Synthetic homoisoflavane derivatives suppress the growth of colorectal cancer cells by disturbing microtubule dynamics.

Microtubules, composed of tubulin proteins, have a crucial role in various cellular processes, including cell cycle regulation. The dynamic instability of microtubules has been an attractive target for cancer therapy. This study investigated two potent anticancer drug candidates, homoisoflavane derivatives SH-19021 and SHA-035, and evaluated their potential as microtubule-targeting agents (MTAs) in human colorectal cancer cells.

Therapeutic Intervention of an Intranasally Administered Monoclonal Antibody Targeting the SARS-CoV-2 Omicron Spike Protein Against SARS-CoV-2 Omicron Infection in Mice.

SARS-CoV-2 has evolved into several variants of concern, with Omicron and its subvariants currently being the most prevalent. Previously, we developed a mouse monoclonal antibody (m1E3H12 mAb) specific to the receptor binding domain of SARS-CoV-2 Omicron spike protein, and the mAb showed neutralizing activity against SARS-CoV-2 Omicron BA.1 and its subvariants BA.

Production of a monoclonal antibody targeting the SARS-CoV-2 Omicron spike protein and analysis of SARS-CoV-2 Omicron mutations related to monoclonal antibody resistance.

SARS-CoV-2 mutations have resulted in the emergence of multiple concerning variants, with Omicron being the dominant strain presently. Therefore, we developed a monoclonal antibody (mAb) against the spike (S) protein of SARS-CoV-2 Omicron for therapeutic applications. We established the 1E3H12 mAb, recognizing the receptor binding domain (RBD) of the Omicron S protein, and found that the 1E3H12 mAb can efficiently recognize the Omicron S protein with weak affinity to the Alpha, Beta, and Mu variants, but not to the parental strain and Delta variant.

Analysis of SARS-CoV-2 Mutations after Nirmatrelvir Treatment in a Lung Cancer Xenograft Mouse Model.

Paxlovid is the first approved oral treatment for coronavirus disease 2019 and includes nirmatrelvir, a protease inhibitor targeting the main protease (M) of SARS-CoV-2, as one of the key components. While some specific mutations emerged in M were revealed to significantly reduce viral susceptibility to nirmatrelvir , there is no report regarding resistance to nirmatrelvir in patients and animal models for SARS-CoV-2 infection yet. We recently developed xenograft tumors derived from Calu-3 cells in immunodeficient mice and demonstrated extended replication of SARS-CoV-2 in the tumors.

Analysis of SARS-CoV-2 omicron mutations that emerged during long-term replication in a lung cancer xenograft mouse model.

SARS-CoV-2 Omicron has the largest number of mutations among all the known SARS-CoV-2 variants. The presence of these mutations might explain why Omicron is more infectious and vaccines have lower efficacy to Omicron than other variants, despite lower virulence of Omicron. We recently established a long-term in vivo replication model by infecting Calu-3 xenograft tumors in immunodeficient mice with parental SARS-CoV-2 and found that various mutations occurred majorly in the spike protein during extended replication.

A mouse xenograft long-term replication yields a SARS-CoV-2 Delta mutant with increased lethality.

We recently established a long-term SARS-CoV-2 infection model using lung-cancer xenograft mice and identified mutations that arose in the SARS-CoV-2 genome during long-term propagation. Here, we applied our model to the SARS-CoV-2 Delta variant, which has increased transmissibility and immune escape compared with ancestral SARS-CoV-2. We observed limited mutations in SARS-CoV-2 Delta during long-term propagation, including two predominant mutations: R682W in the spike protein and L330W in the nucleocapsid protein.

Contribution of HSP90 Cleavage to the Cytotoxic Effect of Suberoylanilide Hydroxamic Acid and the Involvement of TXNIP in HSP90 Cleavage.

Heat shock protein (HSP) 90 is expressed in most living organisms, and several client proteins of HSP90 are necessary for cancer cell survival and growth. Previously, we found that HSP90 was cleaved by histone deacetylase (HDAC) inhibitors and proteasome inhibitors, and the cleavage of HSP90 contributes to their cytotoxicity in K562 leukemia cells. In this study, we first established mouse xenograft models with K562 cells expressing the wild-type or cleavage-resistant mutant HSP90β and found that the suppression of tumor growth by the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was interrupted by the mutation inhibiting the HSP90 cleavage .

Analysis of spike protein variants evolved in a novel long-term replication model for SARS-CoV-2.

Introduction: The spectrum of SARS-CoV-2 mutations have increased over time, resulting in the emergence of several variants of concern. Persistent infection is assumed to be involved in the evolution of the variants. Calu-3 human lung cancer cells persistently grow without apoptosis and release low virus titers after infection.

SARS-CoV-2 infection induces expression and secretion of lipocalin-2 and regulates iron in a human lung cancer xenograft model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to various clinical symptoms including anemia. Lipocalin-2 has various biological functions, including defense against bacterial infections through iron sequestration, and it serves as a biomarker for kidney injury. In a human protein array, we observed increased lipocalin-2 expression due to parental SARS-CoV-2 infection in the Calu-3 human lung cancer cell line.

In vitro and in vivo suppression of SARS-CoV-2 replication by a modified, short, cell-penetrating peptide targeting the C-terminal domain of the viral spike protein.

Peptides are promising therapeutic agents for COVID-19 because of their specificity, easy synthesis, and ability to be fine-tuned. We previously demonstrated that a cell-permeable peptide corresponding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike C-terminal domain (CD) inhibits the interaction between viral spike and nucleocapsid proteins that results in SARS-CoV-2 replication in vitro. Here, we used docking studies to design R-t-Spike CD(D), a more potent short cell-penetrating peptide composed of all D-form amino acids and evaluated its inhibitory effect against the replication of SARS-CoV-2 S clade and other variants.

Production of a Monoclonal Antibody to the Nucleocapsid Protein of SARS-CoV-2 and Its Application to ELISA-Based Detection Methods with Broad Specificity by Combined Use of Detector Antibodies.

The coronavirus disease 2019 pandemic, elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is ongoing. Currently accessible antigen-detecting rapid diagnostic tests are limited by their low sensitivity and detection efficacy due to evolution of SARS-CoV-2 variants. Here, we produced and characterized an anti-SARS-CoV-2 nucleocapsid (N) protein-specific monoclonal antibody (mAb), 2A7H9.

Effect of Previous COVID-19 Vaccination on Humoral Immunity 3 Months after SARS-CoV-2 Omicron Infection and Booster Effect of a Fourth COVID-19 Vaccination 2 Months after SARS-CoV-2 Omicron Infection.

In this study, we aimed to determine the effect of COVID-19 vaccination on 3-month immune response and durability after natural infection by the Omicron variant and to assess the immune response to a fourth dose of COVID-19 vaccination in patients with prior natural infection with the Omicron variant. Overall, 86 patients aged ≥60 years with different vaccination histories and 39 health care workers (HCWs) vaccinated thrice before Omicron infection were enrolled. The sVNT50 titer was significantly lower in patients with incomplete vaccination before SARS-CoV-2 infection with the S clade ( < 0.

Metformin ameliorates olanzapine-induced obesity and glucose intolerance by regulating hypothalamic inflammation and microglial activation in female mice.

Olanzapine (OLZ), a widely used second-generation antipsychotic drug, is known to cause metabolic side effects, including diabetes and obesity. Interestingly, OLZ-induced metabolic side effects have been demonstrated to be more profound in females in human studies and animal models. Metformin (MET) is often used as a medication for the metabolic side effects of OLZ.

Comparison of vaccination efficacy using live or ultraviolet-inactivated influenza viruses introduced by different routes in a mouse model.

Influenza is a major cause of highly contagious respiratory illness resulting in high mortality and morbidity worldwide. Annual vaccination is an effective way to prevent infection and complication from constantly mutating influenza strains. Vaccination utilizes preemptive inoculation with live virus, live attenuated virus, inactivated virus, or virus segments for optimal immune activation.

Differential effect of SARS-CoV-2 infection on stress granule formation in Vero and Calu-3 cells.

Stress granule formation is induced by numerous environmental stressors, including sodium arsenite treatment and viral infection. Accordingly, stress granules can inhibit viral propagation and function as part of the antiviral host response to numerous viral infections. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antagonizes stress granule formation, in part, via interaction between SARS-CoV-2 nucleocapsid (N) protein and Ras-GTPase-activating SH3-domain-binding protein 1 (G3BP1).

Abiraterone Acetate Attenuates SARS-CoV-2 Replication by Interfering with the Structural Nucleocapsid Protein.

The drug repurposing strategy has been applied to the development of emergency COVID-19 therapeutic medicines. Current drug repurposing approaches have been directed against RNA polymerases and viral proteases. Recently, we found that the inhibition of the interaction between the SARS-CoV-2 structural nucleocapsid (N) and spike (S) proteins decreased viral replication.

Targeting the Interaction Between Spike Protein and Nucleocapsid Protein for Suppression and Detection of Human Coronavirus OC43.

Human coronavirus OC43 (HCoV-OC43) is the coronavirus most associated with "common colds", infections of the upper respiratory tract. Previously, we reported that direct interactions of nucleocapsid (N) protein and C-terminal domain of Spike protein (Spike CD) are essential for replication of SARS-CoV-2 and MERS-CoV. Thus, we developed a novel ELISA-based strategy targeting these specific interactions to detect SARS-CoV-2 and MERS-CoV.

Antiviral drug discovery by targeting the SARS-CoV-2 polyprotein processing by inhibition of the main protease.

The spread of SARS-CoV-2, the causative agent for COVID-19, has led to a global and deadly pandemic. To date, few drugs have been approved for treating SARS-CoV-2 infections. In this study, a structure-based approach was adopted using the SARS-CoV-2 main protease (M) and a carefully selected dataset of 37,060 compounds comprising M and antiviral protein-specific libraries.

Production of SARS-CoV-2 N Protein-Specific Monoclonal Antibody and Its Application in an ELISA-Based Detection System and Targeting the Interaction Between the Spike C-Terminal Domain and N Protein.

SARS-CoV-2 infections continue to spread quickly by human-to-human transmission around the world. Therefore, developing methods to rapidly detect SARS-CoV-2 with high sensitivity are still urgently needed. We produced a monoclonal antibody that specifically detects the N protein of SARS-CoV-2 and recognizes N protein in cell lysates of SARS-CoV-2-infected Vero cells but not in cell lysates of MERS-CoV- or HCoV-OC43-infected Vero cells.

Apoptosis Enhances the Replication of Human Coronavirus OC43.

Human coronavirus OC43 (HCoV-OC43) is one of the coronaviruses causing a mild common cold, but few studies have been made on this strain. Here, we identified the molecular mechanisms involved in HCoV-OC43-induced apoptosis and its implications for viral reproduction in Vero cells and MRC-5 cells. HCoV-OC43 infection induced apoptosis that was accompanied by cleavage of caspase-3 and PARP, degradation of cyclin D1, and cell cycle arrest at S and G2M phases.