Effects of Zinc Supplementation on Metabolomic Profiles in Tanzanian Infants: A Randomized Trial.

BACKGROUND: Provision of zinc supplementation to young children has been associated with reduced infectious morbidity and better growth outcomes. However, the metabolic pathways underlying these outcomes are unclear, and metabolomic data from humans undergoing zinc supplementation, particularly infants, are generally lacking. OBJECTIVES: This study aimed to examine the effect of zinc supplementation on metabolic profiles in Tanzanian infants aged 6 wk and 6 mo. METHODS: Blood samples were collected at age 6 wk and 6 mo from 50 Tanzanian infants who were enrolled in a randomized placebo-controlled trial of zinc supplementation (5 mg oral daily). Metabolomic analysis using an ultrahigh-performance liquid chromatography/tandem mass spectroscopy platform was performed to identify potential metabolomic profiles and biomarkers associated with zinc supplementation. Principal component analysis (PCA) was used to summarize metabolomic data from all samples. Two-way repeated measures analysis of variance with compound symmetry covariance structures were used to compare metabolome levels over time between infants in the 2 treatment arms. RESULTS: In PCA, the samples tended to be more separated by child age (6 wk compared with 6 mo) than by zinc supplementation status. We found that zinc supplementation affected a variety of metabolites associated with amino acid, lipid, nucleotide, and xenobiotic metabolism, including indoleacetate in the tryptophan metabolism pathway; 3-methoxytrosine and 4-hydrxoyphenylphruvate in the tyrosine pathway; eicosanedioate, 2-aminooctanoate, and N-acetyl-2-aminooctanoate in the fatty acid pathway; and N6-succinyladenosine in the purine metabolism pathway. Compared to the relatively small number of metabolites associated with zinc supplements, many infant metabolites changed significantly from age 6 wk to 6 mo. CONCLUSIONS: Zinc supplementation, despite having overall clinical benefits, appears to induce limited metabolomic changes in blood metabolites in young infants. Future larger studies may be warranted to further examine metabolic pathways associated with zinc supplementation. The parent trial was registered at clinicaltrials.gov as NCT00421668.

Zinc supplementation in patients with acute myocardial infarction.

This single-centre prospective feasibility study (UMIN000030232) evaluated whether zinc supplementation was safe and effective for improving outcomes among patients with acute myocardial infarction (AMI). Within 24 h after successful primary percutaneous coronary intervention, consenting patients with AMI were randomly assigned 1:1 to receive conventional treatment (conventional treatment group) or conventional treatment plus zinc acetate supplementation (zinc supplementation group). The two groups were compared in terms of major adverse cardiovascular events (MACE), and scar size, which was evaluated using cardiac magnetic resonance imaging (CMR) at 4 weeks after discharge. A total of 56 patients underwent randomization (with 26 assigned to the zinc supplementation group and 27 to the conventional treatment group). The two groups had generally similar laboratory findings and clinical characteristics. The two groups also had similar lengths of hospital stay and rates of MACE. Forty of the 53 patients underwent CMR and it revealed that % core zone was numerically lower in the zinc supplementation group than in the conventional treatment group (9.3 ± 6.9% vs. 14.2 ± 9.1%, P = 0.07). This small single-centre study failed to detect a significant reduction in mid-term MACE after AMI among patients who received zinc supplementation.

Severe copper deficiency anemia caused by zinc supplement use.

Copper deficiency is an uncommon condition primarily affecting the hematologic and neurologic systems. We report a unique case of severe anemia in a patient with copper deficiency caused by zinc supplement use.

Can Zinc Supplementation Attenuate High Fat Diet-Induced Non-Alcoholic Fatty Liver Disease?

The pathogenesis of non-alcoholic fatty liver disease (NAFLD), the most prevalent chronic liver disease, is associated with zinc deficiency. Previous studies show zinc supplementation improves steatosis and glucose metabolism, but its therapeutic effects in patients with established NAFLD remain unclear. We developed an in vivo model to characterize the effects of zinc supplementation on high-fat diet (HFD) induced NAFLD and hypothesized that the established NAFLD would be attenuated by zinc supplementation. Male C57BL/6J mice were fed a control diet or HFD for 12 weeks. Mice were then further grouped into normal and zinc-supplemented diets for 8 additional weeks. Body composition and glucose tolerance were determined before and after zinc supplementation. At euthanasia, plasma and liver tissue were collected for characterization and downstream analysis. As expected, 12 weeks of HFD resulted in reduced glucose clearance and altered body composition. Eight weeks of subsequent zinc supplementation did not alter glucose handling, plasma transaminases, steatosis, or hepatic gene expression. Results from our model suggest 8-week zinc supplementation cannot reverse established NAFLD. The HFD may have caused NAFLD disease progression beyond rescue by an 8-week period of zinc supplementation. Future studies will address these limitations and provide insights into zinc as a therapeutic agent for established NAFLD.

Effectiveness of interleukin-4 administration or zinc supplementation in improving zinc deficiency-associated thymic atrophy and fatty degeneration and in normalizing T cell maturation process.

Nutritional zinc deficiency induces thymic atrophy, but the underlying mechanisms remain unknown. In this study, we investigated the mechanism of thymic atrophy and fatty degeneration associated with zinc deficiency and its effect on T cell maturation. Building on previous research demonstrating the beneficial effect of IL-4 administration or zinc supplementation on the spleen in zinc-deficient rats, we further examined whether these supplements also improve thymic atrophy. Five-week-old male Sprague-Dawley rats were fed a standard diet, zinc-deficient diet (n = 16 each) with either saline or IL-4, or a zinc-deficient diet for 6 weeks followed by a standard diet for 4 weeks. Relative thymus weights, serum thymulin concentrations, and the number of cytokeratin-8-positive cells, AIRE-positive cells, IL-7-positive cells, CD8+ T cells, CD4+ T cells, pre-T cells, and CD25+ CD44+ (DN3) cells in the thymus of zinc-deficient rats significantly decreased compared with those in all other groups. Conversely, PPAR-γ-positive cells, oil red O-positive areas, pro T cells, CD25- CD44+ cells, TUNEL-positive cells, Viobility 405/452 Fixable Dye-positive cells, CD68-, CD163- or CD169- macrophages, and IL-1ß concentrations were significantly increased in the thymus of zinc-deficient rats as compared to those in the other groups. After IL-4 administration or zinc supplementation for zinc deficiency, all the measurement indices were recovered to levels in standard rats. It was demonstrated that zinc deficiency caused thymic atrophy, accompanied by fatty degeneration in the cortical regions and affected T cell maturation. IL-4 administration or zinc supplementation for zinc deficiency ameliorated thymic fatty degeneration.

Different Doses, Forms, and Frequencies of Zinc Supplementation for the Prevention of Diarrhea and Promotion of Linear Growth among Young Bangladeshi Children: A Six-Arm, Randomized, Community-Based Efficacy Trial.

BACKGROUND: Children in resource-limited settings remain vulnerable to zinc deficiency and its consequences. OBJECTIVES: To evaluate the effects of different doses, durations, and frequencies of zinc supplementation on the incidence of diarrhea and change in linear growth among young children. METHODS: We conducted a randomized, partially double-blind, controlled, 6-arm, community-based efficacy trial in Dhaka, Bangladesh. Children aged 9-11 mo were randomly assigned to receive 1 of the following interventions for 24 wk: 1) standard micronutrient powder (MNP) containing 4.1 mg zinc and 10 mg iron, daily; 2) high-zinc (10 mg), low-iron (6 mg) (HiZn LoFe) MNP, daily; 3) HiZn (10 mg) LoFe (6 mg)/HiZn (10 mg), no-iron MNPs on alternating days; 4) dispersible zinc tablet (10 mg), daily; 5) dispersible zinc tablet (10 mg), daily for 2 wk at enrollment and 12 wk; 6) placebo powder, daily. Primary outcomes were incidence of diarrhea and change in length-for-age z-score (LAZ) over the 24-wk intervention period. Home visits were conducted twice weekly to assess diarrhea and other morbidity. Incidence and prevalence outcomes were compared among groups with Poisson regression; continuous outcomes were compared using ANCOVA. RESULTS: A total of 2886 children were enrolled between February 2018 and July 2019. The mean incidence and prevalence of diarrhea among all participants was 1.21 episodes per 100 d and 3.76 d per 100 d, respectively. There were no differences in the incidence or prevalence of diarrhea across intervention groups. The decline in LAZ was slightly smaller among children in the daily HiZn LoFe MNP group compared with the placebo powder group (P < 0.05). CONCLUSIONS: The dose of zinc in MNPs as well as the duration and frequency of supplementation evaluated in this trial were not effective in reducing diarrhea; however, the daily HiZn LoFe MNP formulation offered modest improvements in linear growth among young children. This trial was registered at clinicaltrials.gov as NCT03406793.

Zinc and COVID-19: Immunity, Susceptibility, Severity and Intervention.

During the coronavirus disease 2019 (COVID-19) pandemic and continuing emergence of viral mutants, there has been a lack of effective treatment methods. Zinc maintains immune function, with direct and indirect antiviral activities. Zinc nutritional status is a critical factor in antiviral immune responses. Importantly, COVID-19 and zinc deficiency overlap in high-risk population. Hence, the potential effect of zinc as a preventive and adjunct therapy for COVID-19 is intriguing. Here, this review summarizes the immune and antiviral function of zinc, the relationship between zinc levels, susceptibility, and severity of COVID-19, and the effect of zinc supplementation on COVID-19. Existing studies have confirmed that zinc deficiency was associated with COVID-19 susceptibility and severity. Zinc supplementation plays a potentially protective role in enhancing immunity, decreasing susceptibility, shortening illness duration, and reducing the severity of COVID-19. We recommend that zinc levels should be monitored, particularly in COVID-19 patients, and zinc as a preventive and adjunct therapy for COVID-19 should be considered for groups at risk of zinc deficiency to reduce susceptibility and disease severity.

Diabetes and zinc dyshomeostasis: Can zinc supplementation mitigate diabetic complications?

Zinc present in the islet cells of the pancreas is crucial for the synthesis, storage, and secretion of insulin. The excretion of large amounts of zinc from the body is reported in diabetic situations. Zinc depletion and increased oxidative stress have a major impact on the pathogenesis of diabetic complications. It would be most relevant to ascertain if intervention with supplemental zinc compensating for its depletion would beneficially mitigate hyperglycemia and the attendant metabolic abnormalities, and secondary complications in diabetes. An exhaustive literature search on this issue indicates: (1) Concurrent hypozincemia and decreased tissue zinc stores in diabetes as a result of its increased urinary excretion and/or decreased intestinal absorption, (2) Several recent experimental studies have documented that supplemental zinc has a potential hypoglycemic effect in the diabetic situation, and also beneficially modulate the attendant metabolic abnormalities and compromised antioxidant status, and (3) Supplemental zinc also alleviates renal lesions, cataract and the risk of cardiovascular disease accompanying diabetes mellitus, and help restore gastrointestinal health in experimental diabetes. These studies have also attempted to identify the precise mechanisms responsible for zinc-mediated beneficial effects in diabetic situation. The evidence discussed in this review highlights that supplemental zinc may significantly contribute to its clinical application in the management of diabetic hyperglycemia and related metabolic abnormalities, and in the alleviation of secondary complications resulting from diabetic oxidative stress.

Retrospective study revealed that Zn relate to improvement of swallowing function in the older adults.

BACKGROUND: Zinc is an essential micronutrient for maintaining biological activity. The level of zinc in the blood is known to decrease with age, especially in those over 75 years of age. In older adults patients with impaired functional status, aspiration pneumonia based on dysphagia often becomes problematic. However, the relationship between zinc deficiency and swallowing function has not been studied before. METHODS: A total of 52 older adults subjects (15 males and 37 females) living in a nursing home were enrolled for this study. At the time of enrollment, data of gender, age, body weight, serum zinc levels, serum albumin levels, and the time in a simple 2-step swallowing provocation test (S-SPT) were collected. In patients with serum zinc levels < 60 µg/dL, we initiated 2 months of oral zinc supplementation therapy with a 34 mg/day zinc load. Those who underwent zinc supplementation were re-evaluated after the treatment period and serum zinc levels and S-SPT time were measured. RESULTS: At the time of enrollment, serum zinc level was significantly correlated with serum albumin levels (Pearson's R = 0.58, p < 0.0001) and time in the S-SPT (Spearman's rho = - 0.32, p = 0.0219). Twenty-five of the 52 patients had zinc deficiency with a serum zinc level < 60 µg/dL. After 2 months of oral zinc supplementation, both serum zinc levels (p < 0.0001) and time in the S-SPT (p = 0.04) significantly improved. Meanwhile, serum albumin level (p = 0.48) or body weight (p = 0.07) did not significantly change following zinc supplementation. Zinc supplementation significantly improved swallowing function, especially in the older adults who had comorbid dysphagia and zinc deficiency. CONCLUSIONS: Zinc deficiency is associated with compromised swallowing function in older adults patients with impaired general functions. Oral zinc supplementation can alleviate dysphagia in older adults patients with zinc deficiency even though this is a retrospective study. Further study will be needed to confirm this positive effect.

Zinc is a strong stimulant of metallothionein synthesis in the ischaemic testis tissue.

This study was performed to determine the effect of zinc supplementation effects on metallothionein levels in testis ischaemia-reperfusion of rats. The experimental groups were designed as Control, Sham, Ischaemia-Reperfusion (I/R) and I/R + Zinc supplemented. Zinc supplemented as 5 mg/kg day for 3 weeks. Testis tissues were analysed for metallothionein by immunohistochemical staining procedures. Group comparison showed that the zinc-supplemented ischaemia-reperfusion group had a significantly higher level of cells strongly stained with metallothionein than all other groups. A general evaluation of the results suggests that zinc supplementation is a strong stimulant of metallothionein synthesis in the ischaemic testis tissue.

Daily Preventive Zinc Supplementation Decreases Lymphocyte and Eosinophil Concentrations in Rural Laotian Children from Communities with a High Prevalence of Zinc Deficiency: Results of a Randomized Controlled Trial.

BACKGROUND: Zinc deficiency impairs immune function and is common among children in South-East Asia. OBJECTIVES: The effect of zinc supplementation on immune function in young Laotian children was investigated. METHODS: Children (n = 512) aged 6-23 mo received daily preventive zinc tablets (PZ; 7 mg Zn/d), daily multiple micronutrient powder (MNP; 10 mg Zn/d, 6 mg Fe/d, plus 13 other micronutrients), therapeutic dispersible zinc tablets only in association with diarrhea episodes (TZ; 20 mg Zn/d for 10 d after an episode), or daily placebo powder (control). These interventions continued for 9 mo. Cytokine production from whole blood cultures, the concentrations of T-cell populations, and a complete blood count with differential leukocyte count were measured at baseline and endline. Endline means were compared via ANCOVA, controlling for the baseline value of the outcome, child age and sex, district, month of enrollment, and baseline zinc status (below, or above or equal to, the median plasma zinc concentration). RESULTS: T-cell cytokines (IL-2, IFN-γ, IL-13, IL-17), LPS-stimulated cytokines (IL-1ß, IL-6, TNF-α, and IL-10), and T-cell concentrations at endline did not differ between intervention groups, nor was there an interaction with baseline zinc status. However, mean ± SE endline lymphocyte concentrations were significantly lower in the PZ than in the control group (5018 ± 158 compared with 5640 ± 160 cells/µL, P = 0.032). Interactions with baseline zinc status were seen for eosinophils (Pixn = 0.0036), basophils (Pixn = 0.023), and monocytes (P = 0.086) but a significant subgroup difference was seen only for eosinophils, where concentrations were significantly lower in the PZ than in the control group among children with baseline plasma zinc concentrations below the overall median (524 ± 44 compared with 600 ± 41 cells/µL, P = 0.012). CONCLUSIONS: Zinc supplementation of rural Laotian children had no effect on cytokines or T-cell concentrations, although zinc supplementation affected lymphocyte and eosinophil concentrations. These cell subsets may be useful as indicators of response to zinc supplementation.This trial was registered at clinicaltrials.gov as NCT02428647.

Successful Management of Glioblastoma Chemotherapy-Associated Dysgeusia with Gabapentin.

Dysgeusia is a frequent, yet underreported side effect of chemotherapy for cancer. We report here the first use of gabapentin in two glioblastoma patients who developed dysgeusia following intra-arterial administration of carboplatin or oral administration of lomustine, respectively. Treatment initiation was followed by resolution of taste alteration within weeks. Both patients reported significant improvement in their quality of life and regained weight, allowing further chemotherapy cycles. We hypothesized that in these two cases, chemotherapy impeded gustatory cells turnover and function, resulting in a gustatory "deafferentation-like" syndrome which was successfully addressed by the medication.

Zinc supplementation improves the harvest purity of ß-glucuronidase from CHO cell culture by suppressing apoptosis.

The variability of trace metals in cell culture media is a potential manufacturing concern because it may significantly affect the production and quality of therapeutic proteins. Variability in trace metals in CHO cell culture has been shown to impact critical production metrics such as cell growth, viability, nutrient consumption, and production of recombinant proteins. To better understand the influence of excess supplementation, zinc and copper were initially supplemented with 50-µM concentrations to determine the impact on the production and quality of ß-glucuronidase, a lysosomal enzyme, in a parallel bioreactor system. Ethylenediaminetetraacetic acid (EDTA), a metal chelator, was included as another treatment to induce a depletion of trace metal bioavailability to examine deficiency. Samples were drawn daily to monitor cell growth and viability, nutrient levels, ß-glucuronidase activity, and trace zinc flux. Cell cycle analysis revealed the inhibition of sub-G0/G1 species in zinc supplemented cultures, maintaining higher viability compared to the control, EDTA-, and copper-supplemented cultures. Enzyme activity analysis in the harvests revealed higher specific activity of ß-glucuronidase in reactors supplemented with zinc. A confirmation run was conducted with supplementations of zinc at concentrations of 50, 100, and 150 µM. Further cell cycle analysis and caspase-3 analysis demonstrated the role of zinc as an apoptosis suppressor responsible for the enhanced harvest purity of ß-glucuronidase from zinc-supplemented bioreactors.

Pre-dialysis serum creatinine as an independent predictor of responsiveness to zinc supplementation among patients on hemodialysis.

BACKGROUND: To investigate whether pre-dialysis level of serum creatinine (SCre) could indicate the responsiveness to zinc supplementation of patients on maintenance hemodialysis (MHD). METHODS: We retrospectively reviewed the results of our previous randomized study of 91 patients who had been on MHD and received zinc supplementation with either zinc acetate hydrate (ZAH; zinc, 50 mg/day) or polaprezinc (PPZ; zinc, 34 mg/day). A late response to zinc supplementation was defined as a serum zinc level of < 80 µg/dL three months after the study began. Patients were divided into two groups: late response (serum zinc level < 80 µg/dL) and early response (serum zinc level ≥ 80 µg/dL). Factors independently associated with a late response to zinc supplementation were determined using inverse probability of treatment weighting (IPTW) multivariate logistic analysis. RESULTS: Of 91 patients, 86 continued to receive zinc supplementation after three months. The mean pre-dialysis SCre level was 10.0 mg/dL. The number of patients with a late response and response to zinc supplementation was 32 and 54, respectively. There was a significant negative correlation between the pre-dialysis SCre and the Δserum zinc change for 3 months. (r = - 0.284, P = 0.008). IPTW multivariate analysis showed that a pre-dialysis SCre level ≥ 10.0 mg/dL (odds ratio, 3.71; 95% confidence interval; 1.24-11.1, P = 0.022) was an independent factor associated with a late response to zinc supplementation. CONCLUSIONS: Pre-dialysis SCre level was independently associated with responsiveness to zinc supplementation after three months in patients on MHD.

Effect of zinc supplementation on relative expression of immune response genes in neonates with sepsis: A preliminary study.

Background & objectives: Zinc alters gene expression mainly by binding to a site on the transcription factor. Genome-wide expression studies have shown early repression of genes related to zinc and immunity in adult patients with sepsis. The present study was conducted to evaluate the role of zinc supplementation on relative expression of immune response genes in neonatal sepsis. Methods: In the present study, a sample of convenience of 22 neonates each was selected from the zinc supplemented and control groups using random numbers for expression of immune-related genes by zinc supplementation. These neonates with sepsis were earlier randomized into two groups: with and without zinc supplementation in addition to standard antibiotics and supportive care. Relative expression of immune response genes were analyzed for 22 neonates in each group using quantitative real-time PCR for calprotectin (S100A8/A9), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), toll-like receptor-4 (TLR-4), cluster of differentiation 14 (CD14) and lipopolysaccharide-binding protein (LBP) genes. Results: An increase in serum zinc levels was observed in zinc-supplemented group compared to controls. S100A8 gene showed downregulation by three-fold (P <0.001) and S100A9 gene showed upregulation by two-fold (P <0.05) in zinc group compared to controls. CD14 gene showed upregulation by one-fold in zinc-supplemented group compared to controls (P <0.05). No significant fold changes were observed with respect to TNF-α, IL-6, LBP and TLR-4 genes between the two groups. Interpretation & conclusions: The results of our preliminary study showed that the zinc supplementation might modulates the relative expression of immune-related genes involved in sepsis pathway among neonates. However, studies with larger sample size are needed to be done to provide a better picture on the outcome by gene expression in neonatal sepsis by zinc supplementation.

[Impaired hematopoiesis due to copper deficiency in a hemodialysis patient supplemented with zinc].

This is a case of a 75-year-old man who was on maintenance hemodialysis for 10 years due to diabetic nephropathy and was prescribed polaprezinc due to a low serum zinc level (55 µg/dl) and dysgeusia. Three months after the polaprezinc treatment was initiated, the patient developed pancytopenia, which persisted even after the serum zinc level was normalized and medication was discontinued. He was referred to our institute so that the progression of pancytopenia could be assessed. A blood biochemical examination revealed a WBC count of 1,700/µl, Hb level of 8.9 g/dl, and Plt count of 9.5×104/µl. A bone marrow aspirate smear showed slight megaloblastic changes and ringed sideroblasts in addition to an elevated WT1 mRNA level (76 copies/µg RNA) in the peripheral blood. Although these findings mimicked those of myelodysplasia, low serum copper (<2 µg/dl) and ceruloplasmin levels (3 mg/dl) were suggestive of hematopoietic abnormalities due to zinc-induced copper deficiency. Treatment with cocoa, a compound generally known to be rich in copper, gradually improved the pancytopenia and dysplastic bone marrow histology. This case indicates that clinicians should consider the risk of zinc-induced copper deficiency and its complications when zinc supplementation is administered to patients with chronic kidney disease, particularly those undergoing hemodialysis.

The Benefit of Zinc Sulfate in Oropharyngeal Mucositis during Hyperfractionated Accelerated Concomitant Boost Radiotherapy with Concurrent Cisplatin for Advanced-Stage Oropharyngeal and Hypopharyngeal Cancers.

BACKGROUND: Radiation-induced oropharyngeal mucositis is a major problem causing widespread clinical symptoms and may interfere with treatment plans, ultimately jeopardizing patient outcome. Zinc supplementation may be considered beneficial in preventing acute toxicity during chemoradiation. AIMS AND OBJECTIVE: The aim of the study is to determine the effect of zinc supplementation on radiation-induced oropharyngeal mucositis in Stage III and IV-A oropharynx and hypopharynx cancers treated by hyperfractionated accelerated concomitant boost radiotherapy with weakly cisplatin. The objective behind the study is to know any changes in the onset, duration, and severity of oropharyngeal mucositis by implementation of oral zinc sulfate. MATERIALS AND METHODS: The study is double-blinded randomized controlled assessment involving 120 patients (60 - control and 60 - experimental) treated with chemoradiation for oropharyngeal and hypopharyngeal cancers. The experimental group received oral zinc sulfate 150 mg once daily during and after treatment, whereas the control group patients were given placebo. The categorical data were analyzed using the Chi-square test and Pearson correlation. The Friedman test was used for comparison of oral mucositis grading between the groups. RESULTS: A statistically significant difference was found in the zinc-supported experimental group showing delay in onset, decrease in severity, and duration of oropharyngeal mucositis. CONCLUSION: Zinc supplementation could be beneficial in managing oropharyngeal mucositis during chemoradiation of head-and-neck cancers with no untoward side effects.

Effect of Zinc Supplementation on Renal Anemia in 5/6-Nephrectomized Rats and a Comparison with Treatment with Recombinant Human Erythropoietin.

Anemia is a severe complication in patients with chronic kidney disease (CKD). Treatment with exogenous erythropoietin (EPO) can correct anemia in many with CKD. We produced 5/6-nephrectomized rats that became uremic and anemic at 25 days post surgery. Injection of the anemic 5/6-nephrectomized rats with 2.8 mg zinc/kg body weight raised their red blood cell (RBC) levels from approximately 85% of the control to 95% in one day and continued for 4 days. We compared the effect of ZnSO4 and recombinant human erythropoietin (rHuEPO) injections on relieving anemia in 5/6-nephrectomized rats. After three consecutive injections, both the ZnSO4 and rHuEPO groups had significantly higher RBC levels (98 ± 6% and 102 ± 6% of the control) than the saline group (90 ± 3% of the control). In vivo, zinc relieved anemia in 5/6-nephrectomized rats similar to rHuEPO. In vitro, we cultured rat bone marrow cells supplemented with ZnCl2, rHuEPO, or saline. In a 4-day suspension culture, we found that zinc induced erythropoiesis similar to rHuEPO. When rat bone marrow cells were supplement-cultured with zinc, we found that zinc stimulated the production of EPO in the culture medium and that the level of EPO produced was dependent on the concentration of zinc supplemented. The production of EPO via zinc supplementation was involved in the process of erythropoiesis.