Efficacy of 100 hz sound stimulation on saccular dysfunction in meniere's disease.

BACKGROUND: Although various medical remedies have been attempted to alleviate the symptoms of Meniere's disease (MD), the risk-benefit ratios of these various treatments remain debatable. OBJECTIVE: We investigated the efficacy of sound stimulation of 100 Hz for treating vestibular dysfunction in patients with Meniere's disease (MD). MATERIALS AND METHODS: Patients with definitive MD with intractable vestibular symptoms and endolymphatic hydrops (EH) in the inner ear were evaluated. The experimental group received sound stimulation of 75 dB at a frequency of 100 Hz for 5 min, and the control group received sound stimulation of 75 dB at a frequency of 250 Hz for 5 min. Cervical vestibular-evoked myogenic potentials (cVEMPs) were measured before and after each sound stimulation, and the results of the clinical tests were compared between the two patient groups. RESULTS: Significant increases in cVEMP amplitudes were observed after sound stimulation of 100 Hz in ears with vestibular endolymphatic hydrops, although no such improvement was observed in the control group. CONCLUSION: Sound stimulation of 75 dB at a frequency of 100 Hz leads to improvement in cVEMP amplitude in patients with definitive MD. Adequate sound stimulation might be a new method for treating vestibular dysfunction associated with MD.

Elevated level of urinary tellurium is a potential risk for increase of blood pressure in humans and mice.

BACKGROUND: People worldwide are routinely exposed to tellurium mainly via dietary ingestion. There has been no study to clarify the contribution of tellurium to blood pressure in humans or animals. METHODS: In this cross-sectional study conducted in a general population of 2592 residents in Japan, the associations of urinary tellurium levels with blood pressure and prevalence of hypertension were investigated. The potential sources of tellurium were also investigated. An interventional study in mice confirmed the effect of tellurium exposure on blood pressure. RESULTS: Linear and logistic regression analyses with consideration of confounders including urinary sodium-potassium ratio showed significant positive associations of urinary tellurium level with prevalence of hypertension and blood pressure. Cereals/beans and vegetables/fruits were determined to be potential dietary sources of tellurium exposure. Intermediary analysis suggested that increased intake of cereals/beans, but not that of vegetables/fruits, is positively associated with the tellurium-mediated risk of hypertension. Correspondingly, the mouse study showed that exposure to a putative human-equivalent dose of tellurium via drinking water increased blood pressure with an elevated level of urinary tellurium. The temporally increased blood pressure was decreased to the normal level by a break of tellurium exposure with a reduced level of urinary tellurium. CONCLUSIONS: The interdisciplinary approach provided the first evidence that tellurium exposure is a potential risk for increase of blood pressure. Since the human urinary tellurium level in this study is comparable with the levels in general populations in other Asian and European countries in previous studies, exposure to tellurium may be a latent universal risk for hypertension.

Approaches to nutritional research using organoids; fructose treatment induces epigenetic changes in liver organoids.

Nutritional researches have successfully used animal models to gain new insights into nutrient action. However, comprehensive descriptions of their molecular mechanisms of action remain elusive as appropriate in vitro evaluation systems are lacking. Organoid models can mimic physiological structures and reproduce in vivo functions, making them increasingly utilized in biomedical research for a better understand physiological and pathological phenomena. Therefore, organoid modeling can be a powerful approach for to understand the molecular mechanisms of nutrient action. The present study aims to demonstrate the utility of organoids in nutritional research by further investigating the molecular mechanisms responsible for the negative effects of fructose intake using liver organoids. Here, we treated liver organoids with fructose and analyzed their gene expression profiles and DNA methylation levels. Microarray analysis demonstrated that fructose-treated organoids exhibited increased selenoprotein p (Sepp1) gene expression, whereas pyrosequencing assays revealed reduced DNA methylation levels in the Sepp1 region. These results were consistent with observations using hepatic tissues from fructose-fed rats. Conversely, no differences in Sepp1 mRNA and DNA methylation levels were observed in two-dimensional cells. These results suggest that organoids serve as an ideal in vitro model to recapitulate in vivo tissue responses and help to validate the molecular mechanisms of nutrient action compared to conventional cellular models.

Impact of maternal fructose intake on liver stem/progenitor cells in offspring: Insights into developmental origins of health and disease.

AIMS: The developmental origin of health and disease (DOHaD) theory postulates that poor nutrition during fetal life increases the risk of disease later in life. Excessive fructose intake has been associated with obesity, diabetes, and nonalcoholic fatty liver disease, and maternal fructose intake during pregnancy has been shown to affect offspring health. In this study, we investigated the effects of high maternal fructose intake on the liver stem/progenitor cells of offspring. MAIN METHOD: A fructose-based DOHaD model was established using Sprague-Dawley rats. Small hepatocytes (SHs), which play an important role in liver development and regeneration, were isolated from the offspring of dams that were fed a high-fructose corn syrup (HFCS) diet. The gene expression and DNA methylation patterns were analyzed on postnatal day (PD) 21 and 60. KEY FINDINGS: Maternal HFCS intake did not affect body weight or caloric intake, but differences in gene expression and DNA methylation patterns were observed in the SHs of offspring. Functional analysis revealed an association between metabolic processes and ion transport. SIGNIFICANCE: These results suggest that maternal fructose intake affects DNA methylation and gene expression in the liver stem/progenitor cells of offspring. Furthermore, the prolonged retention of these changes in gene expression and DNA methylation in adulthood (PD 60) suggests that maternal fructose intake may exert lifelong effects. These findings provide insights into the DOHaD for liver-related disorders and highlight the importance of maternal nutrition for the health of the next generation.

Elevated arsenic level in fasting serum via ingestion of fish meat increased the risk of hypertension in humans and mice.

Aims: There has been a shortage of human studies to elucidate the association between serum arsenic levels and the prevalence of hypertension. This study multidirectionally investigated associations among arsenic exposure, dietary ingestion, and the risk of hypertension by combined human epidemiological and mouse experimental studies. Methods and results: This study focused on the total arsenic level in fasting serum, a biomarker of arsenic exposure. Associations among ingestion frequencies of 54 diet items of Japanese food separated into six categories, total arsenic level in fasting serum, and the prevalence of hypertension were investigated in 2709 general people in Japan. Logistic regression analysis demonstrated a dose-dependent association between serum arsenic level and hypertension and a positive association between the ingestion of fish meat and hypertension. Further analysis showed that the latter association was fully mediated by increased fasting serum arsenic levels in humans. Similarly, oral exposure to the putative human-equivalent dose of arsenic species mixture with the same ratios in a common fish meat in Japan increased systolic blood pressure and arsenic levels in fasting serum in mice. Conclusion: This interdisciplinary approach suggests that fish-meat ingestion is a potential risk factor for arsenic-mediated hypertension. Because the increased consumption of fish meat is a recent global trend, health risks of the increased ingestion of arsenic via fish meat should be further investigated.

Zinc deficiency is associated with the development of ovarian endometrial cysts.

Ovarian cancers derived from endometrial cysts, also known as endometriosis in ovaries, are widespread histological types in Japan. Several studies suggest that zinc deficiency plays a role in endometriosis; however, the biological mechanism of zinc deficiency and endometrial cyst remains unknown. Thus, we investigated the association between zinc status and endometrial cysts. We measured the serum zinc levels in patients who had undergone surgery for endometrial cysts (n=19) and non-endometrial benign cysts (n=36). We analyzed cell proliferation, microarray data, and gene expression using N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a zinc chelator, in human immortalized endometrial epithelial cells (EMosis). The endometrial cyst group had considerably lower serum zinc levels than the non-endometrial benign cyst group. After adjusting for age, body mass index, alcohol consumption, smoking, and supplement use, endometrial cysts were markedly associated with serum zinc levels. EMosis cells treated with 5 µM TPEN demonstrated extensively increased proliferation compared to untreated cells. In the microarray analysis of EMosis cells treated with 5 µM TPEN, the enriched cellular components contained nucleoplasm, nuclear parts, and nuclear lumen. The upregulated biological processes included responses to hypoxia and decreased oxygen levels. The upregulated Kyoto Encyclopedia of Genes and Genomes pathway included the hypoxia-inducible factor-1 signaling pathway. EMosis cells treated with 5 µM TPEN demonstrated increased activator 1 (SRA1) expression and decreased AT-rich interaction domain 1A (ARID1A) expression. Protein-protein interaction network analysis indicated that ARID1A and SRA1 were associated with SMARCD1 and ATF1 among the differentially expressed genes in the microarray. EMosis cells treated with 5 µM TPEN revealed increased SRA1 mRNA levels and decreased ARID1A mRNA expression, whereas EMosis cells treated with 5 µM TPEN together with 10 µM zinc did not reveal changes in the mRNA levels of SRA1 or ARID1A compared with those without TPEN. These results suggest that zinc deficiency contributes to endometrial cyst development. Accordingly, zinc supplementation may suppress endometrial cyst development.

Calcitriol inhibits arsenic-promoted tumorigenesis through regulation of arsenic-uptake in a human keratinocyte cell line.

Chronic arsenic exposure from drinking water causes a variety of diseases and it is now recognized that at least 140 million people in 50 countries have been drinking water containing arsenic at levels above the WHO provisional guideline value of 10 µg/L. Long-term exposure to arsenic is associated with various types of cancers in humans including skin cancers. However, there is limited information on key molecules regulating arsenic-promoted carcinogenesis, and methods for the prevention and therapy of arsenic-promoted carcinogenesis have not yet been fully developed. Our in vitro study in human nontumorigenic HaCaT skin keratinocytes showed that calcitriol (activated vitamin D3, 1,25(OH)2D3) inhibited arsenic-mediated anchorage-independent growth with downregulations of cancer-related activation of MEK, ERK1/2 and AKT and activity of cell cycle. Moreover, calcitriol significantly repressed arsenic uptake in HaCaT cells with inhibition of expressions of aquaporin genes (AQP7, 9 and 10) which were modified by arsenic exposure. VDR, a vitamin D receptor, expression was significantly increased by arsenic exposure whereas calcitriol had no effect on its expression. These results suggest that treatment of calcitriol inhibits arsenic uptake via suppressions of aquaglyceroporin gene expressions resulting in inhibition of arsenic-promoted tumorigenesis in keratinocytes.

Vascular endothelium as a target tissue for short-term exposure to low-frequency noise that increases cutaneous blood flow.

Harmful health effects of exposure to low-frequency noise (LFN) defined as noise with frequencies at ≤100 Hz on the circulatory system have been a concern. However, there has been no study on the effects of exposure to LFN on the circulatory system with consideration of its frequencies and decibels. In this study, the effects of short-term exposure to broad-band LFNs and their pure-tone components (pure-tone LFNs) on cutaneous blood flow in the extremities including the hands were investigated. In our fieldwork study, we first sampled some kinds of common broad-band LFNs. Our human study then showed that broad-band LFN with a narrower frequency range more strongly increased cutaneous blood flow than did broad-band LFN with a wider frequency range. Pure-tone LFNs of 70-100 Hz at ≤85 dB(Z), but not pure-tone LFNs exceeding 100 Hz, further increased levels of cutaneous blood flow. Our wavelet-transform spectrum analysis of cutaneous blood flow next revealed that the nitric oxide (NO)-dependent and -independent vascular activities of the vascular endothelium were specifically increased by exposure to pure-tone LFN. Our animal study again indicated that exposure to pure-tone LFN increased cutaneous blood flow in mice with impairments of bilateral inner ears as well as cutaneous blood flow in control mice, suggesting a limited effect of inner ear function on the LFN-mediated increase in cutaneous blood flow. The NO-dependent suppressive effect of pure-tone LFN on cutaneous blood flow was confirmed by inhibition of vascular endothelial activity through intravenous injection of an NO inhibitor in wild-type mice. Taken together, the results of this study demonstrated that the vascular endothelium is a target tissue of LFN and that NO is an effector of the LFN-mediated increase in cutaneous blood flow. Since improvement of peripheral circulation could generally promote human health, short-term exposure to LFN may be beneficial for health.

Potential application of a hydrotalcite-like compound for reduction of toxicity to aquatic organisms via rapid and efficient removal of hydrogen sulfide.

Hydrogen sulfide (H2S) is known to have wide ranging toxicities not only as a gas but also as dissolved forms in aquatic environments. The diversity of aquatic organisms can be severely affected by hydrogen sulfide at very low concentrations, indicating the urgent necessity to develop an efficient method for removal of hydrogen sulfide in water. In this study, the removal capacity for hydrogen sulfide of our originally developed hydrotalcite-like compound composed of magnesium and iron (MF-HT) was investigated and its potential application for reduction of toxicity to aquatic organisms was evaluated. The MF-HT experimentally showed a high adsorption capacity of 146.5 mg/g with a fast adsorption equilibrium time of 45 min, both of which are top-class compared with those of other adsorbents previously reported. In fact, removal of hydrogen sulfide (1.2-152.5 mg/L) at an average rate of >97.6% was achieved in groundwater samples (n = 16) by the MF-HT within 60 min. The toxicities of groundwater, indicated by inhibition rate for microalgae (primary producers) and immobilization rate for crustaceans (secondary consumers), were reduced by 96.1% and 82.5% in 2-fold and 4-fold diluted groundwater, respectively, after treatment with the MF-HT for 60 min. These results indicate that MF-HT has an excellent safety record for aquatic organisms. After clarifying the adsorption mechanism, excellent reusability of MF-HT was also confirmed after regeneration using 1 M Na2CO3 solution. Considering the efficacy, speed, safety and cost of MF-HT, it could be a novel promising material for solving the problem of hydrogen sulfide pollution in the hydrosphere.

Decreased hearing levels at frequencies for understanding speech in tannery workers exposed to a high level of trivalent chromium in Bangladesh.

Hexavalent chromium [Cr(VI)], which has a strong corrosive effect, has been reported to cause perforation of the eardrum. Trivalent chromium [Cr(III)] also has a weak corrosive effect. However, there has been no study on the effects of exposure to Cr, either Cr(VI) or Cr(III), on hearing levels in animals or humans. In this study, the effect of Cr(III) exposure on hearing levels was determined in a human study. Then the reproducibility of the results obtained in the human study and the etiology were investigated in an animal study. The mean levels of total chromium (t-Cr) in hair and toenails from 100 Bangladeshi tannery workers were >20-fold and >360-fold higher, respectively, than those in hair and toenails from 49 Bangladeshi non-tannery workers (office workers). Multivariate analysis revealed decreases of hearing levels (DHLs) at 1 k and 4 k Hz, frequencies that are crucial for understanding language, but not at 8 k and 12 k Hz, in the tannery workers. Since >99.99% of t-Cr in the wastewater that the workers were in direct contact with in the tanneries was Cr(III), the epidemiological results suggest Cr(III)-mediated DHLs in the tannery workers. The results of animal experiments in this study further showed that treatment with eardrops but not intraperitoneal injection with the same amount of Cr(III) that tannery workers might be exposed to resulted in DHL with a damaged eardrum in mice. Previous studies suggested that Cr(III) can directly reach the eardrums of tannery workers via droplets in the air. Cr(III) could also reach the eardrum via picking an ear canal with a finger contaminated with tannery wastewater including Cr(III). Taken together, the results of both human and animal studies suggest the risk of DHLs caused by damage of the eardrum through external exposure to Cr(III) via the ear canal.

Development of an efficient remediation system with a low cost after identification of water pollutants including phenolic compounds in a tannery built-up area in Bangladesh.

Water pollution caused by tannery wastewater is an important issue in developing countries. Most studies have focused on inorganic chemicals represented by chromium as a tannery-related main pollutant. This is the first study in which pollution of water by tannery-related organic chemicals was assessed by a combination of qualitative and quantitative analyses. Our quantitative analysis showed that the maximum concentration of total phenolic compounds (phenols), consisting of phenol, bisphenol F, p-cresol and chlorocresol, in canal water in a tannery built-up area in Bangladesh was >67-fold higher than the Environmental, Health and Safety (EHS) guideline value. Mapping of our results indicated tanneries as the sources of phenols pollution. Our original depurative, a hydrotalcite-like compound consisting of magnesium and iron (MF-HT), could adsorb all kinds of phenols and exhibited the highest phenol adsorption ability (115.8 mg/g) among reported hydrotalcite-like compounds. The levels of phenols in canal water samples were reduced to levels below the guideline value by using MF-HT with assistance of a photocatalytic reaction. Moreover, the mean level of chromium (112.2 mg/L) in canal water samples was decreased by 99.7% by using the depurative. Thus, the depurative has the potential for solving the problem of tannery-related water pollution by phenols and chromium.

Intranasal levels of lead as an exacerbation factor for allergic rhinitis in humans and mice.

BACKGROUND: Air pollutants are suspected to affect pathological conditions of allergic rhinitis (AR). OBJECTIVES: After detecting Pb (375 µg/kg) in Japanese cedar pollen, the effects of intranasal exposure to Pb on symptoms of AR were investigated. METHODS: Pollen counts, subjective symptoms, and Pb levels in nasal epithelial lining fluid (ELF) were investigated in 44 patients with Japanese cedar pollinosis and 57 controls from preseason to season. Effects of intranasal exposure to Pb on symptoms were confirmed by using a mouse model of AR. RESULTS: Pb levels in ELF from patients were >40% higher than those in ELF from control subjects during the pollen season but not before the pollen season. Pb level in ELF was positively associated with pollen counts for the latest 4 days before visiting a hospital as well as scores of subjective symptoms. Intranasal exposure to Pb exacerbated symptoms in allergic mice, suggesting Pb as an exacerbation factor. Pb levels in ELF and nasal mucosa in Pb-exposed allergic mice were higher than those in Pb-exposed nonallergic mice, despite intranasally challenging the same amount of Pb. Because the increased Pb level in the nasal mucosa of Pb-exposed allergic mice was decreased after washing the nasal cavity, Pb on the surface of but not inside the nasal mucosa may have been a source of increased Pb level in ELF of allergic mice. CONCLUSIONS: Increased nasal Pb level partially derived from pollen could exacerbate subjective symptoms of AR, indicating Pb as a novel hazardous air pollutant for AR.

Loss-of-function mutation of c-Ret causes cerebellar hypoplasia in mice with Hirschsprung disease and Down's syndrome.

The c-RET proto-oncogene encodes a receptor-tyrosine kinase. Loss-of-function mutations of RET have been shown to be associated with Hirschsprung disease and Down's syndrome (HSCR-DS) in humans. DS is known to involve cerebellar hypoplasia, which is characterized by reduced cerebellar size. Despite the fact that c-Ret has been shown to be associated with HSCR-DS in humans and to be expressed in Purkinje cells (PCs) in experimental animals, there is limited information about the role of activity of c-Ret/c-RET kinase in cerebellar hypoplasia. We found that a loss-of-function mutation of c-Ret Y1062 in PCs causes cerebellar hypoplasia in c-Ret mutant mice. Wild-type mice had increased phosphorylation of c-Ret in PCs during postnatal development, while c-Ret mutant mice had postnatal hypoplasia of the cerebellum with immature neurite outgrowth in PCs and granule cells (GCs). c-Ret mutant mice also showed decreased numbers of glial fibers and mitogenic sonic hedgehog (Shh)-positive vesicles in the external germinal layer of PCs. c-Ret-mediated cerebellar hypoplasia was rescued by subcutaneous injection of a smoothened agonist (SAG) as well as by reduced expression of Patched1, a negative regulator for Shh. Our results suggest that the loss-of-function mutation of c-Ret Y1062 results in the development of cerebellar hypoplasia via impairment of the Shh-mediated development of GCs and glial fibers in mice with HSCR-DS.

Hair graying with aging in mice carrying oncogenic RET.

Hair graying is a representative sign of aging in animals and humans. However, the mechanism for hair graying with aging remains largely unknown. In this study, we found that the microscopic appearance of hair follicles without melanocyte stem cells (MSCs) and descendant melanocytes as well as macroscopic appearances of hair graying in RET-transgenic mice carrying RET oncogene (RET-mice) are in accordance with previously reported results for hair graying in humans. Therefore, RET-mice could be a novel model mouse line for age-related hair graying. We further showed hair graying with aging in RET-mice associated with RET-mediated acceleration of hair cycles, increase of senescent follicular keratinocyte stem cells (KSCs), and decreased expression levels of endothelin-1 (ET-1) in bulges, decreased endothelin receptor B (Ednrb) expression in MSCs, resulting in a decreased number of follicular MSCs. We then showed that hair graying in RET-mice was accelerated by congenitally decreased Ednrb expression in MSCs in heterozygously Ednrb-deleted RET-mice [Ednrb(+/-);RET-mice]. We finally partially confirmed common mechanisms of hair graying with aging in mice and humans. Taken together, our results suggest that age-related dysfunction between ET-1 in follicular KSCs and endothelin receptor B (Ednrb) in follicular MSCs via cumulative hair cycles is correlated with hair graying with aging.

Increased levels of renal damage biomarkers caused by excess exposure to trivalent chromium in workers in tanneries.

BACKGROUND: The process for leather material production is carried out in developing countries using a large amount of trivalent chromium [Cr(III)]. Assesment of health risks for millions of workers in tanneries worldwide that are highly polluted with Cr(III) is needed. METHODS: Levels of total Cr and its chemical species in wastewater samples from tannery built-up areas of Bangladesh were investigated. Cr-mediated renal damage was assessed in 100 male tannery workers by epidemiological analysis consisting of questionnaires and measurements of levels of urinary Cr and urinary renal damage markers [urinary levels of total protein and kidney injury molecule-1 (KIM-1)]. RESULTS: High levels of total Cr (mean ± standard deviation = 1,908,762 ± 703,450 µg/L) were detected in wastewater samples from 13 sites of tanneries. More than 99.99% of total Cr in the wastewater was Cr(III), indicating that workers in the tanneries were exposed to large concentrations of Cr(III). Cr levels (mean ± standard, 2.89 ± 4.23 µg/g creatinine) in urine samples from the workers in tanneries were >24-fold higher than the levels in a general population previously reported. Multivariate analysis showed significant correlations between urinary levels of Cr and urinary levels of renal damage biomarkers. Nagelkerke Pseudo R2 values also showed that Cr level is the strongest contributor to the levels of renal damage biomarkers in the workers. CONCLUSION: Our results newly suggest that excess exposure to Cr(III) could be a risk for renal damage in humans.

Multidisciplinary approach to assess the toxicities of arsenic and barium in drinking water.

Well water could be a stable source of drinking water. Recently, the use of well water as drinking water has been encouraged in developing countries. However, many kinds of disorders caused by toxic elements in well drinking water have been reported. It is our urgent task to resolve the global issue of element-originating diseases. In this review article, our multidisciplinary approaches focusing on oncogenic toxicities and disturbances of sensory organs (skin and ear) induced by arsenic and barium are introduced. First, our environmental monitoring in developing countries in Asia showed elevated concentrations of arsenic and barium in well drinking water. Then our experimental studies in mice and our epidemiological studies in humans showed arsenic-mediated increased risks of hyperpigmented skin and hearing loss with partial elucidation of their mechanisms. Our experimental studies using cultured cells with focus on the expression and activity levels of intracellular signal transduction molecules such as c-SRC, c-RET, and oncogenic RET showed risks for malignant transformation and/or progression arose from arsenic and barium. Finally, our original hydrotalcite-like compound was proposed as a novel remediation system to effectively remove arsenic and barium from well drinking water. Hopefully, comprehensive studies consisting of (1) environmental monitoring, (2) health risk assessments, and (3) remediation will be expanded in the field of environmental health to prevent various disorders caused by environmental factors including toxic elements in drinking water.

A new method with an explant culture of the utricle for assessing the influence of exposure to low-frequency noise on the vestibule.

Health risks attributed to low-frequency noise (LFN) exposure are a serious global issue. Therefore, the development of a method for a prevention based upon risk assessments for LFN is important. Previously in vivo exposure of mice to LFN at 100 Hz, 95 dB for 1 hr produced imbalance with breakage of the otoconial membrane, which covers hair cells as well as impaired activity of hair cells in the vestibule. However, methods for inhibition of LFN-mediated imbalance have not been developed. At present, there are no apparent techniques available with in vitro or ex vivo assessments to evaluate LFN-mediated imbalance by direct administration of preventive chemicals into the vestibule. Our findings demonstrated the usefulness of an explant culture of the utricle with a fluorescent styryl dye, FM1-43FX. In addition, examination of the morphology of the otoconial membrane with explant cultures of utricles was conducted to determine the risk of LFN. Ex vivo exposure of the utricle to LFN at 100 Hz, 95 dB for 1 hr induced breaks in the otoconial membrane as well as decreased uptake of FM1-43FX in hair cells. Taken together, the results of this study provide a novel technique for assessing the risk of LFN exposure using an ex vivo experiment.

Peptides containing the MXXCW motif inhibit oncogenic RET kinase activity with a novel mechanism of action.

REarranged during Transition (RET) is a tyrosine kinase associated with the development of several malignancies. Identification of RET kinase inhibitors promises valuable therapeutic tools for the intervention of RET-driven tumors. Most currently available tyrosine kinase inhibitors target the ATP binding site, but there are several drawbacks of these ATP-competitive drugs. Therefore, there is a need to develop new kinase inhibitors with alternative mechanisms of action. We have previously reported that a conserved cysteine in the MXXCW motif of RET is crucial to the disulfide-bonded dimerization-linked activation of RET kinases. Reagents which bind to this cysteine may inhibit the activity of RET kinases through disulfide-bond mediated dimerization. Here, we examine the potential of MXXCW motif-containing peptides as candidate kinase inhibitors. We demonstrate that MXXCW motif-containing peptides bind to RET in a redox-sensitive manner and block enzymatic activity, causing inhibition of the RET-dependent activity of extracellular signal-regulated kinases and effectively reducing the malignant potential of RET-papillary thyroid carcinoma-1 (PTC)-expressing cells. These motif-containing peptides were also found to be effective against the drug resistant mutant of RET. The inhibition of RET kinase activity by these peptides resulted in suppression of RET-PTC-1-mediated cancer growth. The great potency of these cysteine targeted peptides could indicate promising approaches for novel molecular-targeted therapies for RET-associated cancers.