Heat shock protein 90 inhibitor RGRN-305 potently attenuates skin inflammation.

Introduction: Chronic inflammatory skin diseases may have a profound negative impact on the quality of life. Current treatment options may be inadequate, offering an unsatisfactory response or side effects. Therefore, ongoing efforts exist to identify novel effective and safe treatments. Heat shock protein (HSP) 90 is a chaperone that promotes the activity of a wide range of client proteins including key proinflammatory molecules involved in aberrant inflammation. Recently, a proof-of-concept clinical trial of 13 patients suggested that RGRN-305 (an HSP90 inhibitor) may be an oral treatment for psoriasis. However, HSP90 inhibition may be a novel therapeutic approach extending beyond psoriasis to include multiple immune-mediated inflammatory skin diseases. Methods: This study aimed to investigate (i) the anti-inflammatory effects and mechanisms of HSP90 inhibition and (ii) the feasibility of topical RGRN-305 administration (new route of administration) in models of inflammation elicited by 12-O-tetradecanoylphorbol-13-acetate (TPA) in primary human keratinocytes and mice (irritative dermatitis murine model). Results/Discussion: In primary human keratinocytes stimulated with TPA, a Nanostring® nCounter gene expression assay demonstrated that HSP90 inhibition with RGRN-305 suppressed many proinflammatory genes. Furthermore, when measured by quantitative real-time polymerase chain reaction (RT-qPCR), RGRN-305 significantly reduced the gene expression of TNF, IL1B, IL6 and CXCL8. We next demonstrated that topical RGRN-305 application significantly ameliorated TPA-induced skin inflammation in mice. The increase in ear thickness (a marker of inflammation) was significantly reduced (up to 89% inhibition). In accordance, RT-qPCR of the ear tissue demonstrated that RGRN-305 robustly reduced the gene expression of proinflammatory markers (Tnf, Il1b, Il6, Il17A and Defb4). Moreover, RNA sequencing revealed that RGRN-305 mitigated TPA-induced alterations in gene expression and suppressed genes implicated in inflammation. Lastly, we discovered that the anti-inflammatory effects were mediated, at least partly, by suppressing the activity of NF-κB, ERK1/2, p38 MAPK and c-Jun signaling pathways, which are consistent with previous findings in other experimental models beyond skin inflammation. In summary, HSP90 inhibition robustly suppressed TPA-induced inflammation by targeting key proinflammatory cytokines and signaling pathways. Our findings suggest that HSP90 inhibition may be a novel mechanism of action for treating immune-mediated skin disease beyond psoriasis, and it may be a topical treatment option.

Sensitizing the Efficiency of ICIs by Neoantigen mRNA Vaccines for HCC Treatment.

This study builds upon the groundbreaking mRNA vaccine Nobel Prize win in 2023 for COVID-19 prevention, paving the way for next-generation mRNA cancer vaccines to revolutionize immunotherapy. Despite the existing challenges, such as the presence of a suppressive tumor microenvironment and the identification of cancer-associated antigens, recent results from the KEYNOTE-942 trial have successfully demonstrated the effectiveness of mRNA-based cancer treatments, providing clinical evidence for the first time. This trial aimed to evaluate the efficacy and safety of combining immune checkpoint inhibitors with mRNA-based therapies in treating cancer. This advancement undeniably represents new hope for hepatocellular carcinoma (HCC) patients. However, progress in this field remains limited. In this article, we summarized the current state of applying immune checkpoint inhibitors (ICIs) combined with neoantigen mRNA vaccines. Additionally, we discussed potential targets for designing novel mRNA vaccines and potential mRNA vaccine delivery vehicles. The objective of this article is to inspire enthusiasm for the exploration of innovative therapeutic strategies that combine ICIs with neoantigen mRNA vaccines for HCC treatment and HCC prevention.

A system biology approach to determine therapeutic targets by identifying molecular mechanisms and key pathways for type 2 diabetes that are linked to the development of tuberculosis and rheumatoid arthritis.

AIMS: Due to traditional endocrinological techniques, there is currently no shared work available, and no therapeutic choices have been presented in type 2 diabetes (T2D), rheumatoid arthritis (RA), and tuberculosis (TB). The purpose of this research is to summarize the prospective molecular complications and potential therapeutic targets associated with T2D that have been connected to the development of TB and RA. MATERIALS AND METHODS: We collected the transcriptomic data as GSE92724, GSE110999 and GSE 148036 for T2D, RA and TB patients. After collecting from NCBI, then GREIN were employed to process our datasets. STRING and Enrichr were used to construct protein-protein interaction (PPI), gene regulatory network (GRN), protein-drug-chemical, gene ontology and pathway network. Finally, Cytoscape and R studio were employed to visualize our proposed network. KEY FINDINGS: We discovered a number of strong candidate hub proteins in significant pathways, namely RAB25, MAL2, SFN, MYO5B, and HLA-DQB1 out of 75 common genes. We also identified a number of TFs (JUN, TFAP2A, FOXC1, and GATA2); miRNA (mir-1-3p, mir-16-5p, and mir-34a5p); drugs (sulfasalazine, cholic acid, and nilflumic acid) and chemicals (Valproic acid, and Aflatoxin B1) may control DEGs in transcription as well as post- transcriptional expression levels. SIGNIFICANCE: To summarize, our computational techniques discovered unique potential biomarkers that show how T2D, RA, and TB interacted, as well as pathways and gene regulators by which T2D may influence autoimmune inflammation and infectious diseases. In the future, more clinical and pharmacological research is needed to confirm the findings at the transcriptional and translational levels.

Piperlongumine, a Potent Anticancer Phytotherapeutic, Induces Cell Cycle Arrest and Apoptosis In Vitro and In Vivo through the ROS/Akt Pathway in Human Thyroid Cancer Cells.

Thyroid cancer (TC) is the most common endocrine malignancy, and its global incidence has steadily increased over the past 15 years. TC is broadly divided into well-differentiated, poorly differentiated, and undifferentiated types, depending on the histological and clinical parameters. Thus far, there are no effective treatments for undifferentiated thyroid cancers or advanced and recurrent cancer. Therefore, the development of an effective therapeutic is urgently needed for such patients. Piperlongumine (PL) is a naturally occurring small molecule derived from long pepper; it is selectively toxic to cancer cells by generating reactive oxygen species (ROS). In this study, we demonstrate the potential anticancer activity of PL in four TC cell lines. For this purpose, we cultured TC cell lines and analyzed the following parameters: Cell viability, colony formation, cell cycle, apoptosis, and cellular ROS induction. PL modulated the cell cycle, induced apoptosis, and suppressed tumorigenesis in TC cell lines in a dose- and time-dependent manner through ROS induction. Meanwhile, an intrinsic caspase-dependent apoptosis pathway was observed in the TC cells under PL treatment. The activation of Erk and the suppression of the Akt/mTOR pathways through ROS induction were seen in cells treated with PL. PL-mediated apoptosis in TC cells was through the ROS-Akt pathway. Finally, the anticancer effect and safety of PL were also demonstrated in vivo. Our findings indicate that PL exhibits antitumor activity and has the potential for use as a chemotherapeutic agent against TC. This is the first study to show the sensitivity of TC cell lines to PL.

Cardiomyocyte Protection by Hibernating Brown Bear Serum: Toward the Identification of New Protective Molecules Against Myocardial Infarction.

Ischemic heart disease remains one of the leading causes of death worldwide. Despite intensive research on the treatment of acute myocardial infarction, no effective therapy has shown clinical success. Therefore, novel therapeutic strategies are required to protect the heart from reperfusion injury. Interestingly, despite physical inactivity during hibernation, brown bears (Ursus arctos) cope with cardiovascular physiological conditions that would be detrimental to humans. We hypothesized that bear serum might contain circulating factors that could provide protection against cell injury. In this study, we sought to determine whether addition of bear serum might improve cardiomyocyte survival following hypoxia-reoxygenation. Isolated mouse cardiomyocytes underwent 45 min of hypoxia followed by reoxygenation. At the onset of reoxygenation, cells received fetal bovine serum (FBS; positive control), summer (SBS) or winter bear serum (WBS), or adult serums of other species, as indicated. After 2 h of reoxygenation, propidium iodide staining was used to evaluate cell viability by flow cytometry. Whereas, 0.5% SBS tended to decrease reperfusion injury, 0.5% WBS significantly reduced cell death, averaging 74.04 ± 7.06% vs. 79.20 ± 6.53% in the FBS group. This cardioprotective effect was lost at 0.1%, became toxic above 5%, and was specific to the bear. Our results showed that bear serum exerts a therapeutic effect with an efficacy threshold, an optimal dose, and a toxic effect on cardiomyocyte viability after hypoxia-reoxygenation. Therefore, the bear serum may be a potential source for identifying new therapeutic molecules to fight against myocardial reperfusion injury and cell death in general.

A novel strategy for glioblastoma treatment combining alpha-cyano-4-hydroxycinnamic acid with cetuximab using nanotechnology-based delivery systems.

Combination therapy that uses multiple drugs against different molecular targets should be considered as interesting alternatives for treating complex diseases such as glioblastoma (GBM). Drugs like alpha-cyano-4-hydroxycinnamic acid (CHC) and the monoclonal antibody cetuximab (CTX) are already explored for their capacity to act against different hallmarks of cancer. Previous reports suggest that the simultaneous use of these drugs, as a novel combining approach, might result in additive or synergistic effects. Therefore, advances in nanotechnology-based delivery systems will inevitably bring nano-mediated therapeutic gains to the proposed combination since they enable the association of different drugs into a single carrier. The current study provides indications that the new dual therapeutic strategy proposed, in association with nanotechnology, provides significative improvements when compared to the use of isolated drugs. Nanotechnological tools were employed by developing polymeric nanoparticles based on poly(lactic-co-glycolic acid) and chitosan for CHC encapsulation. Furthermore, these structures were conjugated with CTX by supramolecular forces. In summary, the encapsulation of the CHC drug into the nanoparticles increased its individual therapeutic capacity. In addition, conjugation with CTX seemed to enhance therapeutic efficacy, especially for U251 GBM cells. In conclusion, developed nanostructured delivery systems exhibited a set of favorable attributes and potential to be applied as a promising new alternative for GBM treatment. Graphical abstract .