Commentary to Gorelenkova Miller and Mieyal (2015): sulfhydryl-mediated redox signaling in inflammation: role in neurodegenerative diseases.

Gorelenkova Miller and Mieyal (Arch Toxicol 89(9): 1439-1467, 2015) recently published a review paper suggesting that reversible cysteine plays a key role in redox-linked signal transduction via alteration of protein function, resulting in an association with many diseases including neurodegenerative disorders. Following their suggestions, we considered the correlation between sulfhydryl-mediated redox signaling and neurodegenerative diseases by focusing on RET proteins, a protein tyrosine kinases (PTKs) potentially sited upstream of the signal transduction cascade. c-RET is the receptor for glial cell line-derived neurotrophic factor family ligands. c-RET has been reported to be involved in not only Hirschsprung disease via development of the enteric nervous system but also neurodegenerative diseases including Parkinson's disease and amyotrophic lateral sclerosis. We also showed that c-RET might be associated with hearing loss via neurodegeneration of spiral ganglion neurons in the inner ear after birth in mice and humans. Moreover, we have reported that three kinds of oxidative stress, ultraviolet light-induced stress, osmotic stress and arsenic-induced stress, modulate kinase activity of RET-PTC1 without an extracellular domain as well as c-RET by conformational change of RET protein (dimerization) via disulfide bond formation. The oxidative stresses also modulate kinase activity of RET-PTC1 with cysteine 365 (C365) replaced by alanine with promotion of dimer formation, but not with cysteine 376 (C376) replaced by alanine. Since C376 of Ret-PTC-1 or its equivalent is most highly conserved and crucial for activity in PTKs, the cysteine could be one of major targets for oxidative stresses.

Limited effectiveness of household sand filters for removal of arsenic from well water in North Vietnam.

Since well water utilized for domestic purposes in the Red River Delta of North Vietnam has been reported to be polluted by arsenic, barium, iron, and manganese, household sand filters consisting of various components are used. Information regarding the effectiveness of various sand filters for removal of the four toxic elements in well water is limited. In this study, arsenic levels in 13/20 of well water samples and 1/7 of tap water samples exceeded World Health Organization (WHO) health-based guideline value for drinking water. Moreover, 2/20, 6/20, and 4/20 of well water samples had levels exceeding the present and previous guideline levels for barium, iron, and manganese, respectively. Levels of iron and manganese, but not arsenic, in well water treated by sand filters were lower than those in untreated water, although previous studies showed that sand filters removed all of those elements from water. A low ratio of iron/arsenic in well water may not be sufficient for efficient removal of arsenic from household sand filters. The levels of barium in well water treated by sand filters, especially a filter composed of sand and charcoal, were significantly lower than those in untreated water. Thus, we demonstrated characteristics of sand filters in North Vietnam.

Biomonitoring of mercury, cadmium, and lead exposure in Japanese children: a cross-sectional study.

OBJECTIVES: To measure current Hg, Cd, and Pb exposure in Japanese children, and to estimate dietary intakes of foods responsible for high body burden. METHODS: Blood, hair, and urine samples were collected from 9 to 10-year-old 229 children in Asahikawa and measured for Hg, Cd, and Pb in these matrices. Diet history questionnaire was used to estimate intake of marine foods and other food items. Hg level was measured by cold vapor atomic absorption spectrometry. Cd and Pb levels were determined with inductively coupled plasma mass spectrometry. RESULTS: Geometric mean (GM) of blood Hg, Cd, and Pb was 4.55 µg/L, 0.34 µg/L, and 0.96 µg/dL, respectively. Urinary Cd level was 0.34 µg/g creatinine (GM) and hair Hg was 1.31 µg/g (GM). Approximately one-third (35%) of blood samples had Hg level above the U.S. EPA reference dose (RfD; 5.8 µg/L). Hair Hg level exceeded U.S. EPA RfD (1.2 µg/g) in 59 % samples. Children in the upper quartile of blood Hg level had significantly higher intake of large predatory fish species compared to those in the lower quartile of blood Hg. CONCLUSIONS: Those with high blood Hg level may be explained by more frequent intake of big predatory fish. Cd and Pb exposure is generally low among Japanese children. As no safety margin exists for Pb exposure and high exposure to MeHg is noted in Japanese population; periodic biomonitoring and potential health risk assessment should continue in high-risk populations, notably among children.

A clinical and novel dermoscopic investigation of combined peels as a hand aging treatment.

BACKGROUND: The hands are one of the areas where skin aging is most noticeable, alongside the face, but limited studies used dermoscopic evaluation on hand aging. The Dermoscopy Photoaging Scale (DPAS) is frequently used to assess face aging but is never used for hand aging. Treating skin aging using chemical peeling is a commonly used method to rejuvenate the skin on the hands, as it is relatively affordable. Using multiple chemical peels may yield more significant results. AIMS: To determine the effectiveness of a chemical peeling combination in retarding hand aging and to assess the utility of DPAS in this process. METHODS: This study involved 69 Fitzpatrick skin types III-IV volunteers aged 20-69. One hand of each participant was treated with 20% glycolic acid (GA), while the other received a combination of peels consisting of 20% GA and 15% trichloroacetic acid (TCA). The hands were clinically examined before and after the treatments, and dermoscopic examinations were performed using a modified DPAS. RESULTS: Four treatments improved clinical and dermoscopic characteristics in both hands. The combined peeling considerably improved pigmentation intensity on the dorsal hand compared to the GA peel (p < 0.001). Post-chemical peeling patient satisfaction increased significantly. CONCLUSIONS: The modified DPAS is a valuable instrument to assess the signs of hand aging. The combination of GA and TCA effectively improves skin aging of the hands and offers an accessible and economical option for addressing skin aging.

COVID-19 Vaccination and Clinical Outcomes at a Secondary Referral Hospital During the Delta Variant-dominant Period in West Sumatra, Indonesia.

OBJECTIVES: The second wave of coronavirus disease 2019 (COVID-19) cases in Indonesia, during which the Delta variant predominated, took place after a vaccination program had been initiated in the country. This study was conducted to assess the impact of COVID-19 vaccination on unfavorable clinical outcomes including hospitalization, severe COVID-19, intensive care unit (ICU) admission, and death using a real-world model. METHODS: This single-center retrospective cohort study involved patients with COVID-19 aged ≥18 years who presented to the COVID-19 emergency room at a secondary referral teaching hospital between June 1, 2021 and August 31, 2021. We used a binary logistic regression model to assess the effect of COVID-19 vaccination on unfavorable clinical outcomes, with age, sex, and comorbidities as confounding variables. RESULTS: A total of 716 patients were included, 32.1% of whom were vaccinated. The elderly participants (≥65 years) had the lowest vaccine coverage among age groups. Vaccination had an effectiveness of 50% (95% confidence interval [CI], 25 to 66) for preventing hospitalization, 97% (95% CI, 77 to 99) for preventing severe COVID-19, 95% (95% CI, 56 to 99) for preventing ICU admission, and 90% (95% CI, 22 to 99) for preventing death. Interestingly, patients with type 2 diabetes had a 2-fold to 4-fold elevated risk of unfavorable outcomes. CONCLUSIONS: Among adults, COVID-19 vaccination has a moderate preventive impact on hospitalization but a high preventive impact on severe COVID-19, ICU admission, and death. The authors suggest that relevant parties increase COVID-19 vaccination coverage, especially in the elderly population.

Non-monotonic dose-response of di-(2-ethylhexyl) phthalate isolated from Penicillium citrinum XT6 on adipogenesis and expression of PPARγ and GLUT4 in 3T3-L1 adipocytes.

OBJECTIVES: Adipogenesis is the fat cell formation process regulated by peroxisome proliferator-activated receptors (PPARγ). The insulin-responsive glucose transporter 4 (GLUT4) has a major role in glucose uptake and metabolism in insulin target tissues (i.e., adipose and muscle cells). The interplay between PPARγ and GLUT4 is essential for proper glucose homeostasis. This study aimed to isolate, elucidate, and investigate the effect of an isolated compound from Penicillium citrinum XT6 on adipogenesis, PPARγ, and GLUT4 expression in 3T3-L1 adipocytes. METHODS: The isolated compound was determined by analyzing spectroscopic data (LC-MS, FT-IR, Spectrophotometry UV-Vis, and NMR). The adipogenesis activity of the isolated compound in 3T3-L1 cells was determined by the Oil Red O staining method. RT-PCR was used to analyze the gene expression of PPARγ and GLUT4. RESULTS: Di-(2-ethylhexyl)-phthalate (DEHP) was the isolated compound from P.citrinum XT6. The results revealed adipogenesis stimulation and inhibition, as well as PPARγ and GLUT4 expressions. CONCLUSIONS: DEHP showed a non-monotonic dose-response (NMDR) effect on adipogenesis and PPARγ and GLUT4 expression. It is the first study that reveals DEHP's NMDR effects on lipid and glucose metabolism in adipocytes.

Laboratory testing of low concentration (<1 ppm) of copper to prolong mosquito pupation and adult emergence time: An alternative method to delay mosquito life cycle.

INTRODUCTION: Larvicide application in ovitrap is one of the currently available methods used in mosquito eradication campaign. We previously reported that copper in liquid form is a promising candidate due to its potent larvicide properties in a laboratory setting and in the field. In the field study, several larvae survived in outdoor ovitrap due to the dilution of copper concentration by rainwater. The surviving larvae were smaller and less motile. This led our interest to study the effect of a sub-lethal dose of copper in ovitrap on mosquito larval development, pupation time and lifespan in the adult stage. METHODS: First instar larvae of Aedes albopictus, Anopheles stephensi, and Culex pipiens were put in water containing 0.15 ppm, 0.30 ppm, and 0.60 ppm of copper. The surviving larvae, the emerging pupae, and adult mosquitoes were observed and counted every 24-hour and statistically analyzed by t-test or Mann-Whitney U test. Inter-species difference in response to different concentration of copper were also analyzed. RESULTS: Copper showed a potent larvicide effect at 0.60 ppm concentration. Prolonged pupation time and a lower number of adult mosquitoes were observed at 0.15 ppm concentration. Copper exposure did not affect adult mosquitoes' lifespan. Culex pipiens was the most susceptible species to copper exposure. CONCLUSION: This study demonstrates the efficacy of copper at <1 ppm to kill mosquito larvae and to prolong pupation and adult emergence time. Utilization of copper at a low concentration is cost-efficient in the public health setting and remains an open option as an environmentally safe vector control strategy.

Sunlight exposed body surface area is associated with serum 25-hydroxyvitamin D (25(OH)D) level in pregnant Minangkabau women, Indonesia.

BACKGROUND: Vitamin D deficiency is highly prevalent in women, and living in a tropical country with a year-round abundance of sunlight as the primary source of vitamin D does not seem to guarantee adequate serum 25(OH)D. While living in the tropics, Minangkabau women are known to dress specifically according to their culture. This study was aimed to elucidate the association of sunlight exposed body surface area with serum 25(OH)D in pregnant Minangkabau women of Indonesia. METHODS: We performed a cross-sectional study on 88 Minangkabau women in late pregnancy. Lifestyle data were collected using a questionnaire, and dietary intake of vitamin D was calculated from 24-h food recall. The skin pigmentation type was determined by the Fitzpatrick scale, and the body surface area exposed to sunlight was estimated. Serum 25(OH)D was quantified by ELISA method. Serum 25(OH)D differences according to the duration of sunlight exposure, skin pigmentation type, and sunscreen use were statistically analyzed by ANOVA. The correlation of sunlight exposed body surface area and serum 25(OH)D was analyzed by Spearman's correlation. RESULTS: Nearly half of the subjects (n = 40; 45.5%) were deficient in vitamin D (< 20 ng/ml) with serum 25(OH)D level 23.0 ± 10.0 ng/ml (mean ± SD) and the estimated daily intake of vitamin D was 5.6 ± 3.9 µg/1000 kcal/day (mean ± SD). The median percentage of body area exposed to sunlight was 15.8%. There were no differences in serum 25(OH)D levels according to sunlight exposure time, skin pigmentation type, and sunscreen use. The percentage of body area exposed to sunlight was positively correlated with serum 25(OH)D level (Spearman's ρ = 0.403; p < 0.001). CONCLUSIONS: Vitamin D deficiency is prevalent in pregnant Minangkabau women. Since increasing body surface area exposed to sunlight may not be culturally acceptable, vitamin D supplementation needs to be considered in this population.

Blood Cd levels and carotid intima-media thickness in young adults living in Padang, Indonesia.

OBJECTIVE: Cd exposure is a non-traditional risk factor of cardiovascular disease and mortality by promoting the development of atherosclerosis. The development of atherosclerosis can be monitored non-invasively by measuring carotid intima-media thickness (CIMT). This study aimed to measure the level of blood Cd and other factors known to be associated with CIMT, measured at the segment of common carotid artery (CCA) and of internal carotid artery (ICA), in young adults from Padang, West Sumatera, Indonesia, and we analyzed whether blood Cd is a predictor of CIMT. RESULTS: We recruited 156 subjects. Median blood Cd level was 0.61 µg/L (range 0.01-5.96 µg/L), with no difference in male compared to female subjects (Mann-Whitney U test, p = 0.60). Multiple regression analysis showed that sex is the predictor of CCA IMT (adjusted R2 = 0.219; ß = -0.438 [95% CI - 0.662, - 0.214]; p < 0.001) and ICA IMT (adjusted R2 = 0.165; ß = - 0.529 [95% CI - 0.761, - 0.297]; p < 0.001). Blood Cd was not a predictor of CCA IMT (adjusted R2 = 0.219; ß = - 0.101 [95% CI - 0.257, 0.055]; p = 0.203) and ICA IMT (adjusted R2 = 0.165; ß = - 0.055 [95% CI - 0.217, 0.107]; p = 0.503) in young adults from Padang, Indonesia.

Green coffee extract modifies body weight, serum lipids and TNF-α in high-fat diet-induced obese rats.

OBJECTIVE: Currently, there are many efforts to find functional nutrients for obesity management, and the green coffee extract is a potential candidate. This study aimed to examine the effect of low dose administration of  green coffee extract on body weight, serum lipids, and TNF-α level in high-fat diet-induced obese rats. RESULTS: Administration of green coffee extract to high-fat diet-induced obese male Wistar rats (Rattus norvegicus) reduced body weight, total serum cholesterol, and triglyceride at the dose of 10, 20, and 40 mg/kg BW/day; lowered serum LDL-cholesterol at the treatment dose of 20 mg/kg BW/day (p < 0.05). The effective dose to decrease serum TNF-α level was 40 mg/kg BW/day, while the effective dose to improve the lipid profile was 10 mg/kg BW/day. These results support the potential use of green coffee extract as a functional nutrient in the management of obesity.

Application of copper-based ovitraps in local houses in West Sumatra, Indonesia: a field test of a simple and affordable larvicide for mosquito control.

BACKGROUND: The application of oviposition traps (ovitraps) is one of the currently available rational methods used in mosquito control campaigns because it eliminates the larval stage. However, the use of current larvicides is hampered by their cost and applicability. Therefore, a more economical and practical alternative is urgently needed. We previously reported that copper in liquid form is a promising candidate due to its potent larvicide properties in a laboratory setting, affordability, and availability. METHODS: In the present study, a field test was performed by randomly placing copper-filled plastic pots with a concentration of 10 ppm in 21 local houses in Painan City, West Sumatra, Indonesia. Three of these pots including a control were placed inside, while another two were placed outside each of the houses. RESULTS: After 14 days, a large number of dead first and second instar larvae of Aedes spp. were observed in the copper-filled pots. Larvae in the control pots were all viable and thriving. Unhatched eggs and pupae were detected in several pots in the copper-treated group but were excluded from the analysis. CONCLUSIONS: Our field data confirmed that copper is a potential larvicide for ovitraps, particularly in under-resourced areas.

Matrix metalloproteinase-9 expression in folliculostellate cells of rat anterior pituitary gland.

Folliculostellate (FS) cells of the anterior pituitary gland express a variety of regulatory molecules. Using transgenic rats that express green fluorescent protein specifically in FS cells, we recently demonstrated that FS cells in vitro showed marked changes in motility, proliferation, and that formation of cellular interconnections in the presence of laminin, a component of the extracellular matrix, closely resembled those observed in vivo. These findings suggested that FS cells express matrix metalloproteinase-9 (MMP-9), which assists their function on laminin. In the present study, we investigate MMP-9 expression in rat anterior pituitary gland and examine its role in motility and proliferation of FS cells on laminin. Immunohistochemistry, RT-PCR, immunoblotting, and gelatin zymography were performed to assess MMP-9 expression in the anterior pituitary gland and cultured FS cells. Real-time RT-PCR was used to quantify MMP-9 expression in cultured FS cells under different conditions and treatments. MMP-9 expression was inhibited by pharmacological inhibitor or downregulated by siRNA and time-lapse images were acquired. A 5-bromo-2'-deoxyuridine assay was performed to analyze the proliferation of FS cells. Our results showed that MMP-9 was expressed in FS cells, that this expression was upregulated by laminin, and that laminin induced MMP-9 secretion by FS cells. MMP-9 inhibition and downregulation did not impair FS motility; however, it did impair the capacity of FS cells to form interconnections and it significantly inhibited proliferation of FS cells on laminin. We conclude that MMP-9 is necessary in FS cell interconnection and proliferation in the presence of laminin.

Expression of chemokine CXCL12 and its receptor CXCR4 in folliculostellate (FS) cells of the rat anterior pituitary gland: the CXCL12/CXCR4 axis induces interconnection of FS cells.

The anterior pituitary gland is composed of five types of hormone-producing cells plus folliculostellate (FS) cells, which do not produce classical anterior pituitary hormones. FS cells are interconnected by cytoplasmic processes and encircle hormone-producing cells or aggregate homophilically. Using living-cell imaging of primary culture, we recently reported that some FS cells precisely extend their cytoplasmic processes toward other FS cells and form interconnections with them. These phenomena suggest the presence of a chemoattractant factor that facilitates the interconnection. In this study, we attempted to discover the factor that induces interconnection of FS cells and succeeded in identifying chemokine (CXC)-L12 and its receptor CXCR4 as potential candidate molecules. CXCL12 is a chemokine of the CXC subfamily. It exerts its effects via CXCR4, a G protein-coupled receptor. The CXCL12/CXCR4 axis is a potent chemoattractant for many types of neural cells. First, we revealed that CXCL12 and CXCR4 are expressed by FS cells in rat anterior pituitary gland. Next, to clarify the function of the CXCL12/CXCR4 axis in FS cells, we observed living anterior pituitary cells in primary culture with specific CXCL12 inhibitor or CXCR4 antagonist and noted that extension of cytoplasmic processes and interconnection of FS cells were inhibited. Finally, we examined FS cell migration and invasion by using Matrigel matrix assays. CXCL12 treatment resulted in markedly increased FS cell migration and invasion. These data suggest that FS cells express chemokine CXCL12 and its receptor CXCR4 and that the CXCL12/CXCR4 axis evokes interconnection of FS cells.

Caveolin 3-mediated integrin ß1 signaling is required for the proliferation of folliculostellate cells in rat anterior pituitary gland under the influence of extracellular matrix.

Folliculostellate (FS) cells in the anterior pituitary gland are believed to have multifunctional properties. Using transgenic rats that express green fluorescent protein (GFP) specifically in FS cells in the anterior pituitary gland (S100b-GFP rats), we recently revealed that FS cells in primary culture exhibited marked proliferation in the presence of laminin, an extracellular matrix (ECM) component of the basement membrane. In a process referred to as matricrine action, FS cells receive ECM as a signal through their receptors, which results in morphological and functional changes. In this study, we investigated matricrine signaling in FS cells and observed that the proliferation of FS cells is mediated by integrin ß1, which is involved in various signaling pathways for cell migration and proliferation in response to ECM. Then, we analyzed downstream events of the integrin ß1 signaling pathway in the proliferation of FS cells and identified caveolin 3 as a potential candidate molecule. Caveolin 3 is a membrane protein that binds cholesterol and a number of signaling molecules that interact with integrin ß1. Using specific small interfering RNA of caveolin 3, the proliferation of FS cells was inhibited. Furthermore, caveolin 3 drove activation of the mitogen-activated protein kinase (MAPK) signaling cascades, which resulted in upregulation of cyclin D1 in FS cells. These findings suggest that matricrine signaling in the proliferation of FS cells was transduced by a caveolin 3-mediated integrin ß1 signaling pathway and subsequent activation of the MAPK pathway.