Targeting lysosomal cysteine protease cathepsin S reveals immunomodulatory therapeutic strategy for oxaliplatin-induced peripheral neuropathy.

Rationale: Oxaliplatin-induced peripheral neuropathy (OIPN) is a common adverse effect that causes delayed treatment and poor prognosis among colorectal cancer (CRC) patients. However, its mechanism remains elusive, and no effective treatment is available. Methods: We employed a prospective cohort study of adult patients with pathologically confirmed stage III CRC receiving adjuvant chemotherapy with an oxaliplatin-based regimen for investigating OIPN. To further validate the clinical manifestations and identify a potential therapeutic strategy, animal models, and in vitro studies on the mechanism of OIPN were applied. Results: Our work found that (1) consistent with clinical findings, OIPN was observed in animal models. Targeting the enzymatic activity of cathepsin S (CTSS) by pharmacological blockade and gene deficiency strategy alleviates the manifestations of OIPN. (2) Oxaliplatin treatment increases CTSS expression by enhancing cytosol translocation of interferon response factor 1 (IRF1), which then facilitates STIM-dependent store-operated Ca2+ entry homeostasis. (3) The cytokine array demonstrated an increase in anti-inflammatory cytokines and suppression of proinflammatory cytokines in mice treated with RJW-58. (4) Mechanistically, inhibiting CTSS facilitated olfactory receptors transcription factor 1 release from P300/CBP binding, which enhanced binding to the interleukin-10 (IL-10) promoter region, driving IL-10 downstream signaling pathway. (5) Serum CTSS expression is increased in CRC patients with oxaliplatin-induced neurotoxicity. Conclusions: We highlighted the critical role of CTSS in OIPN, which provides a therapeutic strategy for the common adverse side effects of oxaliplatin.

Efficacy of green onion root extract in cosmetics and skin care products / Eficácia do extrato de raiz de cebola verde em cosméticos e produtos de cuidado da pele

In this study, leftover roots of Sansing green onions grown without toxic chemicals in Sansing Township, Ilan County, Taiwan were used as a raw material of skincare products. The raw material was extracted from the green onion roots by ultrasound in a low-temperature, safe and pollution-free environment. We hope to develop cleansers and other facial care products made of this natural, environmentally friendly, safe and affordable raw material so that people with sensitive skin can also use these products. We also hope that this study can contribute to circular economy and achieve the goal of green innovation by recycling the leftover roots. In terms of anti-oxidation, the DPPH free radical scavenging ability of 2.5 mg/mL green onion root extract was equivalent to 98% of that of 1 mg/mL BHT; the Fe2+ chelating ability was equivalent to 87.0% of that of 0.02 mg/mL EDTA; the superoxide anions scavenging ability of 2.5 mg/mL green onion root extract was equivalent to 84.2% of that of 1 mg/mL BHT and 80.4% of that of 0.05 mg/mL vitamin C. With respect to melanin synthesis inhibition, the green onion root extract's ability to inhibit dopachrome, the intermediate product of melanin, was positively correlated to its concentration, i.e., the higher the concentration of the green onion root extract, the better the inhibition ability. The IC50 of green onion root extract was 1.83 mg/mL, while, for comparison, the IC50 of vitamin C was 0.62 mg/mL. Furthermore, according to the cell survival assay, no obvious cytotoxic effect was found with the increase in the concentration of the green onion root extract. The whitening effect improved after 30 days of test. The improvement rate was 5.6% for 2.5 mg/mL green onion root extract, 3.1% for 1.25 mg/mL extract, and 1.7% for 0.625 mg/mL extract. The moisture retention also improved after 30 days of test. The moisture retention improvement rate was 22.7% for 2.5 mg/mL green onion root extract, 21.6% for 1.25 mg/mL extract, and 15.4% for 0.625 mg/mL extract. Based on the experiments, the green onion root extract obtained from ultrasound not only did not cause skin allergy and irritation but also showed anti-aging, melanin synthesis inhibition, whitening and moisture retention effects. The results showed that the green onion root extract can improve the moisture retention and whitening effect of the mask.

Neste estudo, restos de raízes de cebolinhas Sansing, cultivadas sem produtos químicos tóxicos no município de Sansing, Condado de Ilan, Taiwan, foram utilizadas como matéria-prima de produtos para a pele. A matéria-prima foi extraída das raízes de cebolinha por ultrassom em um ambiente de baixa temperatura, seguro e livre de poluição. Esperamos desenvolver produtos de limpeza e outros produtos para cuidados faciais produzidos com essa matéria-prima natural, ecologicamente correta, segura e acessível, para Improvement rate (%) Moisture retention Whitening effect 7.65 1.29 que pessoas com pele sensível também possam usar esses produtos. Também esperamos que este estudo possa contribuir para a economia circular e alcançar o objetivo da inovação ecológica, reciclando restos das raízes. Em termos de anti-oxidação, a capacidade de sequestro do radical livre DPPH de 2,5 mg/mL de extrato de raiz de cebolinha foi equivalente a 98% de 1 mg/mL de BHT; a capacidade quelante do Fe2+ foi equivalente a87,0% de 0,02 mg/mL de EDTA; a capacidade de sequestro de ânions superóxidos de 2,5 mg/mL de extrato de raiz de cebolinha foi equivalente a 84,2% de 1 mg/mL BHT e 80,4% de 0,05 mg/mL de vitamina C. No que diz respeito à inibição da síntese de melanina, a capacidade do extrato de raiz de cebolinha de inibir o dopacrômio, o metabolito intermediário de melanina, foi positivamente correlacionada com a sua concentração, ou seja, quanto maior a concentração do extrato de raiz de cebolinha, maior a capacidade de inibição. O IC50 de extrato de raiz de cebolinha foi de 1,83 mg/mL, enquanto que, por comparação, o IC50 de vitamina C foi de 0,62mg/mL. Além disso, de acordo com o ensaio de sobrevivência celular, nenhum efeito citotóxico foi observado com o aumento da concentração do extrato de raiz de cebolinha. O efeito de branqueamento melhora após 30 dias de ensaio. A melhoria foi de 5,6% para 2,5 mg/mL de extrato de raiz de cebolinha, 3,1% para 1,25 mg/mL de extrato e 1,7% para 0,625 mg/mL de extrato. A retenção de umidade também melhorou depois de 30 dias de teste. A taxa de melhoria de retenção de umidade foi de 22,7% para 2,5 mg/mL de extrato de raiz de cebolinha, 21,6% para 1,25 mg/mL de extrato, e 15,4% para 0,625 mg/mL de extrato.Com base nas experiências efetuadas, o extrato de raiz de cebolinha obtida por ultrassom não só não causa alergia nem irritação da pele, mas também demonstrou atividade anti-envelhecimento, inibição da síntese de melanina, capacidade de branqueamento e retenção de umidade. Os resultados mostraram que o extrato de raiz de cebolinha pode melhorar a retenção de umidade e efeito de branqueamento da máscara.

Neonatal isolation decreases cued fear conditioning and frontal cortical histone 3 lysine 9 methylation in adult female rats.

Early life stress is thought to enhance adult susceptibility to stress and stress-related mood disorders. In this study, fear-potentiated startle was used to model the acquisition of a traumatic event-related memory in female rats experiencing early life stress. Daily 1-hr maternal and sibling separation throughout day 2-9 postpartum (D2-9 PP) caused a decrease in the fear-potentiated startle, but not acoustic startle baseline, in adult female rats. The separation procedure did not affect corticosterone secretion but produced an increase in serum estradiol concentration. Moreover, the separation procedure did not affect histone 3 lysine 9 (H3K9) acetylation but decreased H3K9 mono- and tri-methylation in frontal cortices. Treatment with 5-aza-2'-deoxycytidine (AZA) (5mg/kg at alternative days from D2PP to D9PP or 10mg/kg at D5PP and D9PP), a DNA methylation inhibitor, did not affect the separation-decreased fear-potentiated startle. Treatment with valproic acid (VPA), a histone deacetylase inhibitor, at 3 dosing regimens (300mg/kg at D2-9PP; 100mg/kg at D2-4PP, 200mg/kg at D5-7PP, 300mg/kg at D8-9PP; 100mg/kg at D2-5PP, 200mg/kg at D6-9PP) prior to daily separation reversed such a decrease in fear-potentiated startle. The lowest effective VPA dosing regimen used (100mg/kg at D2-5PP, 200mg/kg at D6-9PP) reversed the separation-decreased H3K9 mono- and tri-methylation in frontal cortices. Eight-day VPA (300mg/kg/day) and AZA (5mg/kg/day) administrations starting at D28PP were ineffective in altering the separation-decreased fear-potentiated startle. We, hereby, suggest that decreased frontal cortical H3K9 mono- and tri-methylation may be involved in early life separation-decreased fear memory of adult rats.