Lysophosphatidic acid receptors 2 and 3 regulate erythropoiesis at different hematopoietic stages.

Hematopoiesis, the complex developmental process that forms blood components and replenishes the blood system, involves multiple intracellular and extracellular mechanisms. We previously demonstrated that lysophosphatidic acid (LPA), a lipid growth factor, has opposing regulatory effects on erythrocyte differentiation through activation of LPA receptors 2 and 3; yet the mechanisms underlying this process remain unclear. In this study, LPA2 is observed that highly expressed in common myeloid progenitors (CMP) in murine myeloid cells, whereas the expression of LPA3 displaces in megakaryocyte-erythroid progenitors (MEP) of later stage of myeloid differentiation. Therefore, we hypothesized that the switching expression of LPA2 and LPA3 determine the hematic homeostasis of mammalian megakaryocytic-erythroid lineage. In vitro colony-forming unit assays of murine progenitors reveal that LPA2 agonist GRI reduces the erythroblast differentiation potential of CMP. In contrast, LPA3 agonist OMPT increases the production of erythrocytes from megakaryocyte-erythrocyte progenitor cells (MEP). In addition, treatment with GRI reduces the erythroid, CMP, and MEP populations in mice, indicating that LPA2 predominantly inhibits myeloid differentiation at an early stage. In contrast, activation of LPA3 increases the production of terminally differentiated erythroid cells through activation of erythropoietic transcriptional factor. We also demonstrate that the LPA3 signaling is essential for restoration of phenylhydrazine (PHZ)-induced acute hemolytic anemia in mice and correlates to erythropoiesis impairment of Hutchinson-Gilford progeria Symptom (HGPS) premature aging expressed K562 model. Our results reveal the distinct roles of LPA2 and LPA3 at different stages of hematopoiesis in vivo, providing potentiated therapeutic strategies of anemia treatment.

In vitro Multistage Malaria Transmission Blocking Activity of Selected Malaria Box Compounds.

PURPOSE: Continuous efforts into the discovery and development of new antimalarials are required to face the emerging resistance of the parasite to available treatments. Thus, new effective drugs, ideally able to inhibit the Plasmodium life-cycle stages that cause the disease as well as those responsible for its transmission, are needed. Eight compounds from the Medicines for Malaria Venture (MMV) Malaria Box, potentially interfering with the parasite polyamine biosynthesis were selected and assessed in vitro for activity against malaria transmissible stages, namely mature gametocytes and early sporogonic stages. METHODS: Compound activity against asexual blood stages of chloroquine-sensitive 3D7 and chloroquine-resistant W2 strains of Plasmodium falciparum was tested measuring the parasite lactate dehydrogenase activity. The gametocytocidal effect was determined against the P. falciparum 3D7elo1-pfs16-CBG99 strain with a luminescent method. The murine P. berghei CTRP.GFP strain was employed to assess compounds activities against early sporogonic stage development in an in vitro assay simulating mosquito midgut conditions. RESULTS: Among the eight tested molecules, MMV000642, MMV000662 and MMV006429, containing a 1,2,3,4-tetrahydroisoquinoline-4-carboxamide chemical skeleton substituted at N-2, C-3 and C-4, displayed multi-stage activity. Activity against asexual blood stages of both strains was confirmed with values of IC50 (50% inhibitory concentration) in the range of 0.07-0.13 µM. They were also active against mature stage V gametocytes with IC50 values below 5 µM (range: 3.43-4.42 µM). These molecules exhibited moderate effects on early sporogonic stage development, displaying IC50 values between 20 and 40 µM. CONCLUSION: Given the multi-stage, transmission-blocking profiles of MMV000642, MMV000662, MMV006429, and their chemical characteristics, these compounds can be considered worthy for further optimisation toward a TCP5 or TCP6 target product profile proposed by MMV for transmission-blocking antimalarials.

Triterpene derivative improves the renal function of streptozotocin-induced diabetic rats: a follow-up study on maslinic acid.

Introduction: Reports indicate that oral administration of plant-derived maslinic acid (MA) exhibits hypoglycemic and renoprotective effects in streptozotocin (STZ)-induced diabetic rats. Challenges with triterpenes such as MA include low bioavailabilty which affects treatment efficacy in experimental animals. The goal of this study was to synthesize the MA derivative phenylhydrazine (PH-MA) in an effort to improve the efficacy of MA. Methods: Separate groups of non-diabetic and STZ-induced diabetic rats (n = 6) were anesthetized and the jugular vein cannulated for the infusion of 0.077 M NaCl at 9 mL/h. The bladder was catheterized for collection the urine samples every 30 min. After 30.5 h equilibration period, consecutive 30 min urine collections were made over the subsequent 4 h of 1 h control, 1.5 h treatment, and 1.5 h recovery periods. PH-MA (22 µg/h) and MA (90 µg/h) were added during the treatment periods for analysis of proximal tubular Na+ handling, plasma aldosterone and arginine vasopressin in male Sprague-Dawley rats. Results: Intravenous infusion of PH-MA (22 µg/h) and MA (90 µg/h) significantly (p Ë‚ .05) increased Na+ output, fractional excretion of Na+ (FENa) and lithium (FELi). Interestingly, like MA, PH-MA significantly (p Ë‚ .05) increased glomerular filtration rate (GFR) over the treatment period and decreased plasma aldosterone levels. Our findings indicate that PH-MA inhibited sodium reabsorption in the proximal and distal tubule as shown by increased FENa and low plasma aldosterone levels, respectively. Conclusions: PH-MA is, therefore, a promising multitarget antidiabetic agent that may ameliorate kidney function of diabetic patients at a dose four times lower than the parent compound (MA).

Efficacy of topical 5-aminosalicylate monotherapy in patients with ulcerative proctitis with skip inflammation.

BACKGROUND AND AIM: In some patients with ulcerative proctitis (UP), skip inflammation is noted in the right side of the colon, but little is known about its clinical course. The aim of this study was to evaluate the clinical course of UP with skip inflammation and the efficacy of topical 5-aminosalicylate (5-ASA) monotherapy. METHODS: This study reviewed the data of 388 patients with an initial diagnosis of UP from January 2005 to October 2015. This study matched each UP patient with skip inflammation 1:2 with controls who had UP without skip inflammation; to reduce bias, this study matched the controls with the cases by age, gender, and initial disease activity. RESULTS: During the follow-up period (median: 69.5 months), the overall progression rates for the control group (n = 192) and the skip inflammation group (n = 96) were 24.0% and 32.9% at 10 years, respectively (log-rank P = 0.71). In the skip inflammation group, the progression rates were not significantly different between the 5-ASA combination group and the topical group, 33.4% and 26.6% at 10 years, respectively (log-rank P = 0.96). The overall acute exacerbation rates for the control and skip inflammation groups were 17.2% and 26.8% at 10 years, respectively (log-rank P = 0.68). In the skip inflammation group, the exacerbation rates were also not significantly different between the combination and topical treatment groups, 26.6% and 23.6% at 10 years, respectively (log-rank P = 0.88). CONCLUSION: The clinical course of UP with skip inflammation was not different from that of typical UP, and topical 5-ASA monotherapy for maintaining remission was as effective as 5-ASA combination therapy irrespective of the presence of skip lesions.

5-aminosalicylic acid agents for prevention of recurrent diverticulitis: A systematic review and meta-analysis.

BACKGROUND AND AIM: Prevalence of colonic diverticulosis is increasing worldwide with age, and up to 25% of patients who have colonic diverticulosis might experience diverticulitis. However, a definitive approach of preventing recurrent diverticulitis remains unknown. 5-aminosalicylic acid (5-ASA) agents are anti-inflammatory agents and have been used to prevent recurrent diverticulitis, and there have been some randomized clinical trials (RCTs). However, the efficacy results for secondary prevention in uncomplicated diverticulitis differed across studies. Our aim was to clarify the efficacy and safety of 5-ASA agents in the prevention of recurrent diverticulitis. METHODS: We searched MEDLINE, EMBASE, Web of Science, and the Cochrane library with no language restrictions. Two reviewers independently assessed and selected RCTs. The data were pooled using a random effect model and were presented in the pooled risk ratio (RR) and 95% confidence interval (CI). Cochrane's Q and I-squared statistics were used to assess heterogeneity. The protocol was registered at PROSPERO. RESULTS: Seven articles with eight RCTs from 329 potentially relevant articles were included. 5-ASA agents were not superior to controls in preventing recurrent diverticulitis (RR 0.86, 95% CI 0.63 to 1.17, I2  = 60%) and the incidence of adverse events was not different between 5-ASA agents and controls (RR 0.97, 95% CI 0.84 to 1.11, I2  = 45%). However, some included studies were few in number of participants and substantial risk of bias. CONCLUSIONS: 5-aminosalicylic acid agents were not associated with prevention of recurrent diverticulitis.

Combined Parthenolide and Balsalazide Have Enhanced Antitumor Efficacy Through Blockade of NF-κB Activation.

Balsalazide is a colon-specific prodrug of 5-aminosalicylate that is associated with a reduced risk of colon cancer in patients with ulcerative colitis. Parthenolide, a strong NF-κB inhibitor, has recently been demonstrated to be a promising therapeutic agent, promoting apoptosis of cancer cells. In the current study, the antitumor effect of balsalazide combined with parthenolide in human colorectal cancer cells and colitis-associated colon cancers (CAC) was investigated. The results demonstrate that the combination of balsalazide and parthenolide markedly suppress proliferation, nuclear translocation of NF-κB, IκB-α phosphorylation, NF-κB DNA binding, and expression of NF-κB targets. Apoptosis via NF-κB signaling was confirmed by detecting expression of caspases, p53 and PARP. Moreover, treatment of a CAC murine model with parthenolide and balsalazide together resulted in significant recovery of body weight and improvement in histologic severity. Administration of parthenolide and balsalazide to CAC mice also suppressed carcinogenesis as demonstrated by uptake of 18F-fluoro-2-deoxy-D-glucose (FDG) using micro-PET/CT scans. These results demonstrate that parthenolide potentiates the efficacy of balsalazide through synergistic inhibition of NF-κB activation and the combination of dual agents prevents colon carcinogenesis from chronic inflammation. IMPLICATIONS: This study represents the first evidence that combination therapy with balsalazide and parthenolide could be a new regimen for colorectal cancer treatment. Mol Cancer Res; 15(2); 141-51. ©2016 AACR.

The macrophage contribution to stress erythropoiesis: when less is enough.

Although the importance of native bone marrow and spleen macrophages in enhancing baseline and stress erythropoiesis has been emphasized over several decades, their kinetic and phenotypic changes during a variety of stress responses have been unclear. Furthermore, whether monocyte-derived recruited macrophages can functionally substitute for inadequate or functionally impaired native macrophages has been controversial and seem to be not only tissue- but also stress-type dependent. To provide further insight into these issues, we made detailed observations at baseline and post-erythroid stress (E-stress) in 2 mouse models with genetically depressed macrophage numbers and compared them to their controls. We documented that, irrespective of the stress-induced (hemolytic or post-erythropoietin [Epo]) treatment, only native CD11b(lo) splenic macrophages expand dramatically post-stress in normal mice without significant changes in the monocyte-derived CD11b(hi) subset. The latter remained a minority and did not change post-stress in 2 genetic models lacking either Spi-C or VCAM-1 with impaired native macrophage proliferative expansion. Although CD11b(lo) macrophages in these mice were one-fifth of normal at their peak response, surprisingly, their erythroid response was not compromised and was similar to controls. Thus, despite the prior emphasis on numerical macrophage reliance to provide functional rescue from E-stress, our data highlight the importance of previously described non-macrophage-dependent pathways activated under certain stress conditions to compensate for low macrophage numbers.

Anti-hyperbilirubinemic and wound healing activity of aqueous extract of Calotropis procera leaves in Wistar rats.

AIMS: The aim of this study was to evaluate the bilirubin lowering and wound healing property of aqueous extract of Calotropis procera (AECP) leaves in Wistar rats. MATERIALS AND METHODS: Albino Wistar rats of either sex were used for the study. Bilirubin lowering property of C. procera leaves was evaluated using phenylhydrazine and paracetamol as inducing agents followed by measuring the concentration of serum total bilirubin in hyperbilirubinemic rats. Wound healing property was evaluated using incision and excision models by measuring tensile breaking strength, percentage wound contractions, and epithelization days, respectively. STATISTICAL ANALYSIS: Statistical comparison between groups in each experiment was done with one-way analysis of variance followed by Dunnett's test. RESULTS: AECP showed a significant (P < 0.05) decrease in concentrations of serum total bilirubin in hyperbilirubinemic rats as well as significant (P < 0.05) increase in breaking strength and percentage wound contractions with decreased epithelization period when compared to control groups. CONCLUSIONS: AECP showed significant bilirubin lowering and wound healing property in Wistar rats.

Pharmacokinetic comparison of ferulic acid in normal and blood deficiency rats after oral administration of Angelica sinensis, Ligusticum chuanxiong and their combination.

Radix Angelica Sinensis (RAS) and Rhizome Ligusticum (RLC) combination is a popular herb pair commonly used in clinics for treatment of blood deficiency syndrome in China. The aim of this study is to compare the pharmacokinetic properties of ferulic acid (FA), a main bioactive constituent in both RAS and RLC, between normal and blood deficiency syndrome animals, and to investigate the influence of compatibility of RAS and RLC on the pharmacokinetic of FA. The blood deficiency rats were induced by injecting 2% Acetyl phenylhydrazine (APH) on the first day, every other day, to a total of five times, at the dosage of 100, 50, 50, 30, 30 mg/kg body mass, respectively. Quantification of FA in rat plasma was achieved by using a simple and rapid HPLC method. Plasma samples were collected at different time points to construct pharmacokinetic profiles by plotting drug concentration versus time, and estimate pharmacokinetic parameters. Between normal and blood deficiency model groups, both AUC((0-) (t) ()) and C(max) of FA in blood deficiency rats after RAS-RLC extract administration increased significantly (P < 0.05), while clearance (CL) decreased significantly. Among three blood deficiency model groups, t(1/2α), V(d), AUC((0-) (t) ()) and AUC((0-∞)) all increased significantly in the RAS-RLC extract group compared with the RAS group. The results indicated that FA was absorbed better and eliminated slower in blood deficiency rats; RLC could significantly prolong the half-life of distribution, increase the volume of distribution and the absorption amount of FA of RAS in blood deficiency rats, which may be due to the synergic action when RAS and RLC were used together to treat blood deficiency syndrome.

Plasmodium vinckei: infectivity of arteether-sensitive and arteether-resistant parasites in different strains of mice.

Malaria is one of the most lethal parasitic infections in the world. The lethality of the parasite depends on the rate of multiplication of the parasite within host erythrocytes. Different strains of the malaria parasite often respond in a different way to the same strain of mice or vice versa. In the present study, we investigated the course of infection of the arteether-sensitive and arteether-resistant Plasmodium vinckei parasites in Swiss albino AKR (inbred) and AJ (outbred) mice. The higher parasite burden and mortality were observed in the sensitive parasite-infected mice, whereas the infection with the resistant parasite was non-lethal. Resistant parasite-infected mice developed a moderate level of parasitemia that decreased gradually throughout the infection. The microscopic examination suggests that the resistant parasite invades reticulocytes more efficiently than normocytes, regardless of the mouse strain examined. Since the reticulocytes are rare in blood circulation, it limits the increase in parasite proliferations, while arteether-sensitive parasites can invade both mature normocytes and reticulocytes, resulting in the mortality of the mice. However, treatment with phenylhydrazine in Swiss mice results in reticulocytosis, which transforms the non-lethal resistant parasites to produce lethal infections. Our findings demonstrate that the characteristic response during infections with the arteether-resistant strain is dependent on the availability of reticulocytes in peripheral blood circulation. We can use this model for identifying the interaction between host and artemisinin derivative-resistant parasites.

Safety and efficacy of a new 3.3 g b.i.d. tablet formulation in patients with mild-to-moderately-active ulcerative colitis: a multicenter, randomized, double-blind, placebo-controlled study.

OBJECTIVES: To evaluate the safety and efficacy of a new twice-daily balsalazide disodium 1.1 g tablet dosing regimen (6.6 g/day, three tablets twice daily) for the treatment of mild-to-moderately-active ulcerative colitis (UC). METHODS: In a double-blind, multicenter study patients with symptoms of acute UC and a baseline Modified Mayo Disease Activity Index (MMDAI) score between 6 and 10, inclusive, with a subscale rating of > or =2 for both rectal bleeding and mucosal appearance were randomized to receive 3.3 g of balsalazide or placebo tablets twice daily for 8 weeks. The primary end point was the proportion of patients achieving clinical improvement (> or =3 point improvement in MMDAI) and improvement in rectal bleeding (> or =1 point improvement) at 8 weeks. Safety assessments were conducted from baseline through 2-weeks post-treatment. RESULTS: A total of 249 patients (166 balsalazide, 83 placebo) received at least 1 dose of study medication. The mean MMDAI score at baseline was 7.9; 62% of patients had a score > or =8.0 (moderate disease). A significantly larger proportion of patients achieved clinical improvement and improvement in rectal bleeding in the balsalazide group vs. the placebo group (55 vs. 40%, P=0.02). The most common adverse events reported were worsening of UC and headache; both were reported more often in the placebo group. CONCLUSIONS: Balsalazide disodium 1.1 g tablets administered as 3.3 g twice daily are effective, well tolerated and significantly better than placebo for improving signs and symptoms of mild-to-moderately-active UC. This new formulation with a reduced pill and dosing burden offers the potential to improve convenience and compliance in patients with active UC.

Comparative effect of melatonin and vitamin E on phenylhydrazine-induced toxicity in the spleen of Funambulus pennanti.

Phenylhydrazine (PHZ) oxidation resulting in free iron release followed by free radical generation has increased frequency of cancer. This study aims towards the dose-dependent response of PHZ and the role of melatonin in comparison with vitamin E following PHZ-induced toxicity within the lymphoid tissue (spleen) of Indian tropical seasonal breeder, Funambulus pennanti, during reproductively active phase. An increase in the damages in terms of lipid peroxidation (LPO), apoptosis percentage, and splenomegaly was observed following different doses of PHZ treatment, i.e., 0.025, 0.5, and 1 mg/100 g body weight (b.wt.), where dose of 1 mg/100 g b.wt. showed more significant damages. Both melatonin (0.5 mg/100 g b.wt.) and vitamin E (1 mg/100 g b.wt.) administration ameliorated oxidative damages of 1 mg/100 g b.wt. PHZ-treated group. Melatonin altered PHZ-induced responses significantly to a greater degree than vitamin E as evidenced by LPO status, SOD activity, and ABTS radical cation scavenging activity of antioxidants. Thus, melatonin might be able to restrict carcinogenic property of PHZ-induced oxidative stress by protecting macromolecules of the cell from harmful effects of PHZ and instead preserving cell viability.

[Experimental modelling of toxic encephalopathy].

The article covers problem of experimental biologic modelling of toxic encephalopathies. The authors represent major methodic approaches to modelling, criteria and methods to evaluate pathologic condition of CNS, present results of own research in creating models of toxic encephalopathies caused by metallic mercury and vinylchloride inhalation.

Balsalazide plus high-potency probiotic preparation (VSL[sharp]3) in the treatment of acute mild-to-moderate ulcerative colitis and uncomplicated diverticulitis of the colon.

Balsalazide is a 5-amino salicylic acid prodrug well-tolerated and effective in treating acute ulcerative colitis. VSL[sharp]3, a high-potency probiotic mixture, has proved to be effective in preventing flare-ups of chronic pouchitis and in obtaining remission of mild-to-moderate ulcerative colitis. Recent studies found the association of low-dose balsalazide/VLS no. 3 effective in treating mild-to-moderate ulcerative colitis and in preventing the recurrence of uncomplicated diverticulitis of the colon. In this paper, the framework for using this association to treat ulcerative colitis or to prevent the recurrence of colonic diverticulitis is reviewed, and 2 studies on this therapeutic approach are briefly summarized.

A two-stage decision analysis to assess the cost of 5-aminosalicylic acid failure and the economics of balsalazide versus mesalamine in the treatment of ulcerative colitis.

Ulcerative colitis (UC) is a costly disease, especially if not properly treated. Epidemiologic studies have shown that many patients progress in one year from initial treatment with prednisone to expensive colonectomy surgery if the UC is not managed with drug therapy. A two-stage decision analysis was conducted to (1) estimate the cost of a 5-aminosalicylic acid (5-ASA) treatment failure using the treatment guidelines recommended by the American College of Gastroenterology and (2) incorporate the cost of a 5-ASA treatment failure to determine which oral 5-ASA agent results in cost minimization and cost effectiveness. The analysis was conducted from the payer perspective, incorporating results from clinical trials directly comparing oral balsalazide capsules and a specific formulation of oral mesalamine. Health care costs related to UC for an oral 5-ASA failure is greater than dollar 11,500 on average in the first six months after therapy. Patients treated with balsalazide capsules had 16% lower total direct health care costs, 32% better outcomes (days without symptoms or steroids), and 37% greater cost effectiveness compared with patients treated with a specific formulation of oral mesalamine. Coordinated efforts should be taken to avoid the cost and morbidity associated with 5-ASA treatment failures.

Treatment of ulcerative colitis with oral mesalamine: advances in drug formulation, efficacy expectations and dose response, compliance, and chemoprevention.

Sulfasalazine, olsalazine, balsalazide, delayed-release mesalamine, controlled-release mesalamine, mesalamine pellets, and Multi-Matrix System mesalamine are effective first-line therapies for the treatment of mildly to moderately active ulcerative colitis and for subsequent maintenance of remission. For induction therapy it is unclear if there is a dose response above 1.5 g, and for maintenance therapy existing data do not support a dose response above 1.5 g. Sulfasalazine has more frequent side effects than olsalazine, balsalazide, and mesalamine formulations. Once-daily dosing with multi-matrix system mesalamine 1.2 g tablets may lead to optimal compliance. Mesalamine >/= 1.2 g and sulfasalazine >/= 2 g reduce the risk of colorectal cancer in patients with ulcerative colitis. Drug formulations, efficacy expectations and dose response, toxicity expectations, compliance considerations, and chemoprevention considerations are reviewed.

Signals for stress erythropoiesis are integrated via an erythropoietin receptor-phosphotyrosine-343-Stat5 axis.

Anemia due to chronic disease or chemotherapy often is ameliorated by erythropoietin (Epo). Present studies reveal that, unlike steady-state erythropoiesis, erythropoiesis during anemia depends sharply on an Epo receptor-phosphotyrosine-343-Stat5 signaling axis. In mice expressing a phosphotyrosine-null (PY-null) Epo receptor allele (EpoR-HM), severe and persistent anemia was induced by hemolysis or 5-fluorouracil. In short-term transplantation experiments, donor EpoR-HM bone marrow cells also failed to efficiently repopulate the erythroid compartment. In each context, stress erythropoiesis was rescued to WT levels upon the selective restoration of an EpoR PY343 Stat5-binding site (EpoR-H allele). As studied using a unique primary culture system, EpoR-HM erythroblasts exhibited marked stage-specific losses in Epo-dependent growth and survival. EpoR-H PY343 signals restored efficient erythroblast expansion, and the selective Epo induction of the Stat5 target genes proviral integration site-1 (Pim-1) and oncostatin-M. Bcl2-like 1 (Bcl-x), in contrast, was not significantly induced via WT-EpoR, EpoR-HM, or EpoR-H alleles. In Kit+ CD71+ erythroblasts, EpoR-PY343 signals furthermore enhanced SCF growth effects, and SCF modulation of Pim-1 kinase and oncostatin-M expression. In maturing Kit- CD71+ erythroblasts, oncostatin-M exerted antiapoptotic effects that likewise depended on EpoR PY343-mediated events. Stress erythropoiesis, therefore, requires stage-specific EpoR-PY343-Stat5 signals, some of which selectively bolster SCF and oncostatin-M action.

[Heme oxygenase induction in rat heart and vessels and peroxidative resistance of erythrocytes during hemolytic anemia development].

The hemolytic anemia development caused by phenylhydrazine injection (7 mg/100 g b.w.) was shown to be caused by the decreasing of both catalase activity and glutathione content in erythrocytes, and by the increasing of spontaneouse hemolysis level of these cells in blood stream. The increasing of heme oxygenase activity and TBA-active products in rat heart and vessels were revealed 24 hrs after phenylhydrazine injection. Possible mechanisms of heme oxygenase-1 induction under hypoxia as response to the hemolytic anemia development and it's role in defense of the cells from damage are discussed.

Anemia and impaired stress-induced erythropoiesis in aceruloplasminemic mice.

Ceruloplasmin (Cp) is an abundant, copper-containing plasma protein with an important role in iron homeostasis. Patients with hereditary Cp deficiency have iron deposits in liver and other organs, consistent with impaired iron flux. The mild anemia reported in some patients suggests a possible role for Cp in iron delivery to red cell precursors during erythropoiesis. To investigate this function of Cp, we determined the hematologic parameters in Cp-deficient mice under normal conditions and after erythropoiesis-inducing stress. Cp(-/-) mice have below normal hematocrit, red cell hemoglobin and volume, and serum iron. Red cell number and turnover and reticulocyte counts were identical in Cp(-/-) and Cp(+/+) mice. Thus, Cp(-/-) have mild microcytic, hypochromic anemia consistent with normal red cell formation but defective iron availability. Cp(-/-) and Cp(+/+) mice subjected to phenylhydrazine-induced hemolytic anemia exhibited identical decreases in hematologic parameters, but Cp(-/-) mice showed diminished recovery after removal of the stress. Administration of purified human Cp or iron-saturated transferrin to Cp(-/-) mice partially restored hemoglobin formation in reticulocytes. The mild anemia in Cp(-/-) mice and the diminished response to stress may reflect inefficient recycling of iron between the reticuloendothelial and erythropoietic systems. Our findings suggest a role for Cp in erythropoiesis by providing sufficient iron to the erythroid tissue and that the requirement for Cp is raised after erythropoietic stress.

[Metabolism of heme and hemeproteins and some indices of the antioxidant system in rat erythrocytes and tissues under anemia caused by phenylhydrazine]. / Metabolizm hemu ta hemoproteïniv i deiaki pokaznyky antioksydantnoï sistemy v erytrotsytakh i tkanynakh shchuriv pry fenilhidrazynovii anemiï.

The decrease of activity of several antioxidant enzymes in erythrocytes in the first hours after injection of phenylhydrazine to rats (7 mg per 100 g body weight) was found to be accompanied by accumulation of heme-containing compounds in rat serum and appearance of free heme in liver and decrease of cytochrome P450 content. Tissue-specific features of dynamics of activity of enzymes studied and reduced glutathione content were revealed, that might be caused by differences in total and free heme content in these organs. The role of key enzymes of heme biosynthesis and degradation in adaptation of metabolism under phenylhydrazine action is discussed.