Delta Peptide Research Articles

Secondary structure propensities of the Ebola delta peptide E40 in solution and model membrane environments

The Ebola delta peptide is an amphipathic, 40-residue peptide encoded by the Ebola virus, referred to as E40. The membrane-permeabilising activity of the E40 delta peptide has been demonstrated in cells and lipid vesicles suggesting the E40 delta peptide likely acts as a viroporin. The lytic activity of the peptide increases in the presence of anionic lipids and a disulphide bond in the C-terminal part of the peptide. Previous in silico work predicts the peptide to show a partially helical structure, but there is no experimental information on the structure of E40. Here, we use circular dichroism spectroscopy to report the secondary structure propensities of the reduced and oxidised forms of the E40 peptide in water, detergent micelles, and lipid vesicles composed of neutral and anionic lipids (POPC and POPG, respectively). Results indicate that the peptide is predominately a random coil in solution, and the disulphide bond has a small but measurable effect on peptide conformation. Secondary structure analysis shows large uncertainties and dependence on the reference data set and, in our system, cannot be used to accurately determine the secondary structure motifs of the peptide in membrane environments. Nevertheless, the spectra can be used to assess the relative changes in secondary structure propensities of the peptide depending on the solvent environment and disulphide bond. In POPC-POPG vesicles, the peptide transitions from a random coil towards a more structured conformation, which is even more pronounced in negatively charged SDS micelles. In vesicles, the effect depends on the peptide-lipid ratio, likely resulting from vesicle surface saturation. Further experiments with zwitterionic POPC vesicles and DPC micelles show that both curvature and negatively charged lipids can induce a change in conformation, with the two effects being cumulative. Electrostatic screening from Na+ ions reduced this effect. The oxidised form of the peptide shows a slightly lower propensity for secondary structure and retains a more random coil conformation even in the presence of PG-PC vesicles.

CD4+ and CD8+ T cells and antibodies are associated with protection against Delta vaccine breakthrough infection: a nested case-control study within the PITCH study.

Defining correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine breakthrough infection informs vaccine policy for booster doses and future vaccine designs. Existing studies demonstrate humoral correlates of protection, but the role of T cells in protection is still unclear. In this study, we explore antibody and T cell immune responses associated with protection against Delta variant vaccine breakthrough infection in a well-characterized cohort of UK Healthcare Workers (HCWs). We demonstrate evidence to support a role for CD4+ and CD8+ T cells as well as antibodies against Delta vaccine breakthrough infection. In addition, our results suggest a potential role for cross-reactive T cells in vaccine breakthrough.

Impacts of delta and omicron variants on inactivated SARS‐CoV‐2 vaccine‐induced T cell responses in patients with autoimmune diseases and healthy controls

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes coronavirus disease 2019 (COVID-19), which is still devastating economies and communities globally. The increasing infections of variants of concern (VOCs) in vaccinated population have raised concerns about the effectiveness of current vaccines. Patients with autoimmune diseases (PAD) under immunosuppressant treatments are facing higher risk of infection and potentially lower immune responses to SARS-CoV-2 vaccination. Blood samples were collected from PAD or healthy controls (HC) who finished two or three doses of inactivated vaccines. Spike peptides derived from wild-type strain, delta, omicron BA.1 were utilisedto evaluate T cell responses and their cross-recognition of delta and omicron in HC and PAD by flow cytometry and ex vivo IFNγ-ELISpot. We found that inactivated vaccine-induced spike-specific memory T cells were long-lasting in both PAD and HC. These spike-specific T cells were highly conserved and cross-recognized delta and omicron. Moreover, a third inactivated vaccine expanded spike-specific T cells that responded to delta and omicron spike peptides substantially in both PAD and HC. Importantly, the polyfunctionality of spike-specific memory T cells was preserved in terms of cytokine and cytotoxic responses. Although the extent of T cell responses was lower in PAD after two-dose, T cell responses were boosted to a greater magnitude in PAD by the third dose, bringing comparable spike-specific T cell immunity after the third dose. Inactivated vaccine-induced spike-specific T cells remain largely intact against delta and omicron variants. This study expands our understanding of inactivated vaccine-induced T cell responses in PAD and HC, which could have important indications for vaccination strategy.

Longitudinal T Cell Responses against Ancestral, Delta, and Omicron SARS-CoV-2 Variants Determined by Rapid Cytokine Release Assay in Whole Blood.

T cell immunity to natural SARS-CoV-2 infection may be more robust and longer lived than Ab responses. Accurate assessment of T cell responses is critical for understanding the magnitude and longevity of immunity across patient cohorts, and against emerging variants. By establishing a simple, accurate, and rapid whole blood test, natural and vaccine-induced SARS-CoV-2 immunity was determined. Cytokine release in whole blood stimulated with peptides specific for SARS-CoV-2 was measured in donors with previous PCR-confirmed infection, suspected infection, or with no exposure history (n = 128), as well as in donors before and after vaccination (n = 32). Longitudinal assessment of T cell responses following initial vaccination and booster vaccination was also conducted (n = 50 and n = 62, respectively). Cytokines were measured by ELISA and multiplex array. IL-2 and IFN-γ were highly elevated in PCR-confirmed donors compared with history-negative controls, with median levels ∼33-fold and ∼48-fold higher, respectively. Receiver operating curves showed IL-2 as the superior biomarker (area under the curve = 0.9950). Following vaccination, all donors demonstrated a positive IL-2 response. Median IL-2 levels increased ∼32-fold from prevaccination to postvaccination in uninfected individuals. Longitudinal assessment revealed that T cell responses were stable up to 6 mo postvaccination. No significant differences in cytokine production were observed between stimulations with Wuhan, Delta, or Omicron peptides. This rapid, whole blood-based test can be used to make comparable longitudinal assessments of vaccine-induced T cell immunity across multiple cohorts and against variants of concern, thus aiding decisions on public health policies.

Humoral and Cellular Response to Spike of Delta SARS-CoV-2 Variant in Vaccinated Patients With Multiple Sclerosis.

ObjectivesWe assessed vaccination-induced antibody and cellular response against spike from the ancestral strain and from the Delta Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) variant in patients with Multiple Sclerosis (MS) treated with disease modifying treatments.MethodsWe enrolled 47 patients with MS and nine controls (“no MS”) having completed the vaccination schedule within 4–6 months from the first dose. The Interferon (IFN)-γ-response to spike peptides derived from the ancestral and the Delta SARS-CoV-2 was measured by enzyme-linked immunoassay (ELISA). Anti-Receptor Binding Domain (RBD) IgG were also evaluated.ResultsNo significant differences were found comparing the IFN-γ-specific immune response between MS and “no MS” subjects to the ancestral (P = 0.62) or Delta peptide pools (P = 0.68). Nevertheless, a reduced IFN-γ-specific response to the ancestral or to the Delta pools was observed in subjects taking fingolimod or cladribine compared to subjects treated with ocrelizumab or IFN-β. The antibody response was significantly reduced in patients with MS compared to “no MS” subjects (P = 0.0452) mainly in patients taking ocrelizumab or fingolimod.ConclusionsCellular responses to Delta SARS-CoV-2 variant remain largely intact in patients with MS. However, the magnitude of these responses depends on the specific therapy.

Alterations in SARS-CoV-2 Omicron and Delta peptides presentation by HLA molecules.

The T-cell immune response is a major determinant of effective SARS-CoV-2 clearance. Here, using the recently developed T-CoV bioinformatics pipeline (https://t-cov.hse.ru) we analyzed the peculiarities of the viral peptide presentation for the Omicron, Delta and Wuhan variants of SARS-CoV-2. First, we showed the absence of significant differences in the presentation of SARS-CoV-2-derived peptides by the most frequent HLA class I/II alleles and the corresponding HLA haplotypes. Then, the analysis was limited to the set of peptides originating from the Spike proteins of the considered SARS-CoV-2 variants. The major finding was the destructive effect of the Omicron mutations on PINLVRDLPQGFSAL peptide, which was the only tight binder from the Spike protein for HLA-DRB1*03:01 allele and some associated haplotypes. Specifically, we predicted a dramatical decline in binding affinity of HLA-DRB1*03:01 and this peptide both because of the Omicron BA.1 mutations (N211 deletion, L212I substitution and EPE 212-214 insertion) and the Omicron BA.2 mutations (V213G substitution). The computational prediction was experimentally validated by ELISA with the use of corresponding thioredoxin-fused peptides and recombinant HLA-DR molecules. Another finding was the significant reduction in the number of tightly binding Spike peptides for HLA-B*07:02 HLA class I allele (both for Omicron and Delta variants). Overall, the majority of HLA alleles and haplotypes was not significantly affected by the mutations, suggesting the maintenance of effective T-cell immunity against the Omicron and Delta variants. Finally, we introduced the Omicron variant to T-CoV portal and added the functionality of haplotype-level analysis to it.

The Feline Calicivirus Leader of the Capsid Protein Has the Functional Characteristics of a Viroporin.

The leader of the capsid (LC) protein is exclusive to the Vesivirus genus, and it is needed for successful feline calicivirus (FCV) replication, as well as an efficient apoptosis induction through the mitochondrial pathway. In this work, we aimed to determine if the LC protein from the FCV is a viroporin. Although lacking in a transmembrane domain or an amphipathic helix, the LC protein from the FCV is toxic when expressed in bacteria and it oligomerizes through disulfide bonds, which are both key characteristics of viroporins. An electron microscopy analysis of LC-expressing E. coli cells suggest that the protein induces osmotic stress. Moreover, we found that the previously studied C40A LC mutant, that fails to induce apoptosis and that hinders the replication cycle, also oligomerizes but it has a reduced toxicity and fails to induce osmotic stress in bacteria. We propose that the LC protein is a viroporin that acts as a disulfide bond-dependent antimicrobial peptide, similar to the Ebola virus delta peptide.

Enterotoxigenic Escherichia coli Heat-Stable Toxin and Ebola Virus Delta Peptide: Similarities and Differences.

Enterotoxigenic Escherichia coli (ETEC) STb toxin exhibits striking structural similarity to Ebola virus (EBOV) delta peptide. Both ETEC and EBOV delta peptide are enterotoxins. Comparison of the structural and functional similarities and differences of these two toxins illuminates features that are important in induction of pathogenesis by a bacterial and viral pathogen.

Ebola virus delta peptide is an enterotoxin.

During the 2013-2016 West African (WA) Ebola virus (EBOV) outbreak, severe gastrointestinal symptoms were common in patients and associated with poor outcome. Delta peptide is a conserved product of post-translational processing of the abundant EBOV soluble glycoprotein (sGP). The murine ligated ileal loop model was used to demonstrate that delta peptide is a potent enterotoxin. Dramatic intestinal fluid accumulation follows injection of biologically relevant amounts of delta peptide into ileal loops, along with gross alteration of villous architecture and loss of goblet cells. Transcriptomic analyses show that delta peptide triggers damage response and cell survival pathways and downregulates expression of transporters and exchangers. Induction of diarrhea by delta peptide occurs via cellular damage and regulation of genes that encode proteins involved in fluid secretion. While distinct differences exist between the ileal loop murine model and EBOV infection in humans, these results suggest that delta peptide may contribute to EBOV-induced gastrointestinal pathology.

Ebola Virus Delta Peptide Is an Enterotoxin

During the 2013-2016 West African Ebola virus (EBOV) outbreak severe gastrointestinal symptoms were common in patients and associated with poor outcome. Delta peptide is a conserved product of post-translational processing of the abundant EBOV soluble glycoprotein (sGP). Here, the murine ligated ileal loop model was used to demonstrate that delta peptide is a potent enterotoxin. Dramatic intestinal fluid secretion followed injection of biologically relevant amounts of delta peptide into ileal loops, along with gross destruction of villous architecture and loss of goblet cell polysaccharides. Transcriptomic analyses showed that delta peptide triggers damage response and cell survival pathways. It also downregulates the expression of transporters and exchangers that mediate absorption of ions, sugars, and small chain fatty acids. Delta peptide induces fluid secretion through pathways that include the ANO1 calcium-activated chloride channel, and prostaglandin signaling. Delta peptide may contribute to EBOV-induced gastrointestinal pathology in humans and presents a potential therapeutic target.

Ion Selective Pentameric Pore Formation by Ebola Virus Delta Peptide

The Ebola produces the pore forming glycoprotein delta peptide which is implicated in facilitating the release of viral particles through the host cell's membrane. In this work, we investigate the molecular details of the pore forming mechanism of the delta peptide viroporin. Using information from experimental studies, we computationally modelled membrane pores formed by delta peptide oligomers. We performed all-atom molecular dynamics (MD) simulations in an explicit membrane environment to investigate the pore-forming mechanism and stability of the pores. Our results suggest that the delta peptide forms stable pentameric pores that are selective for chloride ion transport. We found that a disulfide bond between cysteine residues in the C-terminal of the peptide is essential for the pore stabilization and ion permeation. Our study provides helpful information on the pore-forming mechanism of filovirus delta peptides and such structural information can be important in designing and developing molecular modulators that target the delta peptide pore and disrupt the pathology of the Ebola virus.

Improving T cell functionality for adoptive T cell therapy in metastatic colorectal cancer

Abstract Adoptive T cell therapy in solid tumors such as colorectal cancers are challenging due the low frequency of tumor infiltrating T cells and high molecular tumor heterogeneity. In this study, we are proposing to address this issue by developing a novel technology to expand patient tumor specific T cells ex-vivo, using patient’s matched tumor and PBMCs. Published data from our group shows T cells isolated from heavily treated lymphoma patients when treated with inhibitors of PI3K delta (idelalisib) and vasoactive intestinal peptide (VIPhyb) signaling results in decreased levels of senescent T cells and increased persistence in-vivo in NSG mice. Additionally, we have demonstrated that tumor membrane vesicles (TMVs) prepared from human tumor cells decorated with IL-12 and B7-1 (decorated TMVs), stimulate expansion of tumor antigen specific T cells with increased IFN gamma release. This study thus combines both strategies to obtain tumor antigen specific T cells with enhanced anti-tumor activity and in-vivo persistence. Preliminary data was generated with PBMCs obtained from consented colon cancer patients expanded with decorated TMVs with/without VIPhyb and idelalisib. Results showed that on day 14 of T cell expansion, T cells expanded with decorated TMVs + VIPhyb + idelalisib resulted in significantly increased number of IFN gamma secreting CD8+ T cells (25% of T cells), when compared to T cells treated with decorated TMVs without VIPhyb and idelalisib (13% of T cells). On the other hand, in the absence of decorated TMVs, there were less IFN gamma secreting T cells, both in the CD4 and CD8 compartment. Further experiments are underway to test the persistence and efficacy of the expanded T cells in PDX mice with matched human colon cancer.

Relative proteome quantification of alpha, beta, gamma and delta globin chains in early eluting peaks of Bio-Rad variant II® CE-HPLC of hemoglobin from healthy and beta-thalassemia subjects in Malaysia

This is the first report of QQQ-mass spectrometric identification and quantification of the Hb subunits, alpha, beta, delta and gamma globin peptides, derived from enzymatic-digestion of proteins in the early unknown peaks of the Bio-Rad cation-exchange chromatography of haemoglobin. The objectives were to assess the relationship of the quantity of the free alpha, beta, delta and gamma globin chains with the phenotypic diversity of beta-thalassaemias (β-thal). The results demonstrate that the pools of free globin chains in red blood cells were correlating with the severity of the disease in patients with different phenotypes of β-thal. The mechanism and the regulation of synthesis of free globin chains pool in a normal individual and in patients with different β-thal phenotypes could arise from several mechanisms which will require further investigation. The role of the free globin pool in patients with β-thal for development of novel therapeutic approaches based on these potential targets requires further investigation. Pertinent biomarkers improves the diagnosis of the β-thal, especially in low-income countries where they are most common and allows more effective therapeutic intervention leading to more successful therapeutic outcome.

Ebola Virus Delta-Peptide Acts as an Enterotoxic Viroporin In Vivo

Ebola virus (EBOV), part of the filovirus family, has a genome that encodes for a partly conserved, 40-residue polypeptide, called the delta peptide, which is produced during Ebola virus disease pathogenesis. Sequence-structure-function analysis and in vitro data suggest that the delta peptide is a viroporin, a term used to describe a diverse family of virally encoded pore-forming peptides and proteins involved in the replication and pathogenesis of numerous viruses. Full-length and conserved C-terminal EBOV delta peptide fragments permeabilize synthetic lipid bilayers and multiple cell types in vitro. Activity requires that the two conserved cysteines are connected by a disulfide linkage. Here, we follow up those results by testing delta peptides using an established mouse model of diarrheal pathology focusing on the small intestine. We hypothesized that the cell permeabilization observed against numerous cell types in vitro would correspond to intestinal pathology, in vivo. We found that the delta peptide exerts potent enterotoxic activity against mouse intestine upon introduction to a closed intestinal ileal loop, resulting in a diarrheal syndrome in the mice. The peak activity of the peptide occurs 9-12 hours after introduction of peptide into the intestinal loop. Histological examination of the intestinal architecture showed severe damage and loss of goblet cells. Our in vivo results demonstrate that the EBOV delta peptide is a potential novel therapeutic target, and neutralizing it could ameliorate some of the severe enterotoxic burden characteristic of EBOV disease pathogenesis. Accordingly, our focus is to generate a high-affinity neutralizing antibody to block the lytic activity of the delta peptide in vitro and in vivo as a potentially efficacious therapeutic agent against EBOV disease.

Membrane pore formation and ion selectivity of the Ebola virus delta peptide

The Ebola virus (EBOV) is a filamentous lipid-enveloped virus that causes severe hemorrhagic fever with a high fatality rate in humans. The EBOV encodes a glycoprotein that when cleaved, produces the delta peptide. Experimental evidence suggests that the delta peptide functions as a viroporin that enhances virus particle release through the host cell membrane. However, the viroporin forming mechanism of the delta peptide is still not well understood. Guided by experimental information, we have computationally investigated the pore formation by different oligomers of the delta peptide. We have performed all-atom molecular dynamics (MD) simulations in an explicit membrane environment to investigate the pore-forming mechanism and stability of the pores. Our results suggest that the delta peptide forms stable pentameric pores. In addition, the pore is selective with respect to chloride ions, and the disulfide bond formed between Cys-29 and Cys-38 in the C-terminal of the peptide is essential for the pore stabilization and ion permeation. Our study provides helpful information on the pore-forming mechanism of filovirus delta peptides and such structural information can be important in designing and developing molecular modulators that target the delta peptide pore and disrupt the pathology of the Ebola virus.

Ebola Virus Delta-Peptide Acts as an Enterotoxic Viroporin In Vivo

Ebola virus (EBOV), part of the filovirus family, has a genome that encodes for a partly conserved, 40-residue polypeptide, called the delta peptide, which is produced during Ebola virus disease pathogenesis. Sequence-structure analysis and a wealth of in vitro data suggest that the delta peptide is a viroporin, a diverse family of pore-forming peptides and proteins involved in replication and pathogenesis of numerous viruses. Specifically, many filovirus delta peptides have a high abundance of cationic and aromatic residues while maintaining amphipathicity; these are properties that are common in membrane-permeabilizing peptides. Full-length and conserved C-terminal EBOV delta peptide fragments were shown to permeabilize synthetic lipid bilayers and multiple cell types in vitro. Here, we follow up those results with an established mouse model of diarrheal pathology focusing on the small intestine. We hypothesized that the lytic activity observed against numerous cell types in vitro would also be apparent when testing the delta peptide in vivo. We found that the delta peptide exerts potent, dose-dependent enterotoxic activity against intestinal cells upon introduction to a closed intestinal loop. The peak activity of the peptide, which results in a diarrheal syndrome in the mice, occurs 9-12 hours after introduction to the small intestine. This conclusion is confirmed with histology studies in which we examined intestinal architecture and found that it was severely damaged by the delta peptide. Further, the density of mucin-producing goblet cells in villi was diminished by the peptide. These results show that the EBOV delta peptide is a potential novel therapeutic target, and neutralizing it could ameliorate some of the severe enterotoxic burden characteristic of EBOV disease pathogenesis.

Ebola Virus Delta Peptide Is a Viroporin.

The Ebola virus (EBOV) genome encodes a partly conserved 40-residue nonstructural polypeptide, called the delta peptide, that is produced in abundance during Ebola virus disease (EVD). The function of the delta peptide is unknown, but sequence analysis has suggested that delta peptide could be a viroporin, belonging to a diverse family of membrane-permeabilizing small polypeptides involved in replication and pathogenesis of numerous viruses. Full-length and conserved C-terminal delta peptide fragments permeabilize the plasma membranes of nucleated cells of rodent, dog, monkey, and human origin; increase ion permeability across confluent cell monolayers; and permeabilize synthetic lipid bilayers. Permeabilization activity is completely dependent on the disulfide bond between the two conserved cysteines. The conserved C-terminal portion of the peptide is biochemically stable in human serum, and most serum-stable fragments have full activity. Taken together, the evidence strongly suggests that Ebola virus delta peptide is a viroporin and that it may be a novel, targetable aspect of Ebola virus disease pathology.IMPORTANCE During the unparalleled West African outbreak of Ebola virus disease (EVD) that began in late 2013, the lack of effective countermeasures resulted in chains of serial infection and a high mortality rate among infected patients. A better understanding of disease pathology is desperately needed to develop better countermeasures. We show here that the Ebola virus delta peptide, a conserved nonstructural protein produced in large quantities by infected cells, has the characteristics of a viroporin. This information suggests a critical role for the delta peptide in Ebola virus disease pathology and as a possible target for novel countermeasures.

The Delta Peptide of Ebola Virus has Potent Viroporin Activity

The Delta peptide, cleaved from the soluble glycoprotein (sGP) of Ebola virus (EBOV), is a partially conserved, 40-residue nonstructural polypeptide that has no known function. This peptide shows high similarity in amino acid composition to membrane permeabilizing peptides, including a peptide in the diarrhea-inducing viroporin, NSP4, of Rotavirus. In addition, EBOV disease (EVD) survivors from West Africa have antibodies against the Delta peptide. Therefore, we hypothesize that the Delta peptide has an important role as a viroporin in EVD pathology. Here we show that a peptide corresponding to the serum-stable, conserved C-terminal sequence of Delta peptide permeabilizes and kills nucleated mammalian cells, and potently increasing ion permeability across synthetic lipid bilayers. Importantly, this permeabilizing activity is eliminated by the reduction of the disulfide bond between conserved cysteines. We conclude that EBOV Delta peptide does not form large unregulated pores through membranes, but rather increases ionic permeation, which is similar to other viroporins. By this mechanism, it could contribute to EVD pathology in human through vascular leakage, enterotoxic effects, or other cytotoxic pathways.

Regulation of CCK-induced ERK1/2 activation by PKC epsilon in rat pancreatic acinar cells

The extracellular signal-regulated kinase ERK1/2 is activated in pancreatic acinar cells by cholecystokinin (CCK) and other secretagogues with this activation mediated primarily by protein kinase C (PKC). To identify the responsible PKC isoform, we utilized chemical inhibitors, cell permeant inhibitory peptides and overexpression of individual PKC dominant negative variants by means of adenoviral vectors. While the broad-spectrum PKC inhibitor GF109203X strongly inhibited ERK1/2 activation induced by 100 pM CCK, Go6976 which inhibits the classical PKC isoforms (alpha, beta and gamma), as well as Rottlerin, a specific PKC delta inhibitor, had no inhibitory effect. To test the role of PKC epsilon, we used specific cell permeant peptide inhibitors which block PKC interaction with their intracellular receptors or RACKs. Only PP93 (PKC epsilon peptide inhibitor) inhibited CCK-induced ERK1/2 activation, while PP95, PP101 and PP98, which are PKC alpha, delta and zeta peptide inhibitors respectively, had no effect. We also utilized adenovirus to express dominant negative PKC isoforms in pancreatic acini. Only PKC epsilon dominant negative inhibited CCK-induced ERK1/2 activation. Dominant negative PKC epsilon expression similarly blocked the effect of carbachol and bombesin to activate ERK1/2. Immunoprecipitation results demonstrated that CCK can induce an interaction of c-Raf-1 and PKC epsilon, but not that of other isoforms of Raf or PKC. We conclude that PKC epsilon is the isoform of PKC primarily involved with CCK-induced ERK1/2 activation in pancreatic acinar cells.

Effects of Reg3 Delta Bioactive Peptide on Blood Glucose Levels and Pancreatic Gene Expression in an Alloxan-Induced Mouse Model of Diabetes.

The endocrine regeneration of the pancreas holds great potential for stable diabetes therapy. The Regeneration (Reg) family of proteins has been associated with pancreas regeneration. Hence, the Reg3 delta bioactive peptide from a mouse was evaluated to see whether it can reverse hyperglycemia in a mouse model of diabetes with any effects on pancreatic gene expression. In this study, we administrated the synthetic Reg3 delta bioactive peptide to healthy mice and to alloxan-induced mouse models of diabetes for 30 days, with weekly measurements of body weight and blood glucose levels. After 1 month, pancreatic gene profiling of these mice was performed for the Ngn-3, Pdx-1, MapK8, IGF-1, IGF2bp2, Reg3 beta and Reg3 delta genes. The glycemic levels in mice with diabetes were decreased significantly, restored almost to normal. Furthermore, the gene expression levels measured by quantitative polymerase chain reaction (qPCR) showed that messenger RNA (mRNA) levels of 2 important transcription factors (Ngn-3 and Pdx-1) were increased during the Reg3 delta peptide treatment. This study shows that Reg3 delta has the potential to reverse hyperglycemia by modulating gene expression in pancreatic endocrine precursor markers Pdx-1 and Ngn-3, which require further investigation at the protein and immunohistology levels.