exposure to pollutants and a rise in the number of neurodegenerative disorders of unknown origin. Notably, triclosan (an antimicrobial agent) is used in concentrations ranging from 0.3% to 1% in various consumer products. Recent studies have also highlighted triclosan as an emerging toxic pollutant due to its increasing global use. However, a definitive link is missing to associate the rising use of triclosan and the growing number of neurodegenerative disorders or neurotoxicity. In this article, we present systematic scientific evidence which are otherwise scattered to suggest that triclosan can indeed induce neurotoxic effects, especially in vertebrate organisms including humans. Mechanistically, triclosan affected important developmental and differentiation genes, structural genes, genes for signaling receptors and genes for neurotransmitter controlling enzymes. Triclosan-induced oxidative stress impacting cellular proteins and homeostasis which triggers apoptosis. Though the scientific evidence collated in this article unequivocally indicates that triclosan can cause neurotoxicity, further epidemiological studies may be needed to confirm the effects on humans.

New insights into inhibitory nature of triclosan on acetylcholinesterase activity.

The antimicrobial agent, triclosan, has been designated as a "contaminant of emerging concern (CEC)". Previous in vivo studies have shown that triclosan exposure can inhibit acetylcholinesterase (AChE) activity. However, mechanistic insights into AChE inhibition by triclosan are missing. Here, using in vitro activity assay with purified AChE, we show that triclosan can directly inhibit AChE. In vivo, triclosan exposure resulted in reduced total antioxidant capacity concomitant with reduced AChE activity in the adult zebrafish brain. Adult zebrafish when pre-treated with antioxidant melatonin, resulted in attenuated oxidative stress and attenuated inhibitory effect of triclosan on the AChE activity. Our results indicate that triclosan can affect AChE activity both by direct binding and indirectly through increased oxidative stress and therefore, provide important mechanistic insights into triclosan induced neurotoxicity.

Triclosan affects motor function in zebrafish larva by inhibiting ache and syn2a genes.

The widespread use of triclosan in personal care products as an antimicrobial agent is leading to its alarming tissue-bioaccumulation including human brain. However, knowledge of its potential effects on the vertebrate nervous system is still limited. Here, we hypothesized that sublethal triclosan concentrations are potent enough to alter motor neuron structure and function in zebrafish embryos exposed for prolonged duration. In this study, zebrafish embryos were used as vertebrate-animal model. Prolonged exposure (up to 4 days) of 0.6 mg/L (LC50, 96 h) and 0.3 mg/L (

Triclosan alters adult zebrafish behavior and targets acetylcholinesterase activity and expression.

Triclosan is widely used in consumer products as an antimicrobial agent. Epidemiological studies have reported the association of triclosan with adverse birth outcomes. The toxic effects of triclosan on the developing stages of zebrafish are reported, however, its role as behavioral modifier is limited. In the present study, adult zebrafish were exposed to triclosan (0.3 and 0.6 mg/L) for 48 h and the exploratory behavior was analyzed using ZebraTrack. Triclosan exposed group showed significantly reduced locomotion concomitant with increased freezing duration. They also showed erratic movements suggesting that triclosan induced anxiety-like behavior in adult zebrafish. Next, we tested the hypothesis that the anxiety-like behavior is linked to altered acetylcholinesterase activity. We found that the triclosan exposure decreased acetylcholinesterase activity in the brain and skeletal muscle but acetylcholinesterase (ache) gene was significantly down-regulated only in the skeletal muscle of the adult zebrafish exposed to triclosan. In addition, we also observed a down-regulation of myelin basic protein (mbp) gene in the skeletal muscle of adult zebrafish treated with triclosan. Thus, our data indicates that even short exposure of triclosan is potent enough to induce behavioral anomalies in adult zebrafish that appear to involve acetylcholinesterase and other structural proteins especially in the skeletal muscle.

Sodium benzoate induced developmental defects, oxidative stress and anxiety-like behaviour in zebrafish larva.

Sodium benzoate (SB) is a common food preservative. Its FDA described safety limit is 1000 ppm. Lately, increased use of SB has prompted investigations regarding its effects on biological systems. Data regarding toxicity of SB is divergent and controversial with studies reporting both harmful and beneficial effects. Therefore, we did a systematic dose dependent toxicity study of SB using zebrafish vertebrate animal model. We also investigated oxidative stress and anxiety-like behaviour in zebrafish larva treated with SB. Our results indicate that SB induced developmental (delayed hatching), morphological (pericardial edema, yolk sac edema and tail bending), biochemical (oxidative stress) and behavioural (anxiety-like behaviour) abnormalities in developing zebrafish larva. LC50 of SB induced toxicity was approximately 400 ppm after 48 h of SB exposure. Our study strongly supports its harmful effects on vertebrates at increasing doses. Thus, we suggest caution in the excessive use of this preservative in processed and convenience foods.

ZebraPace: An Open-Source Method for Cardiac-Rhythm Estimation in Untethered Zebrafish Larvae.

For the assessment of cardiac function, heartbeat represents one key parameter. Current methods of heartbeat measurements in the zebrafish larvae usually require larval immobilization, fluorescent transgenic strains and a confocal microscope, costly commercial software for analysis, or strong programming skills if the software is open-source. Here, we present a simple yet powerful method of heartbeat analysis using untethered, unlabeled zebrafish larva using ImageJ (open-source software), which does not require programming skills. We named it as ZebraPace for Zebrafish Precise Algorithm for Cardiac-rhythm Estimation. ZebraPace works directly with AVI videos and requires no image processing steps. ZebraPace uses pixel intensity change in a grayscale video to count the number of beats. We have validated the ZebraPace method by pharmacological alterations of the heartbeat in zebrafish larvae of 48 and 72 hpf stages. We have also determined beat-to-beat interval, which relates to rhythmicity of heartbeat. The results obtained by using ZebraPace corroborates well with the heartbeat values previously reported for similarly aged larvae as determined by using specialized software. We believe that the ZebraPace method is simple, cost-effective, and easy to grasp as it involves fewer steps. It not only reduces the manual workload but also eliminates sample preparation time and researcher subjectivity.