Exposure to environmental pollutant bisphenol A causes oxidative damage and lipid accumulation in Zebrafish larvae: Protective role of WL15 peptide derived from cysteine and glycine-rich protein 2.

Humans are exposed to obesity causing Bisphenol A in various ways, especially through diet and food containers. Bioactive peptides are already reported to have antioxidant, antidiabetic, and antiobesity properties, which can mimic the role of mediators involved in obesity prevention. The protective effect of a short molecule or peptide, WL15 from cysteine and glycine-rich protein 2 of a teleost of aquatic resource on Bisphenol A (BPA)-induced lipid accumulation in zebrafish larvae was investigated. BPA exposure disrupted the antioxidant enzymes, apoptosis, and nitric oxide and led to changes in biochemical markers including alkaline phosphatase, lactate dehydrogenase, lipid peroxidation, glutathione S-transferases, glutathione peroxidase, and reduced glutathione. However, WL15 inhibited the overproduction of oxidative stress, which correlates with its lipid-lowering potential. BPA-induced lipid accumulation in zebrafish showed an increase in triglyceride, cholesterol, and glucose level; simultaneously, WL15 treatment significantly reduced such accumulation in zebrafish. Evidenced by Oil red O staining and Nile red assay, WL15 inhibited lipid accumulation. At the same time, WL15 at 50 µM increases 2-(N-[7-nitrobenz-2-oxa-1,3-diazol-4-yl]amino)-2-deoxy-d-glucose (2NBDG) glucose uptake in zebrafish. In addition, gene expression studies in zebrafish larvae demonstrated that the WL15 peptide could play a crucial role in preventing lipid accumulation by downregulating the expression of lipogenesis-specific genes. These results revealed an interesting and novel property of WL15, suggesting its potential application in preventing lipid accumulation through the hypolipidemic and antioxidant properties.

Anti-Inflammatory Actions of Expectorants in a Rat Carrageenan-Induced Footpad Edema Model.

S-Carboxymethyl-L-cysteine (SCMS) exhibits sputum-regulating and anti-inflammatory actions. Previous studies reported the anti-inflammatory effects of SCMS on chronic inflammatory diseases, but no study has examined these effects on acute inflammatory diseases. In this study, we investigated the anti-inflammatory effects of SCMS in a rat carrageenan-induced footpad edema model, which is routinely used as an acute inflammation model. Expectorants were administered to rats with footpad edema induced by subcutaneously administering 1%λ-carrageenan to the footpad of the left posterior limb, and the dose dependency of the anti-inflammatory effects was evaluated. As a result, even when the dose of SCMS was increased to 400 mg/kg, there were no inhibitory effects on edema. Furthermore, we examined the inhibitory effects of other expectorants (ambroxol hydrochloride, N-acetyl-L-cysteine, L-cysteine ethylester hydrochloride, and L-cysteine methylester hydrochloride), which were reported to exhibit anti-inflammatory effects on chronic inflammation, on edema. However, none of these expectorants inhibited edema.

[DMARDs (Focusing on iguratimod)].

Conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) other than methotrexate (MTX: anchor csDMARDs) are effective for single use, reinforcement of MTX, biologics and induction and maintenance of biologics-free condition. Newly developed iguratimod (IGU) does not suppress immunological reaction, therefore, it is useful for single use or combination with other csDMARDs in patients with complications. IGU can be used as a first csDMARDs before MTX use during the screening for MTX. IGU might be effective for reinforcement of MTX, biologics and induction and maintenance of biologics-free condition just like other csDMARDs. IGU can be used in wide variety of situation of the treatment of rheumatoid arthritis and it is desired that after the all-case surveillance condition for approval, IGU become a standard csDMARDs all over the world which was made in Japan.

Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning.

Acetaminophen (APAP) overdose causes severe and occasionally fatal liver injury. Numerous drugs that attenuate APAP toxicity have been described. However these compounds frequently protect by cytochrome P450 inhibition, thereby preventing the initiating step of toxicity. We have previously shown that pretreatment with allopurinol can effectively protect against APAP toxicity, but the mechanism remains unclear. In the current study, C3HeB/FeJ mice were administered allopurinol 18h or 1h prior to an APAP overdose. Administration of allopurinol 18h prior to APAP overdose resulted in an 88% reduction in liver injury (serum ALT) 6h after APAP; however, 1h pretreatment offered no protection. APAP-cysteine adducts and glutathione depletion kinetics were similar with or without allopurinol pretreatment. The phosphorylation and mitochondrial translocation of c-jun-N-terminal-kinase (JNK) have been implicated in the progression of APAP toxicity. In our study we showed equivalent early JNK activation (2h) however late JNK activation (6h) was attenuated in allopurinol treated mice, which suggests that later JNK activation is more critical for the toxicity. Additional mice were administered oxypurinol (primary metabolite of allopurinol) 18h or 1h pre-APAP, but neither treatment protected. This finding implicated an aldehyde oxidase (AO)-mediated metabolism of allopurinol, so mice were treated with hydralazine to inhibit AO prior to allopurinol/APAP administration, which eliminated the protective effects of allopurinol. We evaluated potential targets of AO-mediated preconditioning and found increased hepatic metallothionein 18h post-allopurinol. These data show metabolism of allopurinol occurring independent of P450 isoenzymes preconditions the liver and renders the animal less susceptible to an APAP overdose.

Long-term cysteine fortification impacts cysteine/glutathione homeostasis and food intake in ageing rats.

PURPOSE: Healthy ageing is associated with higher levels of glutathione. The study aimed to determine whether long-term dietary fortification with cysteine increases cysteine and glutathione pools, thus alleviating age-associated low-grade inflammation and resulting in global physiological benefits. METHODS: The effect of a 14-week dietary fortification with cysteine was studied in non-inflamed (NI, healthy at baseline) and in spontaneously age-related low-grade inflamed (LGI, prefrail at baseline) 21-month-old rats. Fifty-seven NI rats and 14 LGI rats received cysteine-supplemented diet (4.0 g/kg of free cysteine added to the standard diet containing 2.8 g/kg cysteine). Fifty-six NI rats and 16 LGI rats received a control alanine-supplemented diet. RESULTS: Cysteine fortification in NI rats increased free cysteine (P < 0.0001) and glutathione (P < 0.03) in the liver and the small intestine. In LGI rats, cysteine fortification increased total non-protein cysteine (P < 0.0007) and free cysteine (P < 0.03) in plasma, and free cysteine (P < 0.02) and glutathione (P < 0.01) in liver. Food intake decreased over time in alanine-fed rats (r² = 0.73, P = 0.0002), whereas it was constant in cysteine-fed rats (r² = 0.02, P = 0.68). Cysteine fortification did not affect inflammatory markers, mortality, body weight loss, or tissue masses. CONCLUSION: Doubling the dietary intake of cysteine in old rats increased cysteine and glutathione pools in selected tissues. Additionally, it alleviated the age-related decline in food intake. Further validation of these effects in the elderly population suffering from age-related anorexia would suggest a useful therapeutic approach to the problem.

Healthy and adverse effects of plant-derived functional metabolites: the need of revealing their content and bioactivity in a complex food matrix.

In recent years, both food quality and its effect on human health have become a fundamental issue all over the world. As a consequence of this new and increased awareness, American, European, and Asian policymakers have strongly encouraged the research programs on food quality and safety thematic. Attempts to improve human health and to satisfy people's desire for healthcare without intake of pharmaceuticals, has led the food industry to focus attention on functional or nutraceutical food. For a long time, compounds with nutraceutical activity have been produced chemically, but the new demands for a sustainable life have gradually led the food industry to move towards natural compounds, mainly those derived from plants. Many phytochemicals are known to promote good health, but, sometimes, undesirable effects are also reported. Furthermore, several products present on the market show few benefits and sometimes even the reverse - unhealthy effects; the evidence of efficacy is often unconvincing and epidemiological studies are necessary to prove the truth of their claims. Therefore, there is a need for reliable analytical control systems to measure the bioactivity, content, and quality of these additives in the complex food matrix. This review describes the most widespread nutraceutics and an analytical control of the same using recently developed biosensors which are promising candidates for routine control of functional foods.

Bucillamine-induced yellow nail in Japanese patients with rheumatoid arthritis: two case reports and a review of 36 reported cases.

Yellow nail syndrome is an idiopathic condition characterized by a triad consisting of yellow nail, lymphedema, and pulmonary manifestations. Thiol compounds such as D-penicillamine have been reported to be the major cause of drug-induced yellow nail syndrome in patients with rheumatoid arthritis (RA). We recently experienced two Japanese cases with RA who developed yellow nail under treatment with bucillamine, a thiol-containing anti-rheumatic drug developed and approved in Japan. We reviewed the literature for similar cases and identified 36 RA cases with bucillamine-induced yellow nail, mostly in Japanese medical journals. Most of these cases (90.3%) showed improvement of yellow nail after discontinuation of bucillamine, whereas lymphedema and pulmonary manifestations improved only in 30.8 and 35.0% of the patients, respectively.

[DMARDs (disease-modifying antirheumatic drugs)].

Disease-modifying antirheumatic drugs (DMARDs) have largely contributed to recent paradigm shift of rheumatoid arthritis (RA) treatment strategy. DMARDs can be indicated for all RA patients and early use of DMARDs after diagnosis of RA is recommended. Individual DMARDs have common characteristics. Understanding these characteristics is very important in treating RA. As for safety, the pattern of adverse reactions (ADRs) associated with DMARDs has been generally understood. It is necessary to select DMARDs and follow up patients with recognition of the pattern of ADRs. Regular monitoring is also essential to ensure the safety of DMARDs. This chapter deals with some major DMARDs in Japan, including methotrexate, which is indispensable in current RA treatment; salazosulfapyridine and bucillamine; tacrolimus, which is recently increasing in use; and iguratimod, which became available in 2012.

Sensitization of GSH synthesis by curcumin curtails acrolein-induced alveolar epithelial apoptosis via Keap1 cysteine conjugation: A randomized controlled trial and experimental animal model of pneumonitis.

INTRODUCTION: Epidemiological studies have reported an association between exposures to ambient air pollution and respiratory diseases, including chronic obstructive pulmonary disease (COPD). Pneumonitis is a critical driving factor of COPD and exposure to air pollutants (e.g., acrolein) is associated with increased incidence of pneumonitis. OBJECTIVES: Currently available anti-inflammatory therapies provide little benefit against respiratory diseases. To this end, we investigated the preventive role of curcumin against air pollutant-associated pneumonitis and its underlying mechanism. METHODS: A total of 40 subjects was recruited from Chengdu, China which is among the top three cities in terms of respiratory mortality related to air pollution. The participants were randomly provided either placebo or curcumin supplements for 2 weeks and blood samples were collected at the baseline and at the end of the intervention to monitor systemic markers. In our follow up mechanistic study, C57BL/6 mice (n = 40) were randomly allocated into 4 groups: Control group (saline + no acrolein), Curcumin only group (curcumin + no acrolein), Acrolein only group (saline + acrolein), and Acrolein + Curcumin group (curcumin + acrolein). Curcumin was orally administered at 100 mg/kg body weight once a day for 10 days, and then the mice were subjected to nasal instillation of acrolein (5 mg/kg body weight). Twelve hours after single acrolein exposure, all mice were euthanized. RESULTS: Curcumin supplementation, with no noticeable adverse responses, reduced circulating pro-inflammatory cytokines in association with clinical pneumonitis as positive predictive while improving those of anti-inflammatory cytokines. In the pre-clinical study, curcumin reduced pneumonitis manifestations by suppression of intrinsic and extrinsic apoptotic signaling, which is attributed to enhanced redox sensing of Nrf2 and thus sensitized synthesis and restoration of GSH, at least in part, through curcumin-Keap1 conjugation. CONCLUSIONS: Our study collectively suggests that curcumin could provide an effective preventive measure against air pollutant-enhanced pneumonitis and thus COPD.

A maxed-out liver: a case of acute-on-chronic liver failure.

A 51-year-old man from Puerto Rico with Child-Turcotte-Pugh Class C decompensated cirrhosis due to genotype 1a chronic hepatitis C was referred for worsening jaundice and diuretic-resistant ascites. He began experiencing symptoms of hepatic decompensation 5 months prior to referral with new-onset ascites and spontaneous bacterial peritonitis, evolving into diuretic-resistant ascites, increasing jaundice, and a MELD increase from 12 to 29. During his hospitalization, his MELD score increased to >40 from a rapidly increasing international normalized ratio (INR) and evolving type 1 hepatorenal syndrome. Clinically, the patient appeared quite well despite such a high MELD score. After an extensive pretransplant evaluation and exclusion of infection, he underwent successful orthotopic liver transplantation. After histologic examination of the explanted liver, he subsequently admitted to 5 months of daily use of a detoxifying supplement known as MaxOne (®), containing D-ribose- L-cysteine, consistent with a drug-induced acute-on-chronic liver failure. The use of complementary and alternative medicines and its potential for causing drug-induced liver injury and acute-on chronic liver failure requires a high index of suspicion and increased awareness among health care providers.

N-biotinyl-S-(1,2-dichlorovinyl)-L-cysteine sulfoxide as a potential model for S-(1,2-dichlorovinyl)-L-cysteine sulfoxide: characterization of stability and reactivity with glutathione and kidney proteins in vitro.

S-(1,2-Dichlorovinyl)-L-cysteine sulfoxide (DCVCS) is a reactive and potent nephrotoxic metabolite of the human trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC). Because DCVCS covalent binding to kidney proteins likely plays a role in its nephrotoxicity, in this study biotin-tagged DCVCS, N-biotinyl-DCVCS (NB-DCVCS), was synthesized, and its stability in buffer alone and in the presence of rat blood or plasma was characterized in vitro. In addition, reactivity toward GSH and covalent binding to selected model enzymes and isolated kidney proteins were characterized. The half-lives of NB-DCVCS (39.6 min) and the DCVCS (diastereomer 1, 14.4 min; diastereomer 2, 6 min) in the presence of GSH were comparable. Incubating the model enzymes glutathione reductase and malate dehydrogenase with 10 µM NB-DCVCS for 3 h at 37 °C followed by immunoblotting using antibiotin antibodies demonstrated that glutathione reductase and malate dehydrogenase were extensively modified by NB-DCVCS. When rat kidney cytosol (6 µg/µL) was incubated with NB-DCVCS (312.5 nM to 5 µM) for 3 h at 37 °C followed by immunoblotting, a concentration-dependent increase in signal with multiple proteins with different molecular weights was observed, suggesting that NB-DCVCS binds to multiple kidney proteins with different selectivity. Incubating rat kidney cytosol with DCVCS (10-100 µM) prior to the addition of NB-DCVCS (2.5 µM) reduced the immunoblotting signal, suggesting that NB-DCVCS and DCVCS compete for the same binding sites. A comparison of the stability of NB-DCVCS and DCVCS in rat blood and plasma was determined in vitro, and NB-DCVCS exhibited higher stability than DCVCS in both media. Collectively, these results suggest that NB-DCVCS shows sufficient stability, reactivity, and selectivity to warrant further investigations into its possible use as a tool for future characterization of the role of covalent modification of renal proteins by DCVCS in nephrotoxicity.

A multicentre trial of bucillamine in the treatment of early rheumatoid arthritis (SNOW study).

In this study, we enrolled early rheumatoid arthritis (RA) patients at multiple institutes who fulfilled the American Rheumatism Association 1987 revised criteria for the classification of RA, and followed the clinical results of disease-modifying anti-rheumatic drug (DMARD) treatment prospectively. With the aim of developing therapeutic guidelines using the disease activity score 28 (DAS28) as disease indices, we investigated the usefulness of bucillamine (BUC), one of the most widely used DMARDs in Japan. Eighty-one patients with early RA who had not previously been treated with DMARDs were suitable for BUC therapy as first-choice treatment. After 24 months of treatment, at least moderate improvement was seen in 87.5% of patients using the DAS28 erythrocyte sedimentation rate (ESR). After 24 months of BUC therapy, 7 patients (43.8%) met the remission criterion of DAS28 (ESR) <2.6. The 24-month BUC continuation rate was 60.5% (49/81, monotherapy + combination therapy), of which 59.2% (29/49) were on BUC monotherapy. From the efficacy and safety viewpoints alike, BUC was useful as first-choice treatment for early RA.

Efficacy and safety of additional use of tacrolimus in patients with early rheumatoid arthritis with inadequate response to DMARDs--a multicenter, double-blind, parallel-group trial.

In this trial, we investigated the safety and efficacy of tacrolimus used in addition to standard antirheumatic drugs in patients with rheumatoid arthritis. Tacrolimus 3 mg or placebo was orally administered once daily for 52 weeks in a double-blind manner to patients with early active rheumatoid arthritis receiving other disease-modifying antirheumatic drugs (DMARDs). A total of 123 patients were randomized to the tacrolimus group (61 patients) and to the placebo group (62 patients). In the tacrolimus group, 70.5% achieved a clinical response according to American College of Rheumatology (ACR) 20 criteria, whereas 45.2% in the placebo group did so (P = 0.005). The tacrolimus group also showed significant improvement in terms of the European League Against Rheumatism (EULAR) response criteria of "good or moderate" versus the placebo group (86.9 vs. 56.5%, respectively). Likewise, significantly more patients in the tacrolimus group versus the placebo group achieved remission of the Disease Activity Score in 28 joints (DAS28) (45 vs. 21%). The mean changes in the Total Sharp Score and erosion score were lower in the tacrolimus group, but the differences between the two groups were not significant. There was no significant difference between the two groups in the incidence of adverse events. Based on these results, we can conclude that the additional use of tacrolimus in patients with early rheumatoid arthritis with inadequate response to other DMARD treatments is useful, and this could become one of the treatment options for these rheumatoid arthritis patients.

Drug-induced pemphigus: A systematic review of 170 patients.

Pemphigus encompasses a rare heterogeneous group of autoimmune blistering diseases characterized by cutaneous and/or mucosal blistering. Multiple factors, such as some specific types of drugs, have been found to be involved in the induction of pemphigus. Here, we have designed a systematic review by searching PubMed/Medline and Embase databases to find the drugs, involved in pemphigus induction and exacerbation (updated on 19 August 2019). From 1856 initially found articles, 134 studies (198 patients; 170 patients in the drug-induced patients and 28 in exacerbation group) have been included. Regarding drug-induced cases, the mean age was 57.19 ± 16.9-year-old (ranged 8-105), and patients had developed pemphigus within a mean of 154.27 days. Pemphigus vulgaris (38.9%), pemphigus foliaceus (33.5%), and paraneoplastic pemphigus (3.6%) were the most common subtypes. Furthermore, penicillamine (33.1%), captopril (7.7%), and bucillamine (6.5%) were the most reported drugs related to pemphigus induction; penicillamine was associated with the most persistent disease. Regardless of disease subtype, cutaneous, mucocutaneous, and mucosal involvements were reported in 68.6%, 30.1%, and 1.3% of patients, respectively. In total, the IgG deposition in the pathological studies, being positive for autoreactive antibodies in the serum against desmoglein 3 (Dsg3), and desmoglein 1 (Dsg1), were reported in 93%, 34.9%, and 72.7% of reported patients, respectively. Regarding the management of such patients, in 75% of healed cases, treatment (mainly transient systemic and topical corticosteroids and/or azathioprine) was needed besides stopping the probable pemphigus-inducing culprit drug, while drug cessation was enough to control the disease in 25%. As the outcomes, the lesions in 129 of 147 (87.8%) patients had been healed, while in 18 (12.2%), no healing was reported; fifteen out of 18 had died. In conclusion, some specific groups of treatments can induce pemphigus, including penicillamine, captopril, and bucillamine; despite the similar clinical and pathological manifestations to classical pemphigus, most of the cases are less severe and have a better prognosis.

Efficacy and safety of intravenous stronger neo-minophagen C and S-adenosyl-L-methionine in treatment of pregnant woman with chronic hepatitis B: a pilot study.

BACKGROUND: There have been no studies evaluating the efficacy and potential risks of stronger neo-minophagen C (SNMC) in pregnant women with chronic hepatitis B CHB. MATERIAL/METHODS: A total of 36 pregnant women with CHB, but without severe complications, were randomized to intravenously receive SNMC or S-adenosyl-L-methionine (SAM) daily for 4 weeks or until birth. Normalization of serum alanine transaminase (ALT) and aspartate transaminase (AST) levels and changes in ALT and AST levels from baseline were determined. All neonates were regularly examined for up to 1 year. RESULTS: Treatment with SNMC and SAM resulted in normalization of ALT levels at 4 weeks in 64.3% and 21.4% of patients, respectively (OR=6.60, 95% CI: 1.23-35.44, P=0.0540). SNMC and SAM significantly decreased ALT (from 558.28+/-390.24 to 47.07+/-24.94 IU/L, P<0.0001 and from 525.61+/-483.87 to 117.43+/-85.44 IU/L, P=0.0041, respectively) and AST (from 419.72+/-409.49 to 38.14+/-18.87 IU/L, P=0.0016, and from 510.78+/-621.58 to 79.93+/-63.25 IU/L, P=0.0152, respectively) at 4 weeks relative to baseline values. Hypokalemia was observed in 4 SNMC-treated patients and in 2 SAM-treated patients and hypernatremia in 3 SNMC-treated and in 3 SAM-treated patients. Hypertension was observed in 1 SNMC-treated patient. There was no significant difference in the volume of amniotic fluid or meconium between SNMC-treated and SAM-treated groups. All the neonates were physically normal at birth and at the 1-year follow-up examination. CONCLUSIONS: Both SNMC and SAM improve liver function, with SNMC appearing more effective, in pregnant women with chronic hepatitis B without impact on fetal development.

Bucillamine-induced gigantomastia with galactorrhea and hyperprolactinaemia.

Gigantomastia is characterised by excessive breast growth and can occur as a rare, drug-induced adverse event. D-penicillamine is the most frequent cause of drug-induced gigantomastia. Only one case of gigantomastia due to bucillamine, an analogue of D-penicillamine, has been reported so far. We herein report a case of bucillamine-induced gigantomastia presenting with acute enlargement of the bilateral breasts and accessory breast tissue in the axillae 7 months after the start of bucillamine therapy. Awareness about this rare adverse event is important since bucillamine is still widely used in Japan and Korea.

Bucillamine-induced Pneumonitis in a Patient with Rheumatoid Arthritis-associated Interstitial Pneumonia: A Case Report and Review of the Literature.

An 81-year-old woman with rheumatoid arthritis (RA) who had been treated with bucillamine presented with dyspnea. Computed tomography of the chest showed ground-glass opacities and consolidations in both lungs and honeycombing in both basal lung areas. An elevation of the serum Krebs von den Lungen-6 level and hypoxemia were seen. Lymphocytosis with a decreased CD4/CD8 ratio was seen in the bronchoalveolar lavage fluid. A transbronchial lung biopsy specimen showed organizing pneumonia. Based on a diagnosis of bucillamine-induced pneumonitis (BIP) with RA-associated pre-existing interstitial pneumonia, she was successfully treated with the cessation of bucillamine and systemic corticosteroid therapy. The risk factors and prognosis of BIP are discussed.

Evidence of a novel docetaxel sensitizer, garlic-derived S-allylmercaptocysteine, as a treatment option for hormone refractory prostate cancer.

The recent introduction of docetaxel in the treatment of hormone refractory prostate cancer (HRPC) has made a small but significant impact on patient survival. However, its effect is limited by intolerance and resistance. The aim of our study was to investigate if the garlic-derived compound, S-allylmercaptocysteine (SAMC), was able to act as a docetaxel sensitizing agent. First, the effect of SAMC on docetaxel sensitivity was examined on 3 HRPC cell lines by colony forming assay. We found that SAMC increased the efficacy of docetaxel on colony forming inhibition by 9-50% compared to single agent treatment. Second, using the HRPC CWR22R nude mice model, we found that the combination of SAMC and docetaxel was 53% more potent than docetaxel alone (p = 0.037). In addition, there was no additive toxicity in the mice treated with the combination therapy evidenced by histological and functional analysis of liver, kidney and bone marrow. These results suggest that SAMC is able to increase the anticancer effect of docetaxel without causing additional toxic effect in vivo. Third, flow cytometry and Western blotting analysis on HRPC cell lines demonstrated that SAMC promoted docetaxel-induced G2/M phase cell cycle arrest and apoptotic induction. In addition, immunohistochemistry on CWR22R xenograft revealed a suppression of Bcl-2 expression and upregulation of E-cadherin in the SAMC and docetaxel treated animals. These results suggest that SAMC may promote docetaxel-induced cell death through promoting G2/M cell cycle arrest and apoptosis. Our study implies a potential role for SAMC in improving docetaxel based chemotherapy for the treatment of HRPC.

Excess dietary L-cysteine causes lethal metabolic acidosis in chicks.

A 72-h time-course study was conducted to elucidate the physiological mechanism underlying cysteine (Cys) toxicity in chicks beginning at 8-d posthatch. Biochemical markers quantified in plasma and liver samples collected from chicks receiving 30 g/kg excess dietary Cys were compared with baseline measurements from chicks receiving an unsupplemented corn-soybean meal diet over a 72-h feeding period. Concomitant with chick mortality were indices of acute metabolic acidosis, including a rapid increase (P < 0.001) in anion gap that resulted from a reduction (P < 0.001) in plasma HCO(3)(-) of approximately 40% and a 2.8-fold increase (P < 0.001) in plasma sulfate in chicks receiving excess Cys. Additionally, provision of 30 g/kg excess Cys resulted in a 1.5-fold increase (P < 0.05) in hepatic oxidized glutathione compared with the 0-h control time-point. Excess dietary Cys did not affect plasma free Met, but plasma free Cys increased (P < 0.05) from 89 to 107 mumol/L at 12 h and remained elevated through 36 h. Strikingly, ingestion of 30 g/kg excess Cys caused more than a doubling (P < 0.001) of plasma free cystine, the oxidized form of Cys, beginning 12 h after initiating the study, and it remained elevated throughout the 72-h feeding period. Taken together, these data suggest that ingestion of 30 g/kg excess l-Cys causes both acute metabolic acidosis and oxidative stress in young chicks when fed a nutritionally adequate, corn-soybean meal diet.