Herbal supplement Spirulina stimulates inflammatory cytokine production in patients with dermatomyositis in vitro.

Spirulina, an herbal supplement and popular ingredient in health foods, is a potent stimulant of the immune system. Spirulina use is temporally associated with the onset or exacerbation of Dermatomyositis (DM), an autoimmune connective tissue disease that frequently affects the skin and muscle. In this study, we investigated the effect of Spirulina on peripheral blood mononuclear cells (PBMCs) in DM and Healthy Controls (HCs), showing that Spirulina stimulates Interferon ß (IFNß), Tumor necrosis factor α (TNFα), and Interferon γ (IFNγ) production of DM PBMCs primarily via Toll-Like Receptor 4 (TLR4) activation using ELISA (enzyme linked immunosorbent assay) and flow cytometry. We show that classical monocytes and monocyte-derived dendritic cells are stimulated by Spirulina and are activated via TLR4. Skin from patients with Spirulina-associated DM exhibits an inflammatory milieu similar to that of idiopathic DM but with a stronger correlation of TLR4 and IFNγ.

Viral target and metabolism-based rationale for combined use of recently authorized small molecule COVID-19 medicines: Molnupiravir, nirmatrelvir, and remdesivir.

The COVID-19 pandemic remains a major health concern worldwide, and SARS-CoV-2 is continuously evolving. There is an urgent need to identify new antiviral drugs and develop novel therapeutic strategies. Combined use of newly authorized COVID-19 medicines including molnupiravir, nirmatrelvir, and remdesivir has been actively pursued. Mechanistically, nirmatrelvir inhibits SARS-CoV-2 replication by targeting the viral main protease (Mpro ), a critical enzyme in the processing of the immediately translated coronavirus polyproteins for viral replication. Molnupiravir and remdesivir, on the other hand, inhibit SARS-CoV-2 replication by targeting RNA-dependent RNA-polymerase (RdRp), which is directly responsible for genome replication and production of subgenomic RNAs. Molnupiravir targets RdRp and induces severe viral RNA mutations (genome), commonly referred to as error catastrophe. Remdesivir, in contrast, targets RdRp and causes chain termination and arrests RNA synthesis of the viral genome. In addition, all three medicines undergo extensive metabolism with strong therapeutic significance. Molnupiravir is hydrolytically activated by carboxylesterase-2 (CES2), nirmatrelvir is inactivated by cytochrome P450-based oxidation (e.g., CYP3A4), and remdesivir is hydrolytically activated by CES1 but covalently inhibits CES2. Additionally, remdesivir and nirmatrelvir are oxidized by the same CYP enzymes. The distinct mechanisms of action provide strong rationale for their combined use. On the other hand, these drugs undergo extensive metabolism that determines their therapeutic potential. This review discusses how metabolism pathways and enzymes involved should be carefully considered during their combined use for therapeutic synergy.

Multidimensional Immune Profiling of Cutaneous Lupus Erythematosus In Vivo Stratified by Patient Response to Antimalarials.

OBJECTIVE: The pathogenesis of cutaneous lupus erythematosus (CLE) is multifactorial, and CLE is difficult to treat due to the heterogeneity of inflammatory processes among patients. Antimalarials such as hydroxychloroquine (HCQ) and quinacrine (QC) have long been used as first-line systemic therapy; however, many patients do not respond to treatment with antimalarials and require systemic immunosuppressants that produce undesirable side effects. Given the complexity and the unpredictability of responses to antimalarial treatments in CLE patients, we sought to characterize the immunologic profile of patients with CLE stratified by subsequent treatment outcomes to identify potential biomarkers of inducible response. METHODS: We performed mass cytometry imaging of multiple immune cell types and inflammation markers in treatment-naive skin biopsy samples from 48 patients with CLE to identify baseline immunophenotypes that may predict the response to antimalarial therapy. Patients were stratified according to their response to treatment with antimalarials, as HCQ responders, QC responders, or nonresponders. RESULTS: HCQ responders demonstrated increased CD4+ T cells compared to the QC responder group. Patients in the nonresponder group were found to have decreased Treg cells compared to QC responders and increased central memory T cells compared to HCQ responders. QC responders expressed increased phosphorylated stimulator of interferon genes (pSTING) and interferon-κ (IFNκ) compared to HCQ responders. Phosphorylated STING and IFNκ were found to be localized to conventional dendritic cells (cDCs), and the intensity of pSTING and IFNκ staining was positively correlated with the number of cDCs on a tissue and cellular level. Neighborhood analysis revealed decreased regulatory cell interactions in nonresponder patients. Hierarchical clustering revealed that nonresponder patients could be further differentiated based on expression of pSTAT2, pSTAT3, pSTAT4, pSTAT5, phosphorylated interferon regulatory factor 3 (pIRF3), granzyme B, pJAK2, interleukin-4 (IL-4), IL-17, and IFNγ. CONCLUSION: These findings indicate differential immune cell compositions between patients with CLE, offering guidance for future research on precision-based medicine and treatment response.

Combinatorial photothermal and immuno cancer therapy using chitosan-coated hollow copper sulfide nanoparticles.

Near-infrared light-responsive inorganic nanoparticles have been shown to enhance the efficacy of cancer photothermal ablation therapy. However, current nanoparticle-mediated photothermal ablation is more effective in treating local cancer at the primary site than metastatic cancer. Here, we report the design of a near-infrared light-induced transformative nanoparticle platform that combines photothermal ablation with immunotherapy. The design is based on chitosan-coated hollow CuS nanoparticles that assemble the immunoadjuvants oligodeoxynucleotides containing the cytosine-guanine (CpG) motifs. Interestingly, these structures break down after laser excitation, reassemble, and transform into polymer complexes that improve tumor retention of the immunotherapy. In this "photothermal immunotherapy" approach, photothermal ablation-induced tumor cell death reduces tumor growth and releases tumor antigens into the surrounding milieu, while the immunoadjuvants potentiate host antitumor immunity. Our results indicated that combined photothermal immunotherapy is more effective than either immunotherapy or photothermal therapy alone against primary treated and distant untreated tumors in a mouse breast cancer model. These hollow CuS nanoparticles are biodegradable and can be eliminated from the body after laser excitation.

A comparative study of hollow copper sulfide nanoparticles and hollow gold nanospheres on degradability and toxicity.

Gold and copper nanoparticles have been widely investigated for photothermal therapy of cancer. However, degradability and toxicity of these nanoparticles remain concerns. Here, we compare hollow CuS nanoparticles (HCuSNPs) with hollow gold nanospheres (HAuNS) in similar particle sizes and morphology following intravenous administration to mice. The injected pegylated HCuSNPs (PEG-HCuSNPs) are eliminated through both hepatobiliary (67 percentage of injected dose, %ID) and renal (23 %ID) excretion within one month postinjection. By contrast, 3.98 %ID of Au is excreted from liver and kidney within one month after iv injection of pegylated HAuNS (PEG-HAuNS). Comparatively, PEG-HAuNS are almost nonmetabolizable, while PEG-HCuSNPs are considered biodegradable nanoparticles. PEG-HCuSNPs do not show significant toxicity by histological or blood chemistry analysis. Principal component analysis and 2-D peak distribution plots of data from matrix-assisted laser desorption ionization-time-of-flight imaging mass spectrometry (MALDI-TOF IMS) of liver tissues demonstrated a reversible change in the proteomic profile in mice receiving PEG-HCuSNPs. This is attributed to slow dissociation of Cu ion from CuS nanoparticles along with effective Cu elimination for maintaining homeostasis. Nonetheless, an irreversible change in the proteomic profile is observed in the liver from mice receiving PEG-HAuNS by analysis of MALDI-TOF IMS data, probably due to the nonmetabolizability of Au. This finding correlates with the elevated serum lactate dehydrogenase at 3 months after PEG-HAuNS injection, indicating potential long-term toxicity. The comparative results between the two types of nanoparticles will advance the development of HCuSNPs as a new class of biodegradable inorganic nanomaterials for photothermal therapy.