Exposures to drinking water disinfection byproducts and kidney function in Chinese women.

BACKGROUND: Disinfection byproducts (DBPs), the ubiquitous contaminants in drinking water, have been shown to impair renal function in experimental studies. However, epidemiological evidence is sparse. OBJECTIVE: To investigate exposures to DBPs in associations with renal function among women. METHODS: A total of 920 women from December 2018 to January 2020 were abstracted from the Tongji Reproductive and Environmental (TREE) Study, an ongoing cohort study in Wuhan, China. Urine samples were gathered at baseline recruitment and analyzed for dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) as biomarkers of DBP exposures. Serum uric acid (UA), creatinine, and estimated glomerular filtration rate (eGFR) were measured as indicators of renal function. Multivariate linear regression and restricted cubic spline (RCS) models were conducted to assess urinary DCAA and TCAA concentrations in associations with renal function indicators. Stratified analyses by age and body mass index (BMI) were also performed. RESULTS: We found null evidence of urinary TCAA in associations with renal function indicators. However, elevated urinary DCAA tertiles were related to decreased eGFR (ß = -1.78%, 95% CI: 3.21%, -0.36%, comparing the upper vs. lower tertile; P for trend = 0.01). This inverse association still existed when urinary DCAA concentration was treated as a continuous variable, and the dose-response relationship was linear based on the RCS model (P for overall association = 0.002 and P for non-linear associations = 0.44). In the stratified analyses, we found an association of urinary DCAA concentration with decreased UA level among women <30 years but an association with increased UA level among women ≥30 years (P for interaction = 0.04). CONCLUSION: Urinary DCAA but not TCAA was associated with impaired renal function among women undergoing assisted reproductive technology.

Exposure to disinfection by-products and reproductive hormones among women: Results from the Tongji Reproductive and Environmental (TREE) study.

BACKGROUND: Disinfection by-products (DBPs) have been shown to impair female reproductive function. However, epidemiological evidence on reproductive hormones is scarce. OBJECTIVE: To investigate the associations between DBP exposures and reproductive hormones among women undergoing assisted reproductive technology. METHODS: We included 725 women from the Tongji Reproductive and Environmental (TREE) Study, an ongoing cohort conducted in Wuhan, China during December 2018 and January 2020. Urine samples collected at recruitment were quantified for dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) as biomarkers of DBP exposures. At day 2-5 of menstruation, serum reproductive hormones including luteinizing hormone (LH), estradiol (E2), total testosterone (T), progesterone (PRGE), and prolactin (PRL) were determined. Multivariate linear regression models were performed to assess the associations of urinary DCAA and TCAA concentrations with reproductive hormone levels. Dose-response relationships were investigated using natural cubic spline (NCS) and restricted cubic spline (RCS) models. RESULTS: After adjusting for relevant confounders, we observed that higher urinary DCAA levels were associated with increased serum PRGE (9.2%; 95% CI: -0.55%, 19.8% for the highest vs. lowest tertile; P for trend = 0.06). Based on NCS models, we observed U-shaped associations of urinary DCAA with serum PRGE and PRL; each ln-unit increment in urinary DCAA concentrations above 3.61 µg/L and 6.30 µg/L was associated with 18.9% (95% CI: 4.8%, 34.7%) and 23.3% (95% CI: -0.92%, 53.5%) increase in serum PRGE and PRL, respectively. The U-shaped associations were further confirmed in RCS models (P for overall association ≤0.01 and P for non-linear associations ≤0.04). We did not observe evidence of associations between urinary TCAA and reproductive hormones. CONCLUSION: Urinary DCAA but not TCAA was associated with altered serum PRGE and PRL levels among women undergoing assisted reproductive technology.

Cytotoxic derivatives of dichloroacetic acid and some metal complexes.

This study outlines a number of studies of dichloroacetic acid (DCA) and some of its derivatives. Although DCA has low cytotoxic potencies, various structural modifications are described which result in potent cytotoxins. In particular, hybrid molecules created from DCA and other bioactive molecules whose modes of action differ from DCA are particularly promising as candidate anticancer agents. Considerable emphasis in this review is placed on various series of compounds that incorporate both platinum and DCA into their structures. In addition, the importance of the formulation of some of the bioactive compounds described herein is revealed.

Dichloroacetic acid-induced dysfunction in rat hippocampus and the protective effect of curcumin.

The present study was designed to evaluate the role of cAMP-PKA-CREB signaling in mediating the neuroprotective effects of curcumin against DCAA-induced oxidative stress, inflammation and impaired synaptic plasticity in rats. Sixty Sprague-Dawley rats were randomly divided into five groups, and we assessed the histomorphological, behavioral and biochemical characteristics to investigate the beneficial effects of different concentrations of curcumin against DCAA-induced neurotoxicity in rat hippocampus. The results indicated that animal weight gain and food consumption were not significantly affected by DCAA. However, behavioral tests, including morris water maze and shuttle box, showed varying degrees of alterations. Additionally, we found significant changes in hippocampal neurons by histomorphological observation. DCAA exposure could increase lipid peroxidation, reactive oxygen species (ROS), inflammation factors while reducing superoxide dismutase (SOD) activity and glutathione (GSH) level accompanied by DNA damage in the hippocampus. Furthermore, we found that DCAA exposure could cause a differential modulation of mRNA and proteins (cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP-response element-binding protein (CREB), p-CREB, brain-derived neurotrophic factor (BDNF), postsynaptic density-95 (PSD-95), synaptophysin (SYP)). Conversely, various doses of curcumin attenuated DCAA-induced oxidative stress, inflammation response and impaired synaptic plasticity, while elevating cAMP, PKA, p-CREB, BDNF, PSD-95, SYP levels. Thus, curcumin could activate the cAMP-PKA-CREB signaling pathway, conferring neuroprotection against DCAA-induced neurotoxicity.

Enhanced antitumor potential induced by chloroacetate-loaded benzophenones acting as fused tubulin-pyruvate dehydrogenase kinase 1 (PDHK1) ligands.

The majority of cancers detected every year are treated with anti-cancer compounds. Unfortunately, many tumors become resistant to antineoplastic drugs. One option is to use cocktails of compounds acting on different targets to try to overcome the resistant cells. This type of approach can produce good results, but is often accompanied by a sharp increase of associated side effects. The strategy presented herein focuses on the use of a single compound acting on two different biological targets enhancing potency and lowering the toxicity of the chemotherapy. In this light, the approach presented in the current study involves the dual inhibition of human pyruvate dehydrogenase kinase-1 (PDHK1) and tubulin polymerization using mono-, di- and tri-chloroacetate-loaded benzophenones and benzothiophenones. Synthesized molecules were evaluated in vitro on tubulin polymerization and on pyruvate dehydrogenase kinase 1. The cell cycle distribution after treatment of DA1-3b leukemic cells with active compounds was tested. Twenty-two benzo(thio)phenones have been selected by the National Cancer Institute (USA) for evaluation of their anti-proliferative potential against NCI-60 cancer cell lines including multidrug-resistant tumor cell lines. Seventeen molecules proved to be very effective in combating the growth of tumor cells exhibiting inhibitory activities up to nanomolar range. The molecular docking of best antitumor molecules in the study was realized with GOLD in the tubulin and PDHK1 binding sites, and allowed to understand the positioning of active molecules. Chloroacetate-loaded benzo(thio)phenones are dual targeted tubulin- and pyruvate dehydrogenase kinase 1 (PDHK1)-binding antitumor agents and exhibited superior antitumor activity compared to non-chlorinated congeners particularly on leukemia, colon, melanoma and breast cancer cell lines.

Synergistic Amplification of Oxidative Stress-Mediated Antitumor Activity via Liposomal Dichloroacetic Acid and MOF-Fe2.

Cancer cells are susceptible to oxidative stress; therefore, selective elevation of intracellular reactive oxygen species (ROS) is considered as an effective antitumor treatment. Here, a liposomal formulation of dichloroacetic acid (DCA) and metal-organic framework (MOF)-Fe2+ (MD@Lip) has been developed, which can efficiently stimulate ROS-mediated cancer cell apoptosis in vitro and in vivo. MD@Lip can not only improve aqueous solubility of octahedral MOF-Fe2+ , but also generate an acidic microenvironment to activate a MOF-Fe2+ -based Fenton reaction. Importantly, MD@Lip promotes DCA-mediated mitochondrial aerobic oxidation to increase intracellular hydrogen peroxide (H2 O2 ), which can be consequently converted to highly cytotoxic hydroxyl radicals (•OH) via MOF-Fe2+ , leading to amplification of cancer cell apoptosis. Particularly, MD@Lip can selectively accumulate in tumors, and efficiently inhibit tumor growth with minimal systemic adverse effects. Therefore, liposome-based combination therapy of DCA and MOF-Fe2+ provides a promising oxidative stress-associated antitumor strategy for the management of malignant tumors.

Pathogenic mechanisms underlying X-linked Charcot-Marie-Tooth neuropathy (CMTX6) in patients with a pyruvate dehydrogenase kinase 3 mutation.

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. An X-linked form of CMT (CMTX6) is caused by a missense mutation (R158H) in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. PDK3 is one of 4 isoenzymes that negatively regulate the activity of the pyruvate dehydrogenase complex (PDC) by reversible phosphorylation of its first catalytic component pyruvate dehydrogenase (designated as E1). Mitochondrial PDC catalyses the oxidative decarboxylation of pyruvate to acetyl CoA and links glycolysis to the energy-producing Krebs cycle. We have previously shown the R158H mutation confers PDK3 enzyme hyperactivity. In this study we demonstrate that the increased PDK3 activity in patient fibroblasts (PDK3(R158H)) leads to the attenuation of PDC through hyper-phosphorylation of E1 at selected serine residues. This hyper-phosphorylation can be reversed by treating the PDK3(R158H) fibroblasts with the PDK inhibitor dichloroacetate (DCA). In the patient cells, down-regulation of PDC leads to increased lactate, decreased ATP and alteration of the mitochondrial network. Our findings highlight the potential to develop specific drug targeting of the mutant PDK3 as a therapeutic approach to treating CMTX6.

Targeting unique metabolic properties of breast tumor initiating cells.

Normal stem cells from a variety of tissues display unique metabolic properties compared to their more differentiated progeny. However, relatively little is known about metabolic properties of cancer stem cells, also called tumor initiating cells (TICs). In this study we show that, analogous to some normal stem cells, breast TICs have distinct metabolic properties compared to nontumorigenic cancer cells (NTCs). Transcriptome profiling using RNA-Seq revealed TICs underexpress genes involved in mitochondrial biology and mitochondrial oxidative phosphorylation, and metabolic analyses revealed TICs preferentially perform glycolysis over oxidative phosphorylation compared to NTCs. Mechanistic analyses demonstrated that decreased expression and activity of pyruvate dehydrogenase (Pdh), a key regulator of oxidative phosphorylation, plays a critical role in promoting the proglycolytic phenotype of TICs. Metabolic reprogramming via forced activation of Pdh preferentially eliminated TICs both in vitro and in vivo. Our findings reveal unique metabolic properties of TICs and demonstrate that metabolic reprogramming represents a potential therapeutic strategy for targeting these cells.

Influence of the metal work function on the photocatalytic properties of TiO2 layers on metals.

The photocatalytic properties of titanium dioxide (TiO2 ) layers on different metal plates are investigated. The metal-semiconductor interface can be described as a Schottky contact, and is part of a depletion layer for the majority carriers in the semiconductor. Many researchers have demonstrated an increase in the photocatalytic activity, due to the formation of a metal-semiconductor contact that are obtained by deposition of small metal islands on the semiconductor. Nevertheless, the influence of a Schottky contact remains uncertain, sparking much interest in this field. The immobilization of nanoparticulate TiO2 layers by dip-coating on different metal substrates results in the formation of a Schottky contact. The recombination rate of photoinduced electron-hole pairs decreases at this interface provided that the thickness of the thin TiO2 layer has a similar magnitude to the depletion layer. The degradation of dichloroacetic acid in aqueous solution and of acetaldehyde in a gas mixture is investigated to obtain information concerning the influence of the metal work function of the back contact on the efficiency of the photocatalytic process.

Preparation and characterization of Pd/Fe bimetallic nanoparticles immobilized on Al2O3/PVDF membrane: Parameter optimization and dechlorination of dichloroacetic acid.

Using a liquid-solid phase inversion method, a hybrid matrix poly(vinylidene fluoride) (PVDF) membrane was prepared with alumina (Al2O3) nanoparticle addition. Pd/Fe nanoparticles (NPs) were successfully immobilized on the Al2O3/PVDF membrane, which was characterized by Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). The micrographs showed that the Pd/Fe NPs were dispersed homogeneously. Several important experimental parameters were optimized, including the mechanical properties, contact angle and surface area of Al2O3/PVDF composite membranes with different Al2O3 contents. At the same time, the ferrous ion concentration and the effect of hydrophilization were studied. The results showed that the modified Al2O3/PVDF membrane functioned well as a support. The Al2O3/PVDF membrane with immobilized Pd/Fe NPs exhibited high efficiency in terms of dichloroacetic acid (DCAA) dechlorination. Additionally, a reaction pathway for DCAA dechlorination by Pd/Fe NPs immobilized on the Al2O3/PVDF membrane system was proposed.

Temporal variability in urinary levels of drinking water disinfection byproducts dichloroacetic acid and trichloroacetic acid among men.

Urinary haloacetic acids (HAAs), such as dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA), have been suggested as potential biomarkers of exposure to drinking water disinfection byproducts (DBPs). However, variable exposure to and the short elimination half-lives of these biomarkers can result in considerable variability in urinary measurements, leading to exposure misclassification. Here we examined the variability of DCAA and TCAA levels in the urine among eleven men who provided urine samples on 8 days over 3 months. The urinary concentrations of DCAA and TCAA were measured by gas chromatography coupled with electron capture detection. We calculated the intraclass correlation coefficients (ICCs) to characterize the within-person and between-person variances and computed the sensitivity and specificity to assess how well single or multiple urine collections accurately determined personal 3-month average DCAA and TCAA levels. The within-person variance was much higher than the between-person variance for all three sample types (spot, first morning, and 24-h urine samples) for DCAA (ICC=0.08-0.37) and TCAA (ICC=0.09-0.23), regardless of the sampling interval. A single-spot urinary sample predicted high (top 33%) 3-month average DCAA and TCAA levels with high specificity (0.79 and 0.78, respectively) but relatively low sensitivity (0.47 and 0.50, respectively). Collecting two or three urine samples from each participant improved the classification. The poor reproducibility of the measured urinary DCAA and TCAA concentrations indicate that a single measurement may not accurately reflect individual long-term exposure. Collection of multiple urine samples from one person is an option for reducing exposure classification errors in studies exploring the effects of DBP exposure on reproductive health.

Use of sodium dichloroacetate for cancer treatment: a scoping review.

In recent years, drug repurposing (DR) has gained significant attention as a promising strategy for identifying new therapeutic uses of existing drugs. One potential candidate for DR in cancer treatment is sodium dichloroacetate (DCA), which has been shown to alter tumor metabolism and decrease apoptosis resistance in cancer cells. In this paper, we present a scoping review of the use of DCA for cancer treatment in adult patients, aiming to identify key research gaps in this area. This scoping review aims to explore the existing scientific literature to provide an overview of the use of DCA (any dose, frequency, or route of administration) in adults with cancer. A comprehensive literature search of the medical databases MEDLINE/PubMed, LILACS, EPISTEMONIKOS, the Cochrane Library, and ClinicalTrials was performed. We included publications reporting on adult patients diagnosed with any type of cancer treated with sodium dichloroacetate in combination or not with other drugs. All types of study design were included. A total of 12 articles were included, most of them were case reports. We found a high degree of heterogeneity between them. The most frequent adverse events in the evaluated studies were asthenia, reversible toxicity, and an increase in liver enzymes. Effectiveness was difficult to evaluate. We conclude that there is insufficient evidence to affirm that treatment with DCA in cancer patients is effective or is safe.

El reposicionamiento de fármacos (RF) es un enfoque terapéutico reciente que se presenta como una estrategia prometedora para identificar nuevos usos terapéuticos de fármacos existentes. Un candidato potencial para RF en el tratamiento del cáncer es el dicloroacetato de sodio (DCA), el cual ha mostrado la capacidad de alterar el metabolismo tumoral y disminuir la resistencia a la apoptosis de células tumorales. La presente es una revisión (scoping review) del uso del DCA para el tratamiento del cáncer en pacientes adultos, que tiene como objetivo identificar brechas de investigación claves en esta área. Esta revisión pretende explorar la literatura científica existente, para proporcionar una visión general del uso del DCA (cualquier dosis, frecuencia o vía de administración) en individuos adultos con cáncer. Se llevó a cabo una búsqueda exhaustiva de la literatura en las bases médicas de datos MEDLINE/PubMed, LILACS, EPISTEMONIKOS, the Cochrane Library y ClinicalTrials. Se incluyeron publicaciones que informaban sobre pacientes adultos diagnosticados con cualquier tipo de cáncer, tratados con DCA, en combinación o no con otros fármacos. Dichos estudios presentaban distintos tipos de diseño. Se incluyó un total de 12 artículos, la mayoría de los cuales fueron reportes de casos. Se encontró un alto grado de heterogeneidad entre los mismos. Los eventos adversos más frecuentes fueron astenia, toxicidad reversible y aumento de las enzimas hepáticas, siendo la efectividad terapéutica difícil de evaluar. Concluimos que existe evidencia insuficiente para afirmar que el tratamiento con DCA en pacientes con cáncer es efectivo y/o seguro.

Urinary haloacetic acid concentrations and thyroid function among women: Results from the TREE study.

BACKGROUND: Disinfection byproducts (DBPs) have been shown to impair thyroid function in experimental models. However, epidemiological evidence is scarce. METHODS: This study included 1190 women undergoing assisted reproductive technology (ART) treatment from the Tongji Reproductive and Environmental (TREE) cohort from December 2018 to August 2021. Serum thyrotropin (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) were measured as indicators of thyroid function. FT4/FT3 and TSH/FT4 ratios were calculated as markers of thyroid hormone homeostasis. Dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA), the two most abundant HAAs, in urine were detected to assess individual DBP exposures. RESULTS: After adjusting for relevant covariates, positive associations were observed between urinary TCAA concentrations and serum TSH and TSH/FT4 levels (e.g., percent change = 5.82 %, 95 % CI: 0.70 %, 11.21 % for TSH), whereas inverse associations were found for serum FT3 and FT4 (e.g., percent change = -1.29 %, 95 % CI: -2.49 %, -0.07 % for FT3). There also was a negative association between urinary DCAA concentration and serum FT4/FT3 (percent change = -2.49 %, 95 % CI: -4.71 %, -0.23 %). These associations were further confirmed in the restricted cubic spline and generalized additive models with linear or U-shaped dose-response relationships. CONCLUSION: Urinary HAAs were associated with altered thyroid hormone homeostasis among women undergoing ART treatment.

Urinary biomarkers of drinking-water disinfection byproducts in relation to diminished ovarian reserve risk: A case-control study from the TREE cohort.

BACKGROUND: Disinfection byproducts (DBPs) as ovarian toxicants have been documented in toxicological studies. However, no human studies have explored the effects of exposure to DBPs on diminished ovarian reserve (DOR). OBJECTIVE: To assess whether urinary biomarkers of exposure to drinking-water DBPs were associated with DOR risk. METHODS: A total of 311 women undergoing assisted reproductive technology were diagnosed with DOR in the Tongji Reproductive and Environmental (TREE) cohort from December 2018 to August 2021. The cases were matched to the controls with normal ovarian reserve function by age in a ratio of 1:1. Urinary trichloroacetic acid (TCAA) and dichloroacetic acid (DCAA) were quantified as biomarkers of drinking-water DBP exposures. The conditional logistic regression and restricted cubic spline (RCS) were used to explore urinary biomarkers of drinking-water DBP exposures in associations with the risk of DOR. RESULTS: Elevated urinary DCAA levels were associated with higher DOR risk [adjusted odds ratio (OR) = 1.87; 95 % confidence interval (CI): 1.16, 3.03 for the highest vs. lowest quartiles; P for trend = 0.016]. The association was confirmed in the RCS model, with a linear dose-response curve (P for overall association = 0.029 and P for non-linear association = 0.708). The subgroup analysis by age and body mass index (BMI) showed that urinary DCAA in association with DOR risk was observed among women ≥35 years old and leaner women (BMI < 24 kg/m2), but the group differences were not statistically significant. Moreover, a U-shaped dose-response curve between urinary TCAA and DOR risk was estimated in the RCS model (P for overall association = 0.011 and P for non-linear association = 0.004). CONCLUSIONS: Exposure to drinking-water DBPs may contribute to the risk of DOR among women undergoing assisted reproductive technology.

Unraveling the therapeutic mechanisms of dichloroacetic acid in lung cancer through integrated multi-omics approaches: metabolomics and transcriptomics.

Objective: The aim of this study was to investigate the molecular mechanisms underlying the therapeutic effects of dichloroacetic acid (DCA) in lung cancer by integrating multi-omics approaches, as the current understanding of DCA's role in cancer treatment remains insufficiently elucidated. Methods: We conducted a comprehensive analysis of publicly available RNA-seq and metabolomic datasets and established a subcutaneous xenograft model of lung cancer in BALB/c nude mice (n = 5 per group) treated with DCA (50 mg/kg, administered via intraperitoneal injection). Metabolomic profiling, gene expression analysis, and metabolite-gene interaction pathway analysis were employed to identify key pathways and molecular players involved in the response to DCA treatment. In vivo evaluation of DCA treatment on tumor growth and MIF gene expression was performed in the xenograft model. Results: Metabolomic profiling and gene expression analysis revealed significant alterations in metabolic pathways, including the Warburg effect and citric acid cycle, and identified the MIF gene as a potential therapeutic target in lung cancer. Our analysis indicated that DCA treatment led to a decrease in MIF gene expression and an increase in citric acid levels in the treatment group. Furthermore, we observed a potential interaction between citric acid and the MIF gene, suggesting a novel mechanism underlying the therapeutic effects of DCA in lung cancer. Conclusion: This study underscores the importance of integrated omics approaches in deciphering the complex molecular mechanisms of DCA treatment in lung cancer. The identification of key metabolic pathways and the novel finding of citric acid elevation, together with its interaction with the MIF gene, provide promising directions for the development of targeted therapeutic strategies and improving clinical outcomes for lung cancer patients.

Dichloroacetic acid and rapamycin synergistically inhibit tumor progression. / äºŒæ°¯ä¹™é ¸è”åˆé›·å¸•éœ‰ç´ ååŒæŠ‘åˆ¶è‚¿ç˜¤è¿›ç¨‹.

Mammalian target of rapamycin (mTOR) controls cellular anabolism, and mTOR signaling is hyperactive in most cancer cells. As a result, inhibition of mTOR signaling benefits cancer patients. Rapamycin is a US Food and Drug Administration (FDA)-approved drug, a specific mTOR complex 1 (mTORC1) inhibitor, for the treatment of several different types of cancer. However, rapamycin is reported to inhibit cancer growth rather than induce apoptosis. Pyruvate dehydrogenase complex (PDHc) is the gatekeeper for mitochondrial pyruvate oxidation. PDHc inactivation has been observed in a number of cancer cells, and this alteration protects cancer cells from senescence and nicotinamide adenine dinucleotide (NAD+|) exhaustion. In this paper, we describe our finding that rapamycin treatment promotes pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) phosphorylation and leads to PDHc inactivation dependent on mTOR signaling inhibition in cells. This inactivation reduces the sensitivity of cancer cells' response to rapamycin. As a result, rebooting PDHc activity with dichloroacetic acid (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, promotes cancer cells' susceptibility to rapamycin treatment in vitro and in vivo.

Associations between drinking water disinfection byproducts and menstrual cycle characteristics: A cross-sectional study among women attending an infertility clinic.

Disinfection byproducts (DBPs) have been shown to alter ovarian steroidogenesis and cause estrous cyclicity disturbance and prolongation in experimental studies, however human studies are lacking. We aimed to evaluate the cross-sectional associations between drinking water DBPs and menstrual cycle characteristics. A total of 1078 women attending an infertility clinic in Wuhan, China were included between December 2018 and January 2020. Characteristics of menstrual cycle were collected by questionnaires. Concentrations of dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) were measured in urine as biomarkers of drinking water DBPs. Multivariate logistic and linear regression models were used to evaluate the associations between urinary DCAA and TCAA concentrations and menstrual cycle characteristics. Higher urinary DCAA concentrations were associated with increased odds ratios (ORs) of irregular menstrual cycle (OR = 1.80; 95% CI: 0.97, 3.33 for the highest vs. lowest quartile; P for trend = 0.05) and long menstrual cycle (OR = 1.62; 95% CI: 0.97, 2.70 for the highest vs. lowest quartile; P for trend = 0.06), as well as prolonged variation in cycle length (ß = 1.27 days; 95% CI: -0.11, 2.66 for the highest vs. lowest quartile; P for trend = 0.04). Higher urinary TCAA concentrations were associated with prolonged bleeding duration (ß = 0.23 days; 95% CI: -0.06, 0.51 for the highest vs. lowest quartile; P for trend = 0.07). These results suggest that exposure to drinking water DBPs is associated with menstrual cycle disturbances. These findings are warranted to confirm in other studies.

Dichloroacetyl Amides of 3,5-Bis(benzylidene)-4-piperidones Displaying Greater Toxicity to Neoplasms than to Non-Malignant Cells.

A series of 3,5-bis(benzylidene)-1-dichloroacetyl-4-piperidones 1a-l was evaluated against Ca9-22, HSC-2, HSC-3, and HSC-4 squamous cell carcinomas. Virtually all of the compounds displayed potent cytotoxicity, with 83% of the CC50 values being submicromolar and several CC50 values being in the double digit nanomolar range. The compounds were appreciably less toxic to human HGF, HPLF, and HPC non-malignant cells, which led to some noteworthy selectivity index (SI) figures. From these studies, 1d,g,k emerged as the lead molecules in terms of their potencies and SI values. A Quantitative Structure-Activity Relationship (QSAR) study revealed that cytotoxic potencies and potency-selectivity expression figures increased when the magnitude of the sigma values in the aryl rings was elevated. The modes of action of the representative cytotoxins in Ca9-22 cells were found to include G2/M arrest and stimulation of the cells to undergo mitosis and cause poly(ADP-ribose) polymerase (PARP) and procaspase 3 cleavage.

Urinary biomarkers of exposure to drinking water disinfection byproducts and ovarian reserve: A cross-sectional study in China.

Experimental studies have demonstrated that disinfection byproducts (DBPs) can cause ovarian toxicity including inhibition of antral follicle growth and disruption of steroidogenesis, but there is a paucity of human evidence. We aimed to investigate whether urinary biomarkers of exposure to drinking water DBPs were associated with ovarian reserve. The present study included 956 women attending an infertility clinic in Wuhan, China from December 2018 to January 2020. Antral follicle count (AFC), ovarian volume (OV), anti-Mullerian hormone (AMH), and follicle-stimulating hormone (FSH) were measured as indicators of ovarian reserve. Urinary dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) were assessed as potential biomarkers of drinking water DBP exposures. Multivariate linear and Poisson regression models were applied to estimate the associations of urinary DCAA and TCAA concentrations with indicators of ovarian reserve. Elevated urinary DCAA and TCAA levels were monotonically associated with reduced total AFC (- 5.98%; 95% CI: - 10.30%, - 1.44% in DCAA and - 12.98%; 95% CI: - 17.00%, - 8.76% in TCAA comparing the extreme tertiles; both P for trends ≤ 0.01), and the former was only observed in right AFC but not in left AFC, whereas the latter was estimated for both right and left AFC. Moreover, elevated urinary TCAA levels were monotonically associated with decreased AMH (- 14.09%; 95% CI: - 24.79%, - 1.86% comparing the extreme tertiles; P for trend = 0.03). These negative associations were still observed for the exposure biomarkers modeled as continuous variables. Our findings suggest that exposure to drinking water DBPs may be associated with decreased ovarian reserve.

Novel copper complexes of metronidazole and metronidazole benzoate: synthesis, characterization, biological and computational studies.

Synthesis and characterization of novel copper complexes of metronidazole benzoate (MTZ Benz), metronidazole (MTZ) in the presence of another ligand; dichloroacetic acid (DCA) were compared and reported in the present work. Different bacterial and fungus strains were ascertained to evaluate the biological potency of the synthesized complexes, that is, Escherichia coli, Bordetella bronceptica, Staphylococcus epidermidis, Baccilus pumilus, Staphylococcus aureus and yeast strain Saccharomyces cerevisiae. Agar diffusion method was employed to investigate in vitro antibacterial activities of the synthesized metal complexes and the tested parent ligands. α-Amylase and α-glucosidase inhibition studies of the synthesized complexes were also carried out. The antibacterial potential and α-amylase and α-glucosidase inhibition studies of complexes were further investigated by molecular docking studies, which supported the experimental results. Significant α-amylase and α-glucosidase inhibition activities were shown by the synthesized complexes. S-1 and S-5 were found to be most inhibitors of α-amylase and α-glucosidase having IC50 42.50, 44.80 and 4.52 µg/mL, 4.80 µg/mL, respectively. The newly synthesized copper complexes showed overall better biological activities compared to each parent ligands used.Communicated by Ramaswamy H. Sarma.