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α-Mercapto-β-(2-furyl) acrylic acid (MFA), α-mercapto-β-(2-hydroxyphenyl) acrylic acid (MHA), β-1,2-phenylene di-α-mercaptoacrylic acid (1,2-PDMA) and β-1,4-phenylene di-α-mercapto acrylic acid (1,4-PDMA) were compared to sodium N-benzyl-D-glucamine dithiocarbamate (NBG-DTC) an effective cadmium chelator, for their ability to mobilize Cd and influence the Cd induced tissue metallothionein (MT) in rats administered 100CdCl2, 72 hr earlier. MFA was almost as effective as NBG-DTC but more effective than MHA in enhancing urinary and faecal excretion of Cd, reducing tissue and blood levels of Cd and in lowering Cd induced increase in hepatic and renal MT contents. 1,2-PDMA and 1,4-PDMA were effective only in reducing the hepatic burden of Cd. The resuls do not indicate any direct relationship between the efficacy of α-mercapto-β-aryl acrylic acids to decorporate body Cd and their lipophilic-hydrophilic character or number-arrangement of their sulfhydryl groups. [ABSTRACT FROM AUTHOR]

α-Mercapto-β-(2-furyl) acrylic acid (MFA), α-mercapto-β-(phenyl) acrylic acid (MPA), α-mercapto-β-(2-hydroxyphenyl) acrylic acid (MHA), α-mercapto-β-(4-methoxyphenyl) acrylic acid (MMA), β-1,2-phenylene di-α-mercapto acrylic acid (1, 2-PDMA) and β-1, 4-phenylene di-α-mercapto acrylic acid (1, 4-PDMA) enhanced faecal excretion and reduced liver, spleen and blood burden of inorganic mercury when administered (0.5 m mol/kg, in two split doses) 24 hr after Hg (II) (1 mg/kg) in rats. MFA, MPA, MHA and MMA were also effective in lowering renal Hg mainly from the cytosol, without any significant increase in urinary excretion of Hg. The results indicate that all the mono-mercapto acrylic acids including MFA were more effective than di-mercapto acrylic acids and act through the mechanism characteristic of thiol chelators, that is, mobilization of Hg as their complexes, contrary to the reported observation that MFA acts through the induction of metallothionein. [ABSTRACT FROM AUTHOR]

Diet and lifestyle-related illnesses including functional gastrointestinal disorders (FGIDs) and obesity are rapidly emerging health issues worldwide. Research has focused on addressing FGIDs via in-person cognitive-behavioral therapies, diet modulation and pharmaceutical intervention. Yet, there is paucity of research reporting on digital therapeutics care delivering weight loss and reduction of FGID symptom severity, and on modeling FGID status and symptom severity reduction including personalized genomic SNPs and gut microbiome signals. Our aim for this study was to assess how effective a digital therapeutics intervention personalized on genomic SNPs and gut microbiome signals was at reducing symptomatology of FGIDs on individuals that successfully lost body weight. We also aimed at modeling FGID status and FGID symptom severity reduction using demographics, genomic SNPs, and gut microbiome variables. This study sought to train a logistic regression model to differentiate the FGID status of subjects enrolled in a digital therapeutics care program using demographic, genetic, and baseline microbiome data. We also trained linear regression models to ascertain changes in FGID symptom severity of subjects at the time of achieving 5% or more of body weight loss compared to baseline. For this we utilized a cohort of 177 adults who reached 5% or more weight loss on the Digbi Health personalized digital care program, who were retrospectively surveyed about changes in symptom severity of their FGIDs and other comorbidities before and after the program. Gut microbiome taxa and demographics were the strongest predictors of FGID status. The digital therapeutics program implemented, reduced the summative severity of symptoms for 89.42% (93/104) of users who reported FGIDs. Reduction in summative FGID symptom severity and IBS symptom severity were best modeled by a mixture of genomic and microbiome predictors, whereas reduction in diarrhea and constipation symptom severity were best modeled by microbiome predictors only. This preliminary retrospective study generated diagnostic models for FGID status as well as therapeutic models for reduction of FGID symptom severity. Moreover, these therapeutic models generate testable hypotheses for associations of a number of biomarkers in the prognosis of FGIDs symptomatology., Competing Interests: All authors except JU and PD were employees of Digbi Health. JU did contractual work for Digbi Health. PD was an advisor to Digbi Health. The authors declare that this study received funding from Digbi Health. The funder Digbi Health was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. SK, DA, and RS had a patent-pending concerning this work: US Application No. 63/246,348, Methods and systems for multi-omic interventions as diagnostics for personalized care of functional gastrointestinal disorders. The digital therapeutics program provided to study participants in this work is a commercially available program developed and marketed by Digbi Health., (Copyright © 2022 Kumbhare, Francis-Lyon, Kachru, Uday, Irudayanathan, Muthukumar, Ricchetti, Singh-Rambiritch, Ugalde, Dulai, Almonacid and Sinha.)

Background: The COVID-19 pandemic has highlighted the urgency of addressing an epidemic of obesity and associated inflammatory illnesses. Previous studies have demonstrated that interactions between single-nucleotide polymorphisms (SNPs) and lifestyle interventions such as food and exercise may vary metabolic outcomes, contributing to obesity. However, there is a paucity of research relating outcomes from digital therapeutics to the inclusion of genetic data in care interventions., Objective: This study aims to describe and model the weight loss of participants enrolled in a precision digital weight loss program informed by the machine learning analysis of their data, including genomic data. It was hypothesized that weight loss models would exhibit a better fit when incorporating genomic data versus demographic and engagement variables alone., Methods: A cohort of 393 participants enrolled in Digbi Health's personalized digital care program for 120 days was analyzed retrospectively. The care protocol used participant data to inform precision coaching by mobile app and personal coach. Linear regression models were fit of weight loss (pounds lost and percentage lost) as a function of demographic and behavioral engagement variables. Genomic-enhanced models were built by adding 197 SNPs from participant genomic data as predictors and refitted using Lasso regression on SNPs for variable selection. Success or failure logistic regression models were also fit with and without genomic data., Results: Overall, 72.0% (n=283) of the 393 participants in this cohort lost weight, whereas 17.3% (n=68) maintained stable weight. A total of 142 participants lost 5% bodyweight within 120 days. Models described the impact of demographic and clinical factors, behavioral engagement, and genomic risk on weight loss. Incorporating genomic predictors improved the mean squared error of weight loss models (pounds lost and percent) from 70 to 60 and 16 to 13, respectively. The logistic model improved the pseudo R 2 value from 0.193 to 0.285. Gender, engagement, and specific SNPs were significantly associated with weight loss. SNPs within genes involved in metabolic pathways processing food and regulating fat storage were associated with weight loss in this cohort: rs17300539_G (insulin resistance and monounsaturated fat metabolism), rs2016520_C (BMI, waist circumference, and cholesterol metabolism), and rs4074995_A (calcium-potassium transport and serum calcium levels). The models described greater average weight loss for participants with more risk alleles. Notably, coaching for dietary modification was personalized to these genetic risks., Conclusions: Including genomic information when modeling outcomes of a digital precision weight loss program greatly enhanced the model accuracy. Interpretable weight loss models indicated the efficacy of coaching informed by participants' genomic risk, accompanied by active engagement of participants in their own success. Although large-scale validation is needed, our study preliminarily supports precision dietary interventions for weight loss using genetic risk, with digitally delivered recommendations alongside health coaching to improve intervention efficacy., (©Ranjan Sinha, Dashyanng Kachru, Roshni Ray Ricchetti, Simitha Singh-Rambiritch, Karthik Marimuthu Muthukumar, Vidhya Singaravel, Carmel Irudayanathan, Chandana Reddy-Sinha, Imran Junaid, Garima Sharma, Patricia Alice Francis-Lyon. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 19.05.2021.)

Chelation is most acceptable means of managing heavy metal poisoning. Piperazine hexahydrate dithiocarbamate (PHD), N-methyl piperazine dithiocarbamate (MPD), N-3-chloro-phenyl piperazine dithiocarbamate (CPD), and N-benzyl piperazine dithiocarbamate (BPD) were investigated for their efficacies to mobilize lead and restore Pb-induced hematopoietic alterations in experimentally intoxicated rats. MPD and CPD were effective in enhancing the urinary excretion of Pb. While PHD and MPD were successful in lowering hepatic Pb, CPD, and BPD were effective in doing so from renal tissue. All the chelating agents decreased the blood level of Pb. The lowering of Pb body burden had no influence on the restoration of biochemical changes which indicates that the latter may not be directly related to the metal mobilizing potential of the chelating agents. None of the compounds caused excessive depletion of body Cu or Zn. No relationship between efficacies of the chelating agents and their structures was seen. However, MPD and CPD appeared to be promising antidotes of Pb poisoning.

The effectiveness of alpha-mercapto-beta-(2-furyl)acrylic acid (MFA) and N-benzyl-N-dithiocarboxy-D-glucamine (NaB), used in combination, in the mobilization and excretion of lead was investigated in rats. Male Wistar rats received 10 mg Pb/kg as lead acetate intragastrically daily for 6 weeks. The lead-exposed rats were treated with either MFA or NaB or both 200 mumol/kg i.p., each, daily for 3 days. Both chelating agents provoked significant urinary and faecal excretion and lowered the soft-organ lead burden. However, combined therapy did not elicit any additive or synergistic response.

The effectiveness of certain substituted dithiocarbamates in mobilizing lead from preexposed rats was investigated. The animals received 10 mg Pb/kg/day, intragastrically, for 8 weeks and were treated thereafter with 400 mumol/kg, intraperitoneally, of morpholine dithiocarbamate, tetraammonium ethylenediamine diacetic acid dithiocarbamate (EDDTC), ammonium diethanolamine dithiocarbamate (ADDTC), sodium diethyldithiocarbamate, N-benzyl-D-glucamine dithiocarbamate (NBGDTC), or dimercaptosuccinic acid, daily for 5 days. All the chelating agents were effective in lowering the hepatic and renal burden of Pb. ADDTC, EDDTC, and NBGDTC were also able to lower the long bone Pb content. The lowering of Pb burden had no relationship to restoration of Pb-induced hematopoietic alterations. The relatively lower lipophilicity of substituted dithiocarbamates, owing to the presence of hydrophilic groups, seems to be advantageous in preventing passage of metal chelate into the brain. None of the substituted dithiocarbamates caused excessive excretion of urinary Cu and Zn. ADDTC and EDDTC appear to be promising in the management of Pb poisoning.

The effect of two polyamino-polycarboxylic acids, N-(2-hydroxyethyl) ethylenediamine triacetic acid (HEDTA) and diethylenetriamine penta-acetic acid (DTPA) and two thiol-chelating agents, sodium diethyldithiocarbamate (DDC) and dimercaptosuccinic acid (DMS) on the excretion of manganese (Mn) in rabbits given Mn i.p. was studied in order to investigate the affinity of this metal to N, O and S-containing compounds. HEDTA and DTPA were effective, and DDC and DMS were ineffective, in enhancing urinary and faecal excretions of Mn, indicating a greater binding capacity of Mn with chelators having N and O, than with those having S as electron donating centres.

alpha-Mercapto-beta-(2-furyl) acrylic acid (MFA), alpha-mercapto-beta-(phenyl) acrylic acid (MPA), alpha-mercapto-beta-(2-hydroxyphenyl) acrylic acid (MHA), alpha-mercapto-beta-(4-methoxyphenyl) acrylic acid (MMA), beta-1,2-phenylene di-alpha-mercapto acrylic acid (1, 2-PDMA) and beta-1, 4-phenylene di-alpha-mercapto acrylic acid (1, 4-PDMA) enhanced faecal excretion and reduced liver, spleen and blood burden of inorganic mercury when administered (0.5 m mol/kg, in two split doses) 24 hr after Hg (II) (1 mg/kg) in rats. MFA, MPA, MHA, and MMA were also effective in lowering renal Hg mainly from the cytosol, without any significant increase in urinary excretion of Hg. The results indicate that all the mono-mercapto acrylic acids including MFA were more effective than di-mercapto acrylic acids and act through the mechanism characteristic of thiol chelators, that is, mobilization of Hg as their complexes, contrary to the reported observation that MFA acts through the induction of metallothionein.

The effect of dose and duration of treatment with chromium on its distribution in certain vital organs and the blood of rats has been investigated. The accumulation of metal was highest in liver and kidneys, followed by testes, brain and blood and was rather more dependent on the dose than on the duration of exposure. The sub-cellular distribution in liver revealed greater concentration of the metal in the nuclear fraction than in the mitochrondrial or the post mitochondrial fraction. The uptake of the metal by the mitochondrial fraction however, increased with the increase in the dose of chromium from 1 mg/kg to 2 or 3 mg/kg.

The effect of pre-treatment with sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), sodium diethyldithiocarbamate (DDC) and calcium trisodium diethylenetriaminepentaacetate (DTPA) on the fate of injected mercuric chloride in rats was investigated. DMPS was the most effective chelator in reducing the uptake of Hg (203) in tissues and was the only chelator to enhance the urinary excretion of Hg (203). The results suggest affinity of Hg towards sulfur moiety and that the protective effects of pre-treatment are also shared by non-steroidal thiol chelators.

alpha-Mercapto-beta-(2-furyl) acrylic acid (MFA), alpha-mercapto-beta-(2-hydroxyphenyl) acrylic acid (MHA), beta-1,2-phenylene di-alpha-mercaptoacrylic acid (1,2-PDMA) and beta-1,4-phenylene di-alpha-mercapto acrylic acid (1,4-PDMA) were compared to sodium N-benzyl-D-glucamine dithiocarbamate (NBG-DTC) an effective cadmium chelator, for their ability to mobilize Cd and influence the Cd induced tissue metallothionein (MT) in rats administered 109CdCl2, 72 hr earlier. MFA was almost as effective as NBG-DTC but more effective than MHA in enhancing urinary and faecal excretion of Cd, reducing tissue and blood levels of Cd and in lowering Cd induced increase in hepatic and renal MT contents. 1,2-PDMA and 1,4-PDMA were effective only in reducing the hepatic burden of Cd. The resuls do not indicate any direct relationship between the efficacy of alpha-mercapto-beta-aryl acrylic acids to decorporate body Cd and their lipophilic-hydrophilic character or number-arrangement of their sulfhydryl groups.

The influence of chelating agents (1 mmol/kg/day X 6,i.p.) on trace metal mobilization and activities of certain metalloenzymes was investigated in rats. Calcium disodium ethylenediamine tetraacetate (CaNa2EDTA) and calcium trisodium diethylenetriamine pentaacetate (CaNa3DTPA) enhanced urinary excretion of Zn, while sodium 2,3-dimercaptopropane-1-sulfonate (NaDMPS) and sodium diethyldithiocarbamate (NaDDC) increased that of Cu. The activity of Zn-metalloenzymes-blood delta-aminolevulinic acid dehydratase (delta-ALA-D), plasma alkaline phosphatase (ALP) and that of Cu-metalloenzyme-plasma amine oxidase was decreased as a consequence of chelation therapy. However, hepatic levels of delta-ALA-D, ALP and alcohol dehydrogenase remained unaffected by chelation. The activity of hepatic Fe-metalloenzyme-catalase was increased by polyaminocarboxylic acids and lowered by thiol chelators. The metal chelators decreased the hepatic glutathione levels.

Seven male silver jewellery workers aged between 25 to 70 years complained of acute abdominal colic, sweet metallic taste, constipation and anorexia. Clinical, hematological examinations and urinalysis confirmed lead poisoning. Oral therapy with D-Penicillamine for seven days led to significant improvement in patients.

beta-1,2-Phenylene di-alpha-mercaptoacrylic acid (1,2-PDMA), beta-1,4-phenylene di-alpha-mercaptoacrylic acid (1,4-PDMA) and alpha-mercapto-beta-(2-hydroxyphenyl) acrylic acid (MHA) were synthesized and compared with 2,3-dimercapto-propane-1-sulfonate (DMPS) for their ability to counteract toxic effects of lead and nickel in rats. 1,2-PDMA and DMPS were most effective in enhancing the excretion of metals, restoring most of the metal induced biochemical alterations and reducing the body burden of the metals; These observations confirm that the chelating agents with two adjacent sulfhydryl groups are better than those with non-adjacent SH groups as metal antidotes. The success of MHA in mobilizing the tissue metals and increasing their urinary excretion indicates participation of the hydroxy group on the benzene nucleus besides the SH group of the MHA molecule, in chelation of the metals.

Male albino rats maintained on low-protein (9%) diets were dosed intraperitoneally with 0.75 mg Cd/kg, as cadmium chloride, for 20 days. Groups of these animals were provided with diets supplemented with 40 ppm Cu, 400 ppm Fe or a combination of both during the exposure period. Hepatic and renal distribution of Cd, Zn, Cu, and Fe along with activity of acid and alkaline phosphatases and ribonuclease and glutathione content were studied. Uptake of Cd both in liver and in kidney was significant and was accompanied by increased Zn and depletion of Fe concentration. The Cu level remained unaltered. Dietary supplementation of Cu or Fe interacted effectively and influenced the metal distribution. Acid and alkaline phosphatases in both liver and kidney were inhibited by Cd exposure. However, Cu and/or Fe supplements could to a varying degree offset the Cd-induced inhibition. Cadmium exposure did not, however, elicit any effect on hepatic and renal ribonuclease activity of low-protein-fed animals. The glutathione concentration registered profound increase on Cd exposure, possibly to act as a defence mechanism.

The influence of sodium diethyldithiocarbamate (DDC) on 63nickel chloride-induced metallothionein (MT) and alterations in essential metal levels in the liver of rats was investigated. The induction of MT, Zn and Cu levels of the hepatic cytosolic "heat stable fraction" (HSF) by DDC increased with time up to 24 hr. Although MT, Zn and Cu were significantly greater at 17 hr than those at 6.5 hr after 63Ni administration, the Ni level decreased. The treatment with DDC at 6 hr, but not at 10 min, prior to 63Ni administration increased significantly the MT, Zn and Cu contents 17 hr after 63Ni administration over that caused by 63Ni alone at 17 hr., showing a synergistic effect. The induction of hepatic MT by 63Ni or DDC alone was prevented by cycloheximide but not by actinomycin D and seemed to be regulated at the protein synthesis level.

The effect of treatment with alpha-mercapto-beta-(2-furyl)acrylic acid (MFA), N-(N-mercaptopropionyl) glycine (MPG) and N-acetylcysteine (NAC) compared to spironolactone (SPL), a steroid, before and after 203 mercury (II) exposure, on the disposition of Hg and induction of tissue metallothionein (MT), was investigated in rats. The pretreatment with SPL, MFA and MPG enhanced faecal elimination of Hg and reduced its accumulation in liver particularly, the "heat stable fraction" resulting in lowered hepatic MT induction. Neither the renal uptake of Hg nor induction of tissue MT was affected by pre-treatment with the chelating agents; SPL and MFA causing re-distribution of Hg among the renal sub-cellular fractions. The post-Hg exposure treatment with MFA enhanced the faecal and MPG the urinary excretion of Hg. However, both the chelating agents increased the hepatic burden of Hg as reflected in the subcellular fractions and increased MT contents indicating mobilization of Hg from other tissue binding sites. The post-treatment with MPG however, depleted renal Hg as reflected by the sub-cellular distribution, without affecting renal MT levels. The results show that MFA and MPG are more promising preventive than therapeutic agents in Hg intoxication acting as metal chelators.

The influence of methionine supplementation on the efficacy of common antidotes to lead poisoning, calcium disodium ethylenediaminetetraacetate (CaNa2EDTA) and D-penicillamine (DPA), was investigated in rats. The animals were given lead acetate (0.1% in drinking water) for 12 weeks and thereafter treated with CaNa2EDTA. DPA (0.3 mmol/kg, intraperitoneally), DL-methionine (1.34 mmol/kg, intragastrically), or the combination of a chelating agent and methionine for 3 days. While chelating agents enhanced the urinary excretion of Pb, methionine increased the fecal excretion of Pb significantly. Treatment with the combination of a chelating agent and methionine did not potentiate the effect of each antidote. However, methionine supplementation increased the efficacy of both chelating agents in reducing the hepatic and renal Pb burden but not the blood Pb level. The Pb-induced inhibition of blood delta-aminolevulinic acid dehydratase activity and the increase in urinary excretion of delta-aminolevulinic acid were reversed to a certain extent by CaNa2EDTA, DPA, and methionine but the combination did not improve their individual performances. The beneficial effects of methionine may be attributed to its ability to increase the bioavailability of glutathione (GSH), useful in chelating Pb and counter-acting the toxic effects, as evidenced by restoration of the Pb-induced decrease in hepatic GSH level by treatment with methionine. Methionine may be useful as a supportive therapy in chelation of Pb.

In view of the reported effectiveness of alpha-mercapto-beta-(2-furyl) acrylic acid (MFA) as an effective antidote to inorganic mercury toxicity, some alpha-mercapto-beta-aryl acrylic acids were synthesized and examined for their efficacy in counteracting nickel and lead intoxication in rats. alpha-mercapto-beta-(3,4-dimethoxyphenyl)acrylic acid (MDA) was most effective and other compounds were less but about equally effective in enhancing urinary excretion and in reducing tissue concentration of Ni. MDA was the only compound to remove Ni from the brain. MFA was also more effective than other structurally related compounds in enhancing urinary and faecal excretion and in lowering body burden of Pb. All the compounds significantly reduced the inhibition of the activity of blood delta-aminolevulinic acid dehydratase (delta-ALA-D) and increase in the urinary excretion of delta-aminolevulinic acid (delta-ALA) caused by Pb. The results do not show any relationship between the nature of the substitution at the beta-position of alpha-mercapto acrylic acids and their ability to reduce the concentration and the toxic effects of the two metals. However, these thiol chelating agents appear promising as antidotes to Ni and Pb poisoning.