Crotamiton 10% lotion

BACKGROUND: Treatment failure is considered to be an important factor in relation to the increase in scabies incidence over the last decade. However, the regional and temporal differences, in addition to the predictors of therapy failure, are unclear. OBJECTIVES: We aimed to conduct a systematic review of the prevalence of treatment failure in patients with scabies and investigation of associated factors. METHODS: We searched MEDLINE, EMBASE, CINAHL, Web of Science, Scopus, Global Health and the Cochrane Central Register of Controlled Trials from inception to August 2021 for randomized and quasi-randomized trials, in addition to observational studies that enrolled children or adults diagnosed with confirmed or clinical scabies treated with permethrin, ivermectin, crotamiton, benzyl benzoate, malathion, sulfur or lindane, and measured treatment failure or factors associated with treatment failure. We performed a random effects meta-analysis for all outcomes reported by at least two studies. RESULTS: A total of 147 studies were eligible for inclusion in the systematic review. The overall prevalence of treatment failure was 15.2% [95% confidence interval (CI) 12.9-17.6; I2 = 95.3%, moderate-certainty evidence] with regional differences between World Health Organization regions (P = 0.003) being highest in the Western Pacific region (26.9%, 95% CI 14.5-41.2). Oral ivermectin (11.8%, 95% CI 8.4-15.4), topical ivermectin (9.3%, 95% CI 5.1-14.3) and permethrin (10.8%, 95% CI 7.5-14.5) had relatively lower failure prevalence compared with the overall prevalence. Failure prevalence was lower in patients treated with two doses of oral ivermectin (7.1%, 95% CI 3.1-12.3) compared with those treated with one dose (15.2%, 95% CI 10.8-20.2; P = 0.021). Overall and permethrin treatment failure prevalence in the included studies (1983-2021) increased by 0.27% and 0.58% per year, respectively. Only three studies conducted a multivariable risk factor analysis; no studies assessed resistance. CONCLUSIONS: A second dose of ivermectin showed lower failure prevalence than single-dose ivermectin, which should be considered in all guidelines. The increase in treatment failure over time hints at decreasing mite susceptibility for several drugs, but reasons for failure are rarely assessed. Ideally, scabicide susceptibility testing should be implemented in future studies.

Abstract licence: CC BY

Background. Scabies is a highly contagious neglected tropical disease and a persistent challenge globally, particularly in regions like the Philippines, where it remains endemic. With conventional treatments facing limitations such as resistance and adverse effects, exploring the potential of traditional medicinal plants offers a promising avenue for novel therapeutics. However, evidence of their comparative efficacy and safety is still lacking. Objectives. To determine the efficacy and safety of Gliricidia sepium (kakawati), Senna alata (akapulko), and Tinospora rumphii (makabuhay) compared to topical scabicides or placebo in the treatment of Filipino patients with scabies using a systematic review. Methods. We searched the following databases from inception to March 2024: MEDLINE via PubMed, CENTRAL, EMBASE, EBSCO, HERDIN, ClinicalTrials.gov, WHO-ICRTP, and PHRR. We included all randomized controlled trials involving Filipino patients diagnosed with scabies where preparations containing one of three plants (G. sepium, S. alata, or T. rumphii) were compared with a topical scabicide or placebo for treatment. Two review authors independently applied eligibility criteria, assessed risk of bias (using Risk of Bias 2.0), and extracted data from the included studies. Primary outcomes were complete clearance of skin lesions, reduction of pruritus, and the presence of serious adverse events. Secondary outcomes were recurrence, any adverse events, adverse events requiring withdrawal, and patientreported outcomes. We used RevMan 5.4 to pool dichotomous outcomes using risk ratios and continuous outcomes using mean difference and applied random-effects meta-analysis. We tested for statistical heterogeneity using both the Chi2 test and the I2 statistic. We presented the results using forest plots with 95% confidence intervals. We intended to conduct a funnel plot analysis to check for reporting bias but were unable to because of the limited number of studies. Quality of evidence was assessed using the GRADE approach, and a Summary of Findings table was created using GRADEpro GDT for the primary outcomes. Results. We included nine RCTs (N=607 participants) that compared various dosage forms (ointments, lotions, poultice, soap, aqueous extract) containing one of the three plants (G. sepium, three studies; S. alata, two studies; T. rumphii, four studies) versus placebo or existing topical scabicides (permethrin, sulfur, crotamiton). Pooled analyses showed that there is probably no difference in complete clearance of lesions between G. sepium and 5% sulfur (RR 0.92 [0.79, 1.07], 2 RCTs, N=85, moderate certainty of evidence). We are uncertain about the difference in complete clearance of lesions between S. alata lotion and placebo (RR 4.94 [1.67, 14.62], 2 RCTs, N=157, very low certainty of evidence), T. rumphii and crotamiton (RR 1.02 [0.76, 1.37], 2 RCTs, N=131, very low certainty of evidence), and T. rumphii lotion and placebo (RR 5.28 [0.76, 36.43], 2 RCTs, N=71, very low certainty of evidence). Data could not be pooled for reduction in pruritus scores due to limited studies for each intervention. No serious adverse events were reported across all studies. Conclusion. Gliricidia sepium (kakawati) is probably as effective and safe as 5% sulfur in the management of patients with scabies and may be a promising alternative herbal treatment. Future RCTs should compare it with scabicides recommended by the Philippine Department of Health and World Health Organization, such as permethrin, benzyl benzoate or oral ivermectin. T. rumphii and S. alata may also be investigated using RCTs that should be adequately powered and with good methodologic quality.

Abstract licence: CC BY-NC-ND

In a chemical genetics study, JM03 derived from crotamiton, an inhibitor of trainsient receptor potential vanilloid-4 channels, was identified to extend lifespan and improve oxidative and hypertonic stress resistance in Caenorhabditis elegans via inhibiting OSM-9.

Abstract licence: CC BY

Article Figures and data Abstract Editor's evaluation Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Abstract While screening our in-house 1072 marketed drugs for their ability to extend the lifespan using Caenorhabditis elegans (C. elegans) as an animal model, crotamiton (N-ethyl-o-crotonotoluidide) showed anti-aging activity and was selected for further structural optimization. After replacing the ortho-methyl of crotamiton with ortho-fluoro, crotamiton derivative JM03 was obtained and showed better activity in terms of lifespan-extension and stress resistance than crotamiton. It was further explored that JM03 extended the lifespan of C. elegans through osmotic avoidance abnormal-9 (OSM-9). Besides, JM03 improves the ability of nematode to resist oxidative stress and hypertonic stress through OSM-9, but not osm-9/capsaicin receptor related-2 (OCR-2). Then the inhibition of OSM-9 by JM03 reduces the aggregation of Q35 in C. elegans via upregulating the genes associated with proteostasis. SKN-1 signaling was also found to be activated after JM03 treatment, which might contribute to proteostasis, stress resistance and lifespan extension. In summary, this study explored a new small molecule derived from crotamiton, which has efficient anti-oxidative, anti-hypertonic, and anti-aging effects, and could further lead to promising application prospects. Editor's evaluation The study proceeds from a large initial C. elegans lifespan screen, comprising over 1000 candidate drugs, to a successful application of structure-activity analysis to yield an optimized lead compound and a likely mechanistic target. In addition to reporting novel compounds affecting lifespan, this work will be of interest to other researchers working at different stages of drug discovery, repurposing and lead optimization. https://doi.org/10.7554/eLife.72410.sa0 Decision letter Reviews on Sciety eLife's review process Introduction In spite the fact that aging is an inevitable process, many efforts have been made to uncover drugs which could delay aging. Numerous aging associated signaling pathways, discovered in Caenorhabditis elegans, are found to be conserved in the mammals (Kenyon, 2010). Moreover, many compounds, which extended the lifespan of C. elegans, also showed anti-aging effects in the mice model. For example, urolithin A was found to prolong the lifespan and normal activity including mobility and pharyngeal pumping in C. elegans, and it also improved the exercise capacity in mice with age-related decline of muscle function (Ryu et al., 2016). Similarly, rapamycin has been also found to increase the lifespan in worms (Robida-Stubbs et al., 2012), yeast (Medvedik et al., 2007), and flies (Bjedov et al., 2010), as well as mean and maximum lifespans in mice (Harrison et al., 2009). Metformin, a first-line drug for type 2 diabetes treatment, has been widely studied to extend the lifespan both in C. elegans (Cabreiro et al., 2013; De Haes et al., 2014; Chen et al., 2017) and mice (Anisimov et al., 2008; Martin-Montalvo et al., 2013). In order to discover novel anti-aging compounds, we screened our in-house 1072 marketed drugs using C. elegans as an animal model for their ability to extend the lifespan. As marketed drugs generally have definite pharmacokinetics and pharmacodynamics properties and are useful for drug repurposing, our research group is focused on searching compounds for drug repurposing. Herein, in this study, the approved drug crotamiton has been found to show anti-aging activity for the first time and was further selected for the structural optimization. Crotamiton is an inhibitor of TRPV4 (Transient Receptor Potential Vanilloid-4) channel and has been used as anti-scabies and anti-itch agent in humans for nearly 70 years (Kittaka et al., 2017). TRPV subfamily proteins are encoded by five genes in C. elegans, including osm-9 (osmotic avoidance abnormal), ocr-1 (osm-9/capsaicin receptor related), ocr-2, ocr-3 and ocr-4 (Xiao and Xu, 2009). Only loss of osm-9 or ocr-2 in worms resulted in the lifespan extension (Sheng et al., 2017). OSM-9 and OCR-2 can form heterotetrameric channels which transduce signals from olfactory, nociceptive, and serotonergic neurons (Tobin et al., 2002; Ohnishi et al., 2020; Zhang et al., 2004); however, the role of OSM-9 and OCR-2 in the regulation of stress resistance involves different mechanisms (Moriuchi et al., 2018). It has been shown in previous studies that the inactivation of OCR-2 extends the L1 starvation survival, while null mutations in osm-9 did not alter L1 starvation survival (Lee and Ashrafi, 2008). Osm-9 null mutants showed more resistance to oxidative or hypertonic stress than the control worms (Lee et al., 2016). Noticeably, it was reported that taurine, an essential amino acid involved in various physiological functions, promoted longevity of C. elegans in oxidative stress condition by inhibiting OSM-9 but not OCR-2 (Moriuchi et al., 2018). Taken together, further extensive research is still needed to decipher the downstream signaling pathways after OSM-9 or OCR-2 activation. With an aim to get a potential anti-ageing tool molecule, structural optimization based on crotamiton led to the identification of JM03. This molecule displayed better activity than crotamiton in terms of the lifespan extension and stress resistance of C. elegans. To further decipher the mechanisms of JM03 involved in the anti-aging activity, this study was conducted with special emphasis on its interaction with OSM-9 or OCR-2. Results Crotamiton prolongs lifespan of C. elegans To identify candidate anti-aging compounds, we initially performed a phenotypic screening of our in-house 1072 marketed drugs with 15 worms per concentration (100 μM) using an C. elegans model for their abilities of lifespan extension (Figure 1—source data 1). Thereafter, 125 drugs which showed up to 10% increase in mean lifespan extension as compared to the controls were selected for the secondary screening with 30 worms per concentration (100 μM) (Figure 1—source data 2). Finally, 10 drugs which showed up to 10% increase in mean lifespan extension were chosen for the third screening with 60 worms per concentration (400 μM, 100 μM, and 25 μM), respectively (Figure 1—source data 2). Apart from recently reported verapamil hydrochloride (Liu et al., 2020) and chlorpropamide (Mao et al., 2022) listed in our screening results, crotamiton was finally selected as one hit compound with significant effect on C. elegans lifespan extension in this study (p < 0.01) (Figure 1a). The distribution of approved drugs combinations per disease area in this phenotypic screening study was showed in Figure 1b. The safety of crotamiton was evaluated by following parameters: (1) The reproductive capacity was not changed in crotamiton-treated worms at 400 μM (Figure 1c); (2) For the normal human fetal lung fibroblasts cells MRC-5, crotamiton showed no toxicity even up to 400 μM (Figure 1d). Figure 1 with 2 supplements see all Download asset Open asset Crotamiton extends the lifespan of Caenorhabditis elegans. (a) Phenotypic screening led to the discovery of crotamiton as a hit compound for prolonging the lifespan in wild type (N2) worms. Data were compared using the Log-rank test. p = 0.0032 for Cro 100 μM. p = 0.0011 for Cro 400 μM. (b) The pie charts show the distribution of approved drug combinations per disease area in this phenotypic screening study. (c) The total brood size of crotamiton-treated N2 worms. Control n = 16 and crotamiton n = 17. (d) The viability of crotamiton-treated MRC-5 cells. (c) Data have been represented as the mean ± SD, and comparisons are made using Student t-test. (d) Data have been represented as the mean ± SD, and comparisons are made using one-way ANOVA test. The graphics represent a compilation of at least three independent experiments. ** p < 0.01. Figure 1—source data 1 Lifespan data in the 1st round screening. https://cdn.elifesciences.org/articles/72410/elife-72410-fig1-data1-v1.xlsx Download elife-72410-fig1-data1-v1.xlsx Figure 1—source data 2 Lifespan data in the 2nd and 3rd round screening. https://cdn.elifesciences.org/articles/72410/elife-72410-fig1-data2-v1.xlsx Download elife-72410-fig1-data2-v1.xlsx Figure 1—source data 3 Lifespan data for (a), brood size for (c), and cell viability for (d). https://cdn.elifesciences.org/articles/72410/elife-72410-fig1-data3-v1.xlsx Download elife-72410-fig1-data3-v1.xlsx In order to exclude the possibility that the anti-aging effect of crotamiton was related to its resistance to scabies, two anti-scabies drugs, permethrin, a sodium channel inhibitor and benzyl benzoate, which exerts toxic effects on the nervous system of scabies (Sunderkötter et al., 2021), were also examined along with crotamiton in the same experiment. However, both of the compounds failed to extend the worm lifespan (Figure 1—figure supplement 1), which indicated that the lifespan-extension of crotamiton was not related to its resistance to scabies, but closely related to its structure and target. Moreover, crotamiton showed no significant effect on the bacterial growth, which further ascertained that the anti-aging effect is not the result of insufficient food (Figure 1—figure supplement 2a). JM03, the derivative of crotamiton, has better life extension activity in C. elegans Structural optimization of crotamiton was conducted to identify more potent compounds with better anti-aging activity. The synthetic route for compounds JM01-JM15 was shown in Figure 2a. Treatment of the substituted N-ethylaniline with acryloyl chloride derivatives and potassium carbonate in dichloromethane at room temperature resulted in the formation of JM01-JM05, JM10, JM12, JM13, JM15, 9–11 in about 90–98% yield. Then, compounds JM10, JM12, JM15, 9–11 were conveniently hydrolyzed to provide the corresponding acid JM06-JM09, JM11, JM14. Figure 2 with 2 supplements see all Download asset Open asset JM03 has better lifespan extension activity in Caenorhabditis elegans. (a) Synthesis of compounds JM01−JM15. Reagents and conditions: a. Acryloyl chloride derivatives, K2CO3, CH2Cl2, 0 °C to rt; b. 1 M NaOH (aq.), CH3OH, rt. (b) JM03 prolonged lifespan in wild-type worms. p-values by Log-rank test. p = 0.0737 for Cro 400 μM. p < 0.0001 for JM03 400 μM. (c) JM03 prolonged lifespan in wild-type worms without FUdR treatment. p-values by Log-rank test. p = 0.0513 for Cro 400 μM. p = 0.0003 for JM03 400 μM. (d) The mobility of JM03-treated N2 worms by analyzing the body bend rate at days 3, 8, and 12. Control n = 15 and JM03 n = 15. (e) The pharyngeal pumping rate of JM03-treated N2 worms. Control n = 15 and JM03 n = 15 at days 3, 6, 9, and 12. p-values by two-way AVOVA. p = 0.0015 for 9 days. (f) The total brood size of JM03-treated N2 worms. Control n = 14 and JM03 n = 15. (b–c) Data are compared using the Log-rank test. (d-e) Data have been represented as the mean ± SD, and comparisons are made using two-way AVOVA. (f) Data have been represented as the mean ± SD, and comparisons are made using Student t-test. The graphics represent a compilation of at least three independent experiments. ** p < 0.01, **** p < 0.0001. Figure 2—source data 1 Lifespan data for (b); number of body bends for (c); number of pumps in 30″ for (d); brood size for (e) and cell viability for (f). https://cdn.elifesciences.org/articles/72410/elife-72410-fig2-data1-v1.xlsx Download elife-72410-fig2-data1-v1.xlsx Studies on the relationship between structure and activity (Figure 2—figure supplement 1) showed the removal of the methyl group from the ortho-position (crotamiton) to meta-position (JM01) led to the minor improvement in the activity for the R1 substituent group at benzene ring. However, moving the methyl group to the para-position (JM02) resulted in better activity. Replacing the ortho-methyl with ortho-fluoro (JM03), chloro (JM04), and bromo (JM05) significantly increased the activity. Additionally, incorporation of the carboxyl (JM06, JM07) on the benzene ring did not increase the activity. Since the introduction of a carboxyl at the terminal of alkenyl of crotamiton (JM08) improved the activity, we conducted additional modification based on the potent compounds JM02 and JM03. Unfortunately, no remarkable increased activity was observed after this step (Figure 2—figure supplement 2). Moreover, the movement of the fluoro substituent from the ortho-position (JM03) to the para-position (JM13) had no effect on the activity. Further adding carboxyl (JM14) or ethoxycarbonyl (JM15) was found to be detrimental. Considering the introduction of fluorine substituents into drugs can enhance biological activity and increase chemical or metabolic stability (Hagmann, 2008), JM03 was selected for the following study. The lifespan of worms treated with JM03 increased significantly as compared to those treated with crotamiton (p < 0.01, Figure 2b). Since 5-Fluorodeoxyuridine (FUdR) was used as contraceptive in our lifespan assay and is known to impact lifespan, we also tested the lifespan-extension effect of crotamiton and JM03 without FUdR and found two compounds could both prolong the lifespan of C. elegans in the absence of FUdR (Figure 2c). It has been reported that aging would lead to slower and uncoordinated body movement in C. elegans (Herndon et al., 2002). Therefore, keeping this in view, we measured the age-dependent muscle deterioration and diminished pharyngeal pumping rate in worms to assess the healthspan of worms treated with JM03. It was found that JM03 did not change the body bend rate of C. elegans at different age (Figure 2d). JM03-treated groups exhibited increased pharyngeal pumping rate at day 9 (Figure 2e). Additionally, no changed reproductive capacity was observed in JM03-treated worms (Figure 2f). Similar to crotamiton, the antiaging effect of JM03 is not the result of insufficient food (Figure 1—figure supplement 2). JM03‐induced extension of lifespan depends on OSM-9 in C. elegans Crotamiton is an inhibitor of TRPV4 channel (Kittaka et al., 2017), which shows similarity to the C. elegans channels OSM-9 (26% amino acid identity, 44% identity or conservative change) and OCR-2 (24% identity, 38% identity or conservative change) (Liedtke et al., 2003). In C. elegans, lacking of TRPV channel OSM-9 or OCR-2 resulted in the lifespan extension (Riera et al., 2014). Therefore, we further performed the lifespan analysis on osm-9 or ocr-2 knockdown worms to investigate the mechanism of JM03. As shown in Figure 3a and b, knockdown of osm-9 or ocr-2 via RNAi (Figure 3d and e) extended the lifespan of worms compared to the empty vector group. This indicated that TRPV inhibition extended C. elegans lifespan. Notably, JM03 failed to extend the lifespan of osm-9 knockdown worms (Figure 3a), but still extended the lifespan of ocr-2 knockdown worms (Figure 3b). Consistently, JM03 was found to be unresponsive to the lifespan of osm-9(ky10) mutants (Figure 3c). These results suggested that OSM-9 not OCR-2, played a leading role in JM03-mediated longevity. Figure 3 Download asset Open asset JM03-induced lifespan extension depends on OSM-9. (a) JM03 failed to extend the lifespan of osm-9 RNAi worms. p-values by Log-rank test. p = 0.0002 between Empty vector Ctrl and Empty vector JM03. p = 0.0028 between Empty vector Ctrl and osm-9 RNAi Ctrl. (b) JM03 extended the lifespan of ocr-2 RNAi worms. p-values by Log-rank test. p = 0.0002 between Empty vector Ctrl and Empty vector JM03. p = 0.0084 between Empty vector Ctrl and ocr-2 RNAi Ctrl. p = 0.0259 between ocr-2 RNAi Ctrl and ocr-2 RNAi JM03. (c) JM03 failed to extend the lifespan of osm-9(ky10) mutants. p-values by Log-rank test. p < 0.0001 for wild-type JM03 and osm-9(ky10) Ctrl. (d) The transcriptional level of osm-9 decreased after RNAi treatment. p-values by Student t-test. p < 0.0001 for osm-9 RNAi. (e) The transcriptional level of ocr-2 decreased after RNAi treatment. p-values by Student t-test. p < 0.0001 for ocr-2 RNAi. (a–c) Data are compared using the Log-rank test. (d-e) Data have been represented as the mean ± SD, and comparisons are made using Student t-test. The graphics represent a compilation of at least three independent experiments. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. N.S., not significant. Figure 3—source data 1 Lifespan data for (a–c) and relative gene expression for (d, e). https://cdn.elifesciences.org/articles/72410/elife-72410-fig3-data1-v1.xlsx Download elife-72410-fig3-data1-v1.xlsx JM03 improves the ability of nematode to resist oxidative and hypertonic stress through OSM-9 It has been previously shown that the loss of OSM-9 enhanced the resistance of nematodes to the oxidative and hypertonic stress (Lee et al., 2016). Therefore, we also evaluated the efficacy of JM03 under the oxidative or hypertonic stress condition. As shown in Figure 4a, the lifespan of C. elegans under paraquat-induced oxidative stress condition was significantly increased in JM03-treated group compared with control or crotamiton-treated group. Then, we examined whether the effect of JM03 under oxidative stress condition is mediated via OSM-9 and OCR-2. It was shown that JM03 treatment did not increase the lifespan osm-9(ky10) mutants (Figure 4b), but increased the lifespan of ocr-2(ak47) mutants under paraquat-induced oxidative stress condition (Figure 4c), which suggested OSM-9 is required for JM03 to improve the anti-oxidative stress ability. Figure 4 Download asset Open asset OSM-9 inhibition induced by JM03 has beneficial effect for Caenorhabditis elegans lifespan under oxidative and hypertonic stress conditions. (a) JM03 extended the lifespan of wild-type (N2) worms under paraquat-induced oxidative stress condition. p-values by Log-rank test. p = 0.0001 between Ctrl and JM03 400 μM. p = 0.0002 between Cro 400 μM and JM03 400 μM. (b) JM03 failed to extend the lifespan of osm-9(ky10) mutants under oxidative stress condition. p-values by Log-rank test. p = 0.0009 between Wild-type Ctrl and Wild-type JM03. p < 0.0001 between Wild-type Ctrl and osm-9(ky10) Ctrl. (c) JM03 extended the lifespan of ocr-2(ak47) mutants under oxidative stress condition. p-values by Log-rank test. p = 0.0005 between Wild-type Ctrl and Wild-type JM03. p = 0.0024 between ocr-2(ak47) Ctrl and ocr-2(ak47) JM03. (d) JM03 significantly reduced the paralysis for wild-type worms under NaCl-induced hypertonic stress condition. p-values by Log-rank test. p = 0.0171 between Ctrl and Cro 400 μM. p < 0.0001 between Ctrl and JM03 400 μM. (e) JM03 reduced the responsiveness for osm-9(ky10) mutants under hypertonic stress condition. p-values by Log-rank test. p < 0.0001 between Wild-type Ctrl and Wild-type JM03. p = 0.0128 between Wild-type Ctrl and osm-9(ky10) Ctrl. p = 0.0254 between osm-9(ky10) Ctrl and osm-9(ky10) JM03. (f) JM03 significantly reduced the paralysis for ocr-2(ak47) mutants similar to wild-type worms under hypertonic stress condition. p-values by Log-rank test. p < 0.0001 between Wild-type Ctrl and Wild-type JM03. p < 0.0001 between ocr-2(ak47) Ctrl and ocr-2(ak47) JM03. (a–f) Data are compared using the Log-rank test. The graphics represent a compilation of at least three independent experiments. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. N.S., not significant. Figure 4—source data 1 lifespan data for (a–c) and relative gene expression data for (d, e). https://cdn.elifesciences.org/articles/72410/elife-72410-fig4-data1-v1.xlsx Download elife-72410-fig4-data1-v1.xlsx In addition, the motile time of C. elegans under hypertonic stress condition revealed by motility assays was significantly increased in JM03-treated group compared with control or crotamiton-treated group (Figure 4d). We also examined whether the effect of JM03 under hypertonic stress condition is mediated via OSM-9 and OCR-2. Osm-9(ky10) mutants exhibited increased motility and viability upon prolonged exposures to high osmotic environments compared with wild-type N2 (Figure 4e), while ocr-2(ak47) mutants exhibited motility and viability similar to wild-type N2 (Figure 4f). For osm-9(ky10) mutants, the increased significance of the motile time under hypertonic stress condition is reduced after JM03 treatment (Figure 4e). But for ocr-2(ak47) mutants, JM03 still significantly increased the motile time of C. elegans under hypertonic stress condition (Figure 4f). Taken together, these results suggested that the OSM-9 inhibition by JM03 increased the anti-oxidative and anti-hypertonic stress ability of C. elegans. JM03 upregulated the genes associated with proteostasis Similar to crotamiton, JM03 also showed no toxicity against MRC-5 cells even up to 400 μM (Figure 5a). Then we investigated the effect of JM03 on cellular proteostatic modules. We observed that 72 hr cell exposure to JM03 induced a mild upregulation of molecular chaperones genes (Clusterin), and a significant upregulation of Nrf2 transcriptional targets genes (Keap1, Nqo1, Txnrd1) (Figure 5b). It has been reported that oxidative (Mark et al., 2016) and hypertonic (Lee et al., 2016) stress enhance rapid and widespread protein aggregation and misfolding in C. elegans. Here, we investigated the efficacy of JM03 to reduce the aggregation of protein using Q35::YFP, a worm strain expressing polyglutamine (Q35) containing yellow fluorescent (YFP) protein in their body wall muscle. Q35::YFP is normally fully soluble in the muscles cells of young worms, but undergoes a slow, progressive aggregation as C. elegans ages (Morley et al., 2002). Here, we observed the anti-hypertonic stress ability of Q35::YFP and wild-type worms was similar (Figure 5c). JM03 significantly increased the motile time of Q35::YFP or wild-type worms exposed to 500 mM NaCl, which is consistent with results shown in Figure 4d. Meanwhile, Q35::YFP aggregation was significantly reduced when treated with JM03 (Figure 5d), which suggested JM03 reduced the aggregation of protein in C. elegans. Figure 5 with 1 supplement see all Download asset Open asset OSM-9 inhibition induced by JM03 has beneficial effect for Caenorhabditis elegans lifespan under hypertonic stress conditions. (a) The viability of JM03-treated MRC-5 cells. p-values by one-way ANOVA test. p = 0.0036 for JM03 200 μM. (b) JM03 significantly increased the transcriptional expression of proteostasis related genes in MRC-5 cells. p-values by Student t-test. p = for p = 0.0001 for p = 0.0003 for (c) JM03 significantly reduced the paralysis for Q35::YFP worms similar to wild-type worms under hypertonic stress condition. p-values by Log-rank test. p < 0.0001 between Wild-type Ctrl and Wild-type JM03. p < 0.0001 between Q35::YFP Ctrl and Q35::YFP JM03. (d) JM03 significantly reduced the Q35::YFP p-values by Student t-test. p < 0.0001 for JM03 treatment. (e) proteostasis genes upregulated by JM03 treatment in N2 control worms but not osm-9(ky10) worms by (a) Data have been represented as the mean ± SD, and comparisons are made using one-way ANOVA test. Data have been represented as the mean ± SD, and comparisons are made using Student t-test. (c) Data are compared using the Log-rank test. The graphics represent a compilation of at least three independent experiments. ** p < 0.01, *** p < 0.001, **** p < 0.0001. Figure data 1 viability for relative gene expression data for (b); lifespan data for (c); number of Q35::YFP of worm for (d); data of genes for Download To a more of the expression after JM03 treatment, worms with JM03 or for 10 days were for to the In order to the of analysis was performed based on the genes between different of As shown in Figure supplement were and the data of the same to in which indicated the It was reported that the improved proteostasis capacity of the osm-9 null was to expression of genes of the proteostasis protein protein protein and (Lee et al., 2016). JM03 can the expression of the genes that known or in proteostasis in N2 worms but not in osm-9(ky10) revealed by results (Figure Taken together, these results the that JM03 the genes associated with proteostasis through OSM-9 leading to enhanced proteostasis which improve the ability of nematode to resist oxidative stress and hypertonic JM03 the SKN-1 stress response in C. elegans The et al., et al., and SKN-1 in stress longevity and proteostasis et al., et al., Therefore, we examined the effect of JM03 on and SKN-1 JM03 prolonged the lifespan of null (Figure supplement 1), that is not required for JM03-induced lifespan extension. the JM03 did not prolonged the lifespan of mutants with loss of function in all SKN-1 and 2007), that SKN-1 played an essential role in JM03-induced effects (Figure the of the SKN-1 in JM03-induced lifespan we further examined our to whether expression of genes of SKN-1 might be by JM03 treatment. We found that and its as and were upregulated by JM03 (Figure Figure with 1 supplement see all Download asset Open asset JM03-induced lifespan extension through SKN-1 (a) JM03 treatment failed to extend the lifespan of mutants. p-values by Log-rank test. p = between Wild-type Ctrl and Wild-type JM03. (b) and its targets genes upregulated by JM03 in wild-type worms by (c) JM03 significantly increased the of = 100 p-values by Student t-test. p < 0.0001 for JM03 treatment. (d) JM03 significantly increased the transcriptional expression of and p-values by Student t-test. p < 0.0001 for p = for p < 0.0001 for p < 0.0001 for p < 0.0001 for p = for p < 0.0001 for (e) JM03 significantly upregulated the of = 100 p-values by Student t-test. p < 0.0001 for JM03 treatment. (f) JM03 treatment failed to extend the lifespan of osm-9(ky10) and mutants under oxidative stress condition. p-values by Log-rank test. p = between Wild-type Ctrl and Wild-type JM03. p < 0.0001 between Wild-type Ctrl and Ctrl. Data are compared using the Log-rank test. The graphics represent a compilation of at least three independent experiments. Data have been represented as the mean ± SD, and comparisons are made using Student t-test. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. N.S., not significant. Figure data 1 Lifespan data for data of and its targets genes for (b); mean of worm for (c); relative gene expression data for (d); mean of worm for lifespan of worm in for (f). Download we examined the effect of JM03 on the of the SKN-1 stress response using a previously to the and et al., 2008). JM03 treatment significantly increased the of by the and Figure it also significantly increased the transcriptional expression of and genes or (Figure we also the increased expression of a downstream of SKN-1 et al., based on the of worms (Figure In addition, JM03 did not extend the lifespan of mutants under oxidative stress condition (Figure In JM03 prolongs the lifespan and improves ability of C. elegans through SKN-1 Discussion repurposing has as an for the rapid identification and of with novel against various based on the known marketed drugs et al., Herein, we explored the possibility of the potent drugs which could increase the longevity by screening our in-house marketed drugs using lifespan extension as

Abstract licence: CC BY

, and it is always associated with an intense, unbearable, nocturnal deteriorating itch. Its presentations include classic burrows, erythema, pruritic papules, pustules, vesicles, and inflammatory nodules, with diffuse or localized distribution on the finger webs, wrist flexors, elbows, axillae, buttocks, genitalia, and breasts. Nodular scabies is an uncommon clinical variant of scabies. Its management is still challenging for some patients up to date, although topical, intralesional or systemic corticosteroids, topical calcineurin inhibitors, and crotamiton as well as cryotherapy alone or in different combinations are used. We here report five male patients of nodular scabies, aged between 14 and 25 years, who had classical scabies that had been cured by sulfur ointment for at least 4 weeks except for their itching nodules, and their residual pruritic nodules also failed in previous treatments including antihistamines, topical applying and intralesional injection of steroids as well as topical tacrolimus in different combinations before being recruited to this study. The patients were administered tofacitinib 5 mg, twice a day, which led to excellent and rapid improvement for both lesions and symptoms after 1-4 weeks of treatment, respectively, without any associations. During 6 months of follow-up, only one had re-infection of scabies associated with nodules that were cured by sulfur ointment and tofacitinib again. No adverse reaction was observed. The present results suggested that tofacitinib might be a potential agent for nodular scabies with excellent response.

Abstract licence: CC BY-NC

Treatment should be initiated for all suspected, clinical, or confirmed cases of scabies. Patients affected should be adequately isolated, and high-risk groups with close contact histories should be treated regardless of their symptoms. Optimal treatment strategies can be selected based on age, clinical subtype, and the patient's health status. In Korea, commercially available preparations for scabies treatment include topical 5% permethrin, topical 10% crotamiton, and oral ivermectin. Topical 5% permethrin is the first-line selective treatment for both classic and crusted scabies. Alternative treatments include topical 10% crotamiton and oral ivermectin. After completing treatment, follow-up visits at 2 and 4 weeks are recommended to monitor the therapeutic response. Treatment is considered to have failed if scabies mites or burrows are detected, new clinical characteristics develop, or there is an aggravation of pruritus. Scabies itch should be adequately managed with emollients, oral antihistamines, and topical corticosteroids. Preventive measures, including personal hygiene, patient education, and environmental control, should besd implemented to reduce the transmission of scabies.

Abstract licence: CC BY-NC

Pharmaceuticals and personal care products (PPCPs) are widely detected in aquatic environments. However, recent studies on the environmental occurrence of currently used PPCPs in Japan are limited. In this study, a nationwide monitoring initiative focusing on PPCPs was undertaken to investigate the occurrence and fate of PPCPs in aquatic environments in Japan. A total of 700 samples were collected and analyzed from 2018 to 2022. Ninety-one PPCPs were detected in the analyzed samples. Three PPCPs (N, N-diethyl-meta-toluamide [DEET], salicylic acid, and crotamiton) were detected at particularly high frequencies, with a prevalence exceeding 99% of analyzed samples. Seasonal variations were observed for several PPCPs across multiple rivers, with concentrations generally increasing during fall/winter and decreasing during spring/summer (except DEET) throughout the sampling period. The detection frequencies and concentrations were higher in PPCPs with higher domestic prescription amounts. Some PPCPs, such as acetylsalicylic acid, exhibited low frequencies and concentrations despite high domestic prescription amounts, suggesting transformation into metabolites or degradates in the aquatic environment. The contribution of sewage treatment plant effluent to the PPCP concentrations in the environment was estimated by examining the correlation between each PPCP and sucralose concentration. Sewage effluents appeared to be a significant contributor to the majority of target PPCPs; however, DEET and certain other PPCPs may originate from alternate sources. This study is the first to provide a comprehensive assessment of the occurrence and fate of PPCPs in Japan's aquatic environment. Future research should assess the environmental and human health risks of these PPCPs and identify the occurrence of their metabolites or degradates in the aquatic environment.

Abstract licence: CC BY