Repurposing of Benzimidazole Anthelmintic Drugs as Cancer Therapeutics.

Benzimidazoles have shown significant promise for repurposing as a cancer therapy. The aims of this review are to investigate the possibilities and limitations of the anti-cancer effects of benzimidazole anthelmintics and to suggest ways to overcome these limitations. This review included studies on the anti-cancer effects of 11 benzimidazoles. Largely divided into three parts, i.e., preclinical anti-cancer effects, clinical anti-cancer effects, and pharmacokinetic properties, we examine the characteristics of each benzimidazole and attempt to elucidate its key properties. Although many studies have demonstrated the anti-cancer effects of benzimidazoles, there is limited evidence regarding their effects in clinical settings. This might be because the clinical trials conducted using benzimidazoles failed to restrict their participants with specific criteria including cancer entities, cancer stages, and genetic characteristics of the participants. In addition, these drugs have limitations including low bioavailability, which results in insufficient plasma concentration levels. Additional studies on whole anti-cancer pathways and development strategies, including formulations, could result significant enhancements of the anti-cancer effects of benzimidazoles in clinical situations.

Experience with and perceptions of non-prescription anthelmintics for cancer treatments among cancer patients in South Korea: A cross-sectional survey.

Although non-prescription anthelmintics are used by many patients as cancer treatment in South Korea, data regarding the experiences or perceptions of these drugs are lacking. This study aimed to investigate the repercussions of non-prescription anthelmintics for cancer treatment and evaluate their perceived effectiveness and adverse effects. This survey included 86 cancer patients, aged 19 years and older, who underwent anthelmintic therapy for cancer. They were recruited from two online communities in South Korea through a structured questionnaire that was provided online. Cancer patients under non-prescription anthelmintic therapy for cancer in South Korea were mostly in their advanced stages and had started the treatment in 2019. About half of the cancer patients had taken non-prescription anthelmintics during their chemotherapy, and 96.5% of them did not inform the clinicians. These participants had a positive perception (79.1%) toward the effectiveness of anthelmintics, as they felt it improved their physical condition. Data on the adverse effects of anthelmintics showed that more than two-third of the participants did not report experiencing any adverse effects. Communication between the clinicians and cancer patients regarding the use of non-prescription anthelmintics should be enhanced to prevent adverse effects.

Toward a Mechanistic Understanding of Color Vision in Insects.

Many visual animals exploit spectral information for seeking food and mates, for identifying preys and predators, and for navigation. Animals use chromatic information in two ways. "True color vision," the ability to discriminate visual stimuli on the basis of their spectral content independent of brightness, is thought to play an important role in object identification. In contrast, "wavelength-specific behavior," which is strongly dependent on brightness, often associates with foraging, navigation, and other species-specific needs. Among animals capable of chromatic vision, insects, with their diverse habitats, stereotyped behaviors, well-characterized anatomy and powerful genetic tools, are attractive systems for studying chromatic information processing. In this review, we first discuss insect photoreceptors and the relationship between their spectral sensitivity and animals' color vision and ecology. Second, we review recent studies that dissect chromatic circuits and explore neural mechanisms of chromatic information processing. Finally, we review insect behaviors involving "true color vision" and "wavelength-specific behaviors," especially in bees, butterflies, and flies. We include examples of high-order color vision, such as color contrast and constancy, which are shared by vertebrates. We focus on Drosophila studies that identified neuronal correlates of color vision and innate spectral preferences. We also discuss the electrophysiological studies in bees that reveal color encoding. Despite structural differences between insects' and vertebrates' visual systems, their chromatic vision appears to employ the same processing principles, such as color opponency, suggesting convergent solutions of neural computation to common problems.

Serum 25-hydroxyvitamin D and insulin resistance in apparently healthy adolescents.

PURPOSE: Vitamin D deficiency is a common condition that is associated with diabetes and insulin resistance. However, the association between vitamin D and insulin resistance has not been fully studied, especially in the general adolescent population. Therefore, we assessed the association between serum 25-hydroxyvitamin D [25(OH)D] level and insulin resistance among apparently healthy Korean adolescents. METHODS: A total of 260 (135 male and 125 female) adolescents in a rural high school were assessed for serum 25(OH)D, fasting plasma glucose, and insulin. All of the participants were aged 15 to 16 years old, and without known hypertension or diabetes. Serum 25(OH)D was analyzed both as a continuous and categorical variable in association with insulin resistance. Insulin resistance was estimated by homeostasis model assessment (HOMA-IR). Increased insulin resistance was operationally defined as a HOMA-IR value higher than the sex-specific 75th percentile. RESULTS: In male adolescents, every 10 ng/ml decrease in 25(OH)D level was associated with a 0.25 unit increase in HOMA-IR (p = 0.003) after adjusting for age and BMI. Compared to those in the highest quartile, male adolescents in the lowest 25(OH)D quartile were at significantly higher risk for insulin resistance: unadjusted odds ratio 4.06 (95% CI, 1.26 to 13.07); age and BMI adjusted odds ratio 3.59 (95% CI, 1.03 to 12.57). However, 25(OH)D level, either in continuous or categorical measure, was not significantly associated with insulin resistance among female adolescents. CONCLUSIONS: This study suggests that serum 25(OH)D level may be inversely associated with insulin resistance in healthy male adolescents.

The pharynx of the nematode C. elegans: A model system for the study of motor control.

Motor control is a complex process that requires interplay among the nervous system, muscles and environment. The simple anatomy, well-characterized muscle movements and ample resources for molecular and cellular dissection make the pharynx of the nematode C. elegans an attractive model system for the study of motor control. The C. elegans pharynx shows two clear muscle movements that are essential for food intake, pharyngeal pumping and isthmus peristalsis. Here, we review our recent findings on the mechanism by which food activates the feeding motions. To understand this process, we characterized the behavior of the feeding motions in response to serotonin, an endogenous pharyngeal pumping activator whose action is triggered by food. We found that: (1) the timing of onset and frequencies of the two feeding motions are distinct; (2) isthmus peristalsis is selectively coupled to the preceding pump; (3) like food, serotonin activates isthmus peristalsis as well as pharyngeal pumping. By genetic analysis, we showed that two separate neural pathways activate the two feeding motions explaining the differences between the two feeding motions. We also proposed a model that explains how the two feeding motions are separately controlled, yet coupled by the interaction between the nervous system and the muscles in the pharynx. Finally, we briefly discuss future approaches to further understand the mechanism that couples the two feeding motions in C. elegans and to possibly understand evolution of motor control in the pharynx by expanding findings in C. elegans to other nematode species.

The jaw of the worm: GTPase-activating protein EAT-17 regulates grinder formation in Caenorhabditis elegans.

Constitutive transport of cellular materials is essential for cell survival. Although multiple small GTPase Rab proteins are required for the process, few regulators of Rabs are known. Here we report that EAT-17, a novel GTPase-activating protein (GAP), regulates RAB-6.2 function in grinder formation in Caenorhabditis elegans. We identified EAT-17 as a novel RabGAP that interacts with RAB-6.2, a protein that presumably regulates vesicle trafficking between Golgi, the endoplasmic reticulum, and plasma membrane to form a functional grinder. EAT-17 has a canonical GAP domain that is critical for its function. RNA interference against 25 confirmed and/or predicted RABs in C. elegans shows that RNAi against rab-6.2 produces a phenotype identical to eat-17. A directed yeast two-hybrid screen using EAT-17 as bait and each of the 25 RAB proteins as prey identifies RAB-6.2 as the interacting partner of EAT-17, confirming that RAB-6.2 is a specific substrate of EAT-17. Additionally, deletion mutants of rab-6.2 show grinder defects identical to those of eat-17 loss-of-function mutants, and both RAB-6.2 and EAT-17 are expressed in the terminal bulb of the pharynx where the grinder is located. Collectively, these results suggest that EAT-17 is a specific GTPase-activating protein for RAB-6.2. Based on the conserved function of Rab6 in vesicular transport, we propose that EAT-17 regulates the turnover rate of RAB-6.2 activity in cargo trafficking for grinder formation.

Recognition of familiar food activates feeding via an endocrine serotonin signal in Caenorhabditis elegans.

Familiarity discrimination has a significant impact on the pattern of food intake across species. However, the mechanism by which the recognition memory controls feeding is unclear. Here, we show that the nematode Caenorhabditis elegans forms a memory of particular foods after experience and displays behavioral plasticity, increasing the feeding response when they subsequently recognize the familiar food. We found that recognition of familiar food activates the pair of ADF chemosensory neurons, which subsequently increase serotonin release. The released serotonin activates the feeding response mainly by acting humorally and directly activates SER-7, a type 7 serotonin receptor, in MC motor neurons in the feeding organ. Our data suggest that worms sense the taste and/or smell of novel bacteria, which overrides the stimulatory effect of familiar bacteria on feeding by suppressing the activity of ADF or its upstream neurons. Our study provides insight into the mechanism by which familiarity discrimination alters behavior.DOI:http://dx.doi.org/10.7554/eLife.00329.001.

Methods for measuring pharyngeal behaviors.

The pharynx is a neuromuscular pump at the anterior end of the alimentary tract. It is made up of 20 muscle cells, 20 neurons, and 20 other cells. Pharyngeal activity correlates with food intake. The proper feeding rate, as well as the precise timing of pharyngeal movements, is required for efficient feeding and likely for survival in nature. For most purposes, pharyngeal behavioral analysis requires no more than a routine stereomicroscope and a pair of eyes, but accuracy can be increased by video recording followed by off-line analysis in slow motion. Like other C. elegans behaviors, pharyngeal behavior is sensitive to both the immediate environmental conditions as well as to the history of such conditions.

Serotonin activates overall feeding by activating two separate neural pathways in Caenorhabditis elegans.

Food intake in the nematode Caenorhabditis elegans requires two distinct feeding motions, pharyngeal pumping and isthmus peristalsis. Bacteria, the natural food of C. elegans, activate both feeding motions (Croll, 1978; Horvitz et al., 1982; Chiang et al., 2006). The mechanisms by which bacteria activate the feeding motions are largely unknown. To understand the process, we studied how serotonin, an endogenous pharyngeal pumping activator whose action is triggered by bacteria, activates feeding motions. Here, we show that serotonin, like bacteria, activates overall feeding by activating isthmus peristalsis as well as pharyngeal pumping. During active feeding, the frequencies and the timing of onset of the two motions were distinct, but each isthmus peristalsis was coupled to the preceding pump. We found that serotonin activates the two feeding motions mainly by activating two separate neural pathways in response to bacteria. For activating pumping, the SER-7 serotonin receptor in the MC motor neurons in the feeding organ activated cholinergic transmission from MC to the pharyngeal muscles by activating the Gsα signaling pathway. For activating isthmus peristalsis, SER-7 in the M4 (and possibly M2) motor neuron in the feeding organ activated the G(12)α signaling pathway in a cell-autonomous manner, which presumably activates neurotransmission from M4 to the pharyngeal muscles. Based on our results and previous calcium imaging of pharyngeal muscles (Shimozono et al., 2004), we propose a model that explains how the two feeding motions are separately regulated yet coupled. The feeding organ may have evolved this way to support efficient feeding.