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Mucoadhesive Andrographolide-Loaded Liposomes for Nasal Delivery Modulate Inflammatory Responses in Tumor Necrosis Factor Alpha-Induced Acute Lung Injury in Mice
(2025-08-12)
Khongkow, Mattaka
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Rimsueb, Natchanon
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Namdee, Katawut
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Bunwatcharaphansakun, Phichaporn
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Saenmuangchin, Rattaporn
Inflammatory lung injury from a fever or sepsis can impair pulmonary function. While anti-inflammatory agents are commonly used, side effects could occur. Andrographolide (AGP) exhibits potent anti-inflammatory activity, making it a promising alternative treatment. Nevertheless, AGP has low solubility and absorption, and drug-delivery liposomes (Lip) improve site-specific targeting and controlled release. This study aimed to develop and evaluate the physicochemical properties, safety, and therapeutic efficacy of AGP-Lip through both in vitro and in vivo studies. The characteristics of AGP-Lip included an average size of 139.7 ± 2.00 nm, a polydispersity index of 0.16 ± 0.02, and a zeta potential of 34.5 ± 0.80 mV, with strong mucoadhesive properties. AGP-Lip exhibited no cytotoxicity in IMR-90 lung fibroblast cells while effectively reducing inflammation by decreasing nitric oxide production in RAW 264.7 murine macrophage cells exposed to lipopolysaccharide. In the animal study, adult male C57BL/6 mice received a single intraperitoneal dose of 100 μg/kg of tumor necrosis factor-α (TNF-α)-induced acute pulmonary systemic inflammation. Mice were randomly assigned to six groups (9 mice per group): control, PBS (negative control), Blank-Lip, AGP-Lip, dexamethasone (POS), and AGP-Lip+POS. All treatments (20 to 25 μL with AGP-Lip, AGP-Lip, and/or POS at 1 mg/kg) were administered via nasal delivery daily for 7 days. The vehicle-treated mice exhibited signs of sickness and systemic inflammation, including reduced body weight gain, hyperlocomotion, decreased exploratory activity, elevated total white blood cell counts, serum IL-6 and TNF-α, and upregulation of targeted mRNA expression of lung inflammatory markers. Histological analysis showed an increase in inflammatory scores, and secretory cells were also observed in the vehicle-treated group. AGP-Lip improved body weight and stress-related behaviors, restored mRNA expression levels of IFN-γ, IL-1α/β, IL-6, IL-10, NF-κBp65, and TNF-α, and alleviated mucus secretion in lung histological analysis. Notably, AGP-Lip effectively mitigated the detrimental effects compared to POS alone, showing significant differences in serum IL-6, lung inflammation-related gene expression (i.e., IFN-γ, IL-1α, NF-κBp50, and VEGF), and PAS staining relative to the combined treatment. These findings suggest that AGP-Lip could serve as a potential alternative treatment for acute respiratory infections, warranting further consideration for long-term administration and clinical trials.
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Targeting multiple genes containing long mononucleotide A-T repeats in lung cancer stem cells
(2021-12-01)
Bhummaphan, Narumol
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Pin-on, Piyapat
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Phiboonchaiyanan, Preeyaporn Plaimee
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Siriluksana, Jirattha
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Aporntewan, Chatchawit
Background: Intratumour heterogeneous gene expression among cancer and cancer stem cells (CSCs) can cause failure of current targeted therapies because each drug aims to target the function of a single gene. Long mononucleotide A-T repeats are cis-regulatory transcriptional elements that control many genes, increasing the expression of numerous genes in various cancers, including lung cancer. Therefore, targeting A-T repeats may dysregulate many genes driving cancer development. Here, we tested a peptide nucleic acid (PNA) oligo containing a long A-repeat sequence [A(15)] to disrupt the transcriptional control of the A-T repeat in lung cancer and CSCs. Methods: First, we separated CSCs from parental lung cancer cell lines. Then, we evaluated the role of A-T repeat gene regulation by counting the number of repeats in differentially regulated genes between CSCs and the parental cells of the CSCs. After testing the dosage and effect of PNA-A15 on normal and cancer cell toxicity and CSC phenotypes, we analysed genome-wide expression to identify dysregulated genes in CSCs. Results: The number of A-T repeats in genes differentially regulated between CSCs and parental cells differed. PNA-A15 was toxic to lung cancer cells and CSCs but not to noncancer cells. Finally, PNA-A15 dysregulated a number of genes in lung CSCs. Conclusion: PNA-A15 is a promising novel targeted therapy agent that targets the transcriptional control activity of multiple genes in lung CSCs.
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Targeting high transcriptional control activity of long mononucleotide A-T repeats in cancer by Argonaute 1
(2019-05-30)
Pin-on, Piyapat
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Aporntewan, Chatchawit
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Siriluksana, Jirattha
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Bhummaphan, Narumol
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Chanvorachote, Pithi
Epigenetic regulatory changes alter the gene regulation function of DNA repeat elements in cancer and consequently promote malignant phenotypes. Some short tandem repeat sequences, distributed throughout the human genome, can play a role as cis-regulatory elements of the genes. Distributions of tandem long (≥10) and short (<10) A-T repeats in the genome are different depending on gene functions. Long repeats are more commonly found in housekeeping genes and may regulate genes in harmonious fashion. Mononucleotide A-repeats around transcription start sites interact with Argonaute proteins (AGOs) to regulate gene expression. miRNA-bound AGO alterations in cancer have been reported; consequently, these changes would affect genes containing mononucleotide A- and T-repeats. Here, we showed an unprecedented hallmark of gene regulation in cancer. We evaluated the gene expression profiles reported in the Gene Expression Omnibus and found a high density of 13–27 A-T repeats in the up-regulated genes in malignancies derived from the bladder, cervix, head and neck, ovary, vulva, breast, colon, liver, lung, prostate, kidney, thyroid, adrenal gland, bone, blood cells, muscle and brain. Transfection of cell-penetrating protein tag AGO1 containing poly uracils (CPP-AGO1-polyUs) to the lung cancer cell lines altered gene regulation depending on the presence of long A-T repeats. CPP-AGO1-polyUs limited cell proliferation and the ability of a cancer cell to grow into a colony in lung cancer cell lines. In conclusion, long A-T repeats up-regulated many genes in cancer that can be targeted by AGO1 to change the expression of many genes and limited cancer growth.
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Ti0.8O2 nanosheets inhibit lung cancer stem cells by inducing production of superoxide anion
(2019-04-01)
Petpiroon, Nalinrat
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Bhummaphan, Narumol
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Soonnarong, Rapeepun
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Chantarawong, Wipa
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Maluangnont, Tosapol
Recent research into the cancer stem cell (CSC) concept has driven progress in the understanding of cancer biology and has revealed promising CSC-specific targets for drug discovery efforts. As malignancies of lung cancer have been shown to be strongly associated with activities of CSCs, we examined the effects of Ti<inf>0.8</inf>O<inf>2</inf> nanosheets on these cells. Here we show that the nanosheets target lung CSCs but not normal primary dermal papilla (DP) stem cells. Whereas Ti<inf>0.8</inf>O<inf>2</inf> caused a dramatic apoptosis along with a decrease in CSC phenotypes, in primary human DP cells such effects of nanosheets have been minimal. Nanosheets reduced the ability of lung cancer cells to generate three-dimensional tumor spheroids, lung CSC markers (CD133 and ALDH1A1), and CSC transcription factors (Nanog and Oct-4). Ti<inf>0.8</inf>O<inf>2</inf> nanosheets reduced CSC signaling through mechanisms involving suppression of protein kinase B (AKT) and Notch-1 pathways. In addition, the nanosheets inhibited the migration and invasive activities of lung cancer cells and reduced epithelial-to-mesenchymal transition (EMT) markers as N-cadherin, vimentin, and Slug, as well as metastasis-related integrins (integrin-av and integrin-b1). Importantly, we found that the selectivity of the Ti<inf>0.8</inf>O<inf>2</inf> nanosheets in targeting cancer cells was mediated by induction of cellular superoxide anion in cancerous but not normal cells. Inhibition of nanosheet-induced superoxide anion restored the suppression of CSC and EMT in cancer cells. These findings demonstrate a promising distinctive effect of Ti<inf>0.8</inf>O<inf>2</inf> nanosheets on lung CSC that may lead to opportunities to use such a nanomaterial in cancer therapy.

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