A Role for Periostin Pathological Variants and Their Interaction with HSP70-1a in Promoting Pancreatic Cancer Progression and Chemoresistance.

Pancreatic ductal adenocarcinoma (PDAC) characterized by an abundant cancer stroma is an aggressive malignancy with a poor prognosis. Periostin (Pn) is a key extracellular matrix (ECM) protein in various tumor progression. Previously, we described the role of Pn alternative splicing variants (ASVs) with specific functional features in breast cancer.

Therapeutic Vaccines and Nucleic Acid Drugs for Cardiovascular Disease.

To combat the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), novel vaccine modalities, such as messenger RNA vaccines, were rapidly developed and have shown high efficacy. This new vaccine technology, underpinned by intensive immunological analysis, is now being applied to the production of other vaccines. For over 10 years, we have been developing therapeutic vaccines for non-infectious diseases.

Expression of Periostin Alternative Splicing Variants in Normal Tissue and Breast Cancer.

(1) Background: Periostin (Pn) is a secreted protein found in the extracellular matrix, and it plays a variety of roles in the human body. Physiologically, Pn has a variety of functions, including bone formation and wound healing. However, it has been implicated in the pathogenesis of various malignant tumors and chronic inflammatory diseases.

The Importance of Suppressing Pathological Periostin Splicing Variants with Exon 17 in Both Stroma and Cancer.

Background: Periostin (POSTN) is a type of matrix protein that functions by binding to other matrix proteins, cell surface receptors, or other molecules, such as cytokines and proteases. POSTN has four major splicing variants (PN1-4), which are primarily expressed in fibroblasts and cancer. We have reported that we should inhibit pathological POSTN (PN1-3), but not physiological POSTN (PN4).

PCPE-1, a brown adipose tissue-derived cytokine, promotes obesity-induced liver fibrosis.

Metabolic dysfunction-associated steatohepatitis (MASH, previously termed non-alcoholic steatohepatitis (NASH)), is a major complication of obesity that promotes fatty liver disease. MASH is characterized by progressive tissue fibrosis and sterile liver inflammation that can lead to liver cirrhosis, cancer, and death. The molecular mechanisms of fibrosis in MASH and its systemic control remain poorly understood.

Efficacy and safety in mice of repeated, lifelong administration of an ANGPTL3 vaccine.

Previously, we reported that an ANGPTL3 vaccine is a hopeful therapeutic option against dyslipidemia. In our current study, we assess durability and booster effects of that vaccine over a period representing a mouse's lifespan. The vaccine remained effective for over one year, and booster vaccination maintained suppression of circulating triglyceride levels thereafter without major adverse effects on lungs, kidneys, or liver, suggesting vaccine efficacy and safety.

Long Term Follow-Up Study of a Randomized, Open-Label, Uncontrolled, Phase I/II Study to Assess the Safety and Immunogenicity of Intramuscular and Intradermal Doses of COVID-19 DNA Vaccine (AG0302-COVID19).

Pharmacological studies have demonstrated antibody production and infection prevention with an intradermal coronavirus disease 2019 (COVID-19) DNA vaccine (AG0302-COVID-19). This clinical trial aimed to investigate the safety and immunogenicity of high doses of AG0302-COVID19 when injected intramuscularly and intradermally. Healthy adults were randomly divided into three intramuscular vaccination groups (2 mg, three times at 2-week intervals; 4 mg, twice at 4-week intervals; and 8 mg, twice at 4-week intervals) and two intradermal groups (1 mg, three times at 2-week intervals or twice at 4-week intervals).

Acquisition of Humoral Immune Responses in Convalescent Japanese People with SARS-CoV-2 (COVID-19) Infection in 2021.

We investigated humoral immune responses in 222 unvaccinated Japanese people after recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in 2021. Anti-spike-protein IgG antibody levels and neutralizing antibody titers were measured in serum samples obtained within 20-180 days after diagnosis. The geometric mean of antibody titers was 1555 ELU/mL (95% confidence interval (CI) = 1257-1923), and the neutralizing activity (50% inhibitory dilution) was 253 (95% CI = 204-313).

Intradermal administration of DNA vaccine targeting Omicron SARS-CoV-2 via pyro-drive jet injector provides the prolonged neutralizing antibody production via germinal center reaction.

Emerging SARS-CoV-2 Omicron variants are highly contagious with enhanced immune escape mechanisms against the initially approved COVID-19 vaccines. Therefore, we require stable alternative-platform vaccines that confer protection against newer variants of SARS-CoV-2. We designed an Omicron B.

R-spondin 3/LGR4 (Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 4) Axis Is a Novel Inflammatory and Neurite Outgrowth Signaling System in the Ischemic Brain in Mice.

Background: Although stimulation of Wnt/β-catenin signaling is an important strategy to treat ischemic stroke, its signaling pathway has not been fully clarified yet. Recently, RSPO3 (R-spondin 3)/LGR4 (leucine-rich repeat-containing G protein-coupled receptor 4) signaling has resolved TLR4 (toll-like receptor 4)-induced inflammation in lung injury; however, whether this signal is critical in the ischemic brain remains unknown. Therefore, we investigated the role of RSPO3/LGR4 signaling in the ischemic brain.

Antiepileptic Drugs Modulate Alzheimer-Related Tau Aggregation in a Neuronal Activity-Independent Manner.

Introduction: A rapidly increasing number of patients with dementia present a serious social problem. Recently, the incidence of epilepsy in patients with Alzheimer's disease (AD) is increasing, drawing attention to the pathological relationship between the two conditions. Clinical studies have suggested the protective action of antiepileptic agents on dementia; however, the underlying mechanism remains unknown.

Peptide-based vaccine targeting IL17A attenuates experimental spondyloarthritis in HLA-B27 transgenic rats.

Objectives: Spondyloarthritis (SpA) is known as series of immune-mediated inflammatory disease of the axial and peripheral joints. Human leucocyte antigen (HLA)-B27 is a genetic risk factor for SpA. Recent evidence suggests that the interleukin -17 (IL17) axis strongly contributes to SpA.

Modified DNA vaccine confers improved humoral immune response and effective virus protection against SARS-CoV-2 delta variant.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global pandemic. New technologies have been utilized to develop several types of vaccines to prevent the spread of SARS-CoV-2 infection, including mRNA vaccines. Our group previously developed an effective DNA-based vaccine.

Blocking Periostin Prevented Development of Inflammation in Rhabdomyolysis-Induced Acute Kidney Injury Mice Model.

Background: Rhabdomyolysis is the collapse of damaged skeletal muscle and the leakage of muscle-cell contents, such as electrolytes, myoglobin, and other sarcoplasmic proteins, into the circulation. The glomeruli filtered these products, leading to acute kidney injury (AKI) through several mechanisms, such as intratubular obstruction secondary to protein precipitation. The prognosis is highly mutable and depends on the underlying complications and etiologies.

Lipoprotein(a) levels in a global population with established atherosclerotic cardiovascular disease.

Objective: Lipoprotein(a) (Lp(a)) is an important genetically determined risk factor for atherosclerotic vascular disease (ASCVD). With the development of Lp(a)-lowering therapies, this study sought to characterise patterns of Lp(a) levels in a global ASCVD population and identify racial, ethnic, regional and gender differences.

Methods: A multicentre cross-sectional epidemiological study to estimate the prevalence of elevated Lp(a) in patients with a history of myocardial infarction, ischaemic stroke or peripheral artery disease conducted at 949 sites in 48 countries in North America, Europe, Asia, South America, South Africa and Australia between April 2019 and July 2021.

Phase I Study to Assess the Safety and Immunogenicity of an Intradermal COVID-19 DNA Vaccine Administered Using a Pyro-Drive Jet Injector in Healthy Adults.

We conducted a nonrandomized, open-label phase I study to assess the safety and immunogenicity of an intradermal coronavirus disease 2019 (COVID-19) DNA vaccine (AG0302-COVID-19) administered using a pyro-drive jet injector at Osaka University Hospital between Yanagida November 2020 and December 2021. Twenty healthy volunteers, male or female, were enrolled in the low-dose (0.2 mg) or high-dose (0.

Prevention of bleomycin-induced pulmonary fibrosis by a RANKL peptide in mice.

Despite the recent therapeutic developments for the treatment of pulmonary fibrosis, its prognosis is still not well controlled, and a novel therapeutic agent is needed. Recently, the critical role of Toll-like receptors (TLRs) in the pathophysiology of pulmonary fibrosis has been reported; however, the effects of multiple TLR signaling inhibition are still unknown. Here, we examined how the inhibition of multiple TLRs affects pulmonary fibrosis using a novel synthetic receptor activator of nuclear factor κB ligand (RANKL) partial peptide, MHP1-AcN, which could suppress TLR2, 3, 4, 7, and 9 signaling through CD14 and RANK.

A novel chronic dural port platform for continuous collection of cerebrospinal fluid and intrathecal drug delivery in free-moving mice.

Background: Cerebrospinal fluid (CSF) provides a close representation of pathophysiological changes occurring in the central nervous system (CNS); therefore, it has been employed in pathogenesis research and biomarker development for CNS disorders. CSF obtained from valid mouse models relevant to CNS disorders can be an important resource for successful biomarker and drug development. However, the limited volume of CSF that can be collected from tiny intrathecal spaces and the technical difficulties involved in CSF sampling has been a bottleneck that has hindered the detailed analysis of CSF in mouse models.

Preclinical study of a DNA vaccine targeting SARS-CoV-2.

To fight against the worldwide COVID-19 pandemic, the development of an effective and safe vaccine against SARS-CoV-2 is required. As potential pandemic vaccines, DNA/RNA vaccines, viral vector vaccines and protein-based vaccines have been rapidly developed to prevent pandemic spread worldwide. In this study, we designed plasmid DNA vaccine targeting the SARS-CoV-2 Spike glycoprotein (S protein) as pandemic vaccine, and the humoral, cellular, and functional immune responses were characterized to support proceeding to initial human clinical trials.

Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice.

Elimination of senescent cells (senolysis) was recently reported to improve normal and pathological changes associated with aging in mice. However, most senolytic agents inhibit antiapoptotic pathways, raising the possibility of off-target effects in normal tissues. Identification of alternative senolytic approaches is therefore warranted.

Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia.

Dyslipidemia is a risk factor for cardiovascular disease (CVD), a major cause of death worldwide. Angiopoietin-like protein 3 (ANGPTL3), recognized as a new therapeutic target for dyslipidemia, regulates the metabolism of low-density lipoprotein-cholesterol (LDL-C) and triglycerides. Here, we design 3 epitopes (E1-E3) for use in development of a peptide vaccine targeting ANGPTL3 and estimate effects of each on obesity-associated dyslipidemia in B6.

Periostin Exon-21 Antibody Neutralization of Triple-Negative Breast Cancer Cell-Derived Periostin Regulates Tumor-Associated Macrophage Polarization and Angiogenesis.

Periostin (Pn) is involved in multiple processes of cancer progression. Previously, we reported that Pn expression is correlated with mesenchymal tumor markers and poor prognosis in triple-negative breast cancer (TNBC). In the TNBC xenograft model, chemotherapy increased expression of a Pn alternative splicing variant (ASV) with exon 21, and administration of the neutralizing antibody against Pn with exon 21 (Pn-21 Ab) overcame chemoresistance with a reduction in the mesenchymal cancer cell fraction.