http://hdl.handle.net/10453/148723 2026-04-04T17:02:54Z http://hdl.handle.net/10453/183611 Title: Evaluation of curcumin nanoparticles of various sizes for targeting multidrug-resistant lung cancer cells via inhalation. Authors: Loo, C-Y; Traini, D; Young, PM; Yeung, S; Leong, CR; Lee, W-H Abstract: INTRODUCTION: Inhalation drug delivery can deliver high doses of chemotherapeutic drugs to the lung tumor. This study evaluates the efficacy and the mechanistic pathways of nebulized Cur NPs at various sizes to treat multidrug resistant lung cancer. METHODS AND RESULTS: Cur-NPs (30 nm and 200 nm) were nebulized separately onto the multidrug-resistant lung cancer cells (H69AR). Smaller NPs induced significantly higher cell death owing to a higher rate of particle internalization via dynamin-dependent clathrin-mediated endocytosis. Owing to the higher lysosome trafficking of Cur-NP30 nm compared to Cur-NP200 nm, oxidation of lysosome was higher (0.47 ± 0.08 vs 0.38 ± 0.08), contributing to significantly higher mitochondrial membrane potential loss (1.57 ± 0.17 vs 1.30 ± 0.11). MRP1 level in H69AR cells was reduced from 352 ± 12.3 ng/µg of protein (untreated cells) to 287 ± 12 ng/µg of protein (Cur-NP30 nm) and 303 ± 13.4 ng/µg of protein (Cur-NP200 nm). NF-κB, and various cytokine expressions were reduced after treatment with nebulized Cur-NPs. CONCLUSIONS: Nebulized Cur-NPs formulations could be internalized into the H69AR cells. The Cur-NPs toxicity toward the H69AR was size and time-dependent. Cur-NP30 nm was more effective than Cur-NP200 nm to retain within the cells to exert higher oxidative stresss-induced cell death. 2024-12-11T00:00:00Z http://hdl.handle.net/10453/182124 Title: Recent trends and therapeutic potential of phytoceutical‐based nanoparticle delivery systems in mitigating non‐small cell lung cancer Authors: Haysom‐McDowell, A; Paudel, KR; Yeung, S; Kokkinis, S; El Sherkawi, T; Chellappan, DK; Adams, J; Dua, K; De Rubis, G Abstract: <jats:p>Lung cancer is the leading cause of cancer death globally, with non‐small cell lung cancer accounting for the majority (85%) of cases. Standard treatments including chemotherapy and radiotherapy present multiple adverse effects. Medicinal plants, used for centuries, are traditionally processed by methods such as boiling and oral ingestion, However, water solubility, absorption, and hepatic metabolism reduce phytoceutical bioavailability. More recently, isolated molecular compounds from these plants can be extracted with these phytoceuticals administered either individually or as an adjunct with standard therapy. Phytoceuticals have been shown to alleviate symptoms, may reduce dosage of chemotherapy and, in some cases, enhance pharmaceutical mechanisms. Research has identified many phytoceuticals' actions on cancer‐associated pathways, such as oncogenesis, the tumour microenvironment, tumour cell proliferation, metastasis, and apoptosis. The development of novel nanoparticle delivery systems such as solid lipid nanoparticles, liquid crystalline nanoparticles, and liposomes has enhanced the bioavailability and targeted delivery of pharmaceuticals and phytoceuticals. This review explores the biological pathways associated with non‐small cell lung cancer, a diverse range of phytoceuticals, the cancer pathways they act upon, and the pros and cons of several nanoparticle delivery systems.</jats:p> http://hdl.handle.net/10453/181192 Title: ApoA-I Protects Pancreatic β-Cells From Cholesterol-Induced Mitochondrial Damage and Restores Their Ability to Secrete Insulin. Authors: Manandhar, B; Pandzic, E; Deshpande, N; Chen, S-Y; Wasinger, VC; Kockx, M; Glaros, EN; Ong, KL; Thomas, SR; Wilkins, MR; Whan, RM; Cochran, BJ; Rye, K-A Abstract: BACKGROUND: High cholesterol levels in pancreatic β-cells cause oxidative stress and decrease insulin secretion. β-cells can internalize apo (apolipoprotein) A-I, which increases insulin secretion. This study asks whether internalization of apoA-I improves β-cell insulin secretion by reducing oxidative stress. METHODS: Ins-1E cells were cholesterol-loaded by incubation with cholesterol-methyl-β-cyclodextrin. Insulin secretion in the presence of 2.8 or 25 mmol/L glucose was quantified by radioimmunoassay. Internalization of fluorescently labeled apoA-I by β-cells was monitored by flow cytometry. The effects of apoA-I internalization on β-cell gene expression were evaluated by RNA sequencing. ApoA-I-binding partners on the β-cell surface were identified by mass spectrometry. Mitochondrial oxidative stress was quantified in β-cells and isolated islets with MitoSOX and confocal microscopy. RESULTS: An F1-ATPase β-subunit on the β-cell surface was identified as the main apoA-I-binding partner. β-cell internalization of apoA-I was time-, concentration-, temperature-, cholesterol-, and F1-ATPase β-subunit-dependent. β-cells with internalized apoA-I (apoA-I+ cells) had higher cholesterol and cell surface F1-ATPase β-subunit levels than β-cells without internalized apoA-I (apoA-I- cells). The internalized apoA-I colocalized with mitochondria and was associated with reduced oxidative stress and increased insulin secretion. The IF1 (ATPase inhibitory factor 1) attenuated apoA-I internalization and increased oxidative stress in Ins-1E β-cells and isolated mouse islets. Differentially expressed genes in apoA-I+ and apoA-I- Ins-1E cells were related to protein synthesis, the unfolded protein response, insulin secretion, and mitochondrial function. CONCLUSIONS: These results establish that β-cells are functionally heterogeneous, and apoA-I restores insulin secretion in β-cells with elevated cholesterol levels by improving mitochondrial redox balance. 2024-02-01T00:00:00Z http://hdl.handle.net/10453/180432 Title: Effect of insulin insufficiency on ultrastructure and function in skeletal muscle. Authors: Kopecky, C; Haug, M; Reischl, B; Deshpande, N; Manandhar, B; King, TW; Lee, V; Wilkins, MR; Morris, M; Polly, P; Friedrich, O; Rye, K-A; Cochran, BJ Abstract: BACKGROUND: Decreased insulin availability and high blood glucose levels, the hallmark features of poorly controlled diabetes, drive disease progression and are associated with decreased skeletal muscle mass. We have shown that mice with β-cell dysfunction and normal insulin sensitivity have decreased skeletal muscle mass. This project asks how insulin deficiency impacts on the structure and function of the remaining skeletal muscle in these animals. METHODS: Skeletal muscle function was determined by measuring exercise capacity and specific muscle strength prior to and after insulin supplementation for 28 days in 12-week-old mice with conditional β-cell deletion of the ATP binding cassette transporters ABCA1 and ABCG1 (β-DKO mice). Abca1 and Abcg1 floxed (fl/fl) mice were used as controls. RNAseq was used to quantify changes in transcripts in soleus and extensor digitorum longus muscles. Skeletal muscle and mitochondrial morphology were assessed by transmission electron microscopy. Myofibrillar Ca2+ sensitivity and maximum isometric single muscle fibre force were assessed using MyoRobot biomechatronics technology. RESULTS: RNA transcripts were significantly altered in β-DKO mice compared with fl/fl controls (32 in extensor digitorum longus and 412 in soleus). Exercise capacity and muscle strength were significantly decreased in β-DKO mice compared with fl/fl controls (P = 0.012), and a loss of structural integrity was also observed in skeletal muscle from the β-DKO mice. Supplementation of β-DKO mice with insulin restored muscle integrity, strength and expression of 13 and 16 of the dysregulated transcripts in and extensor digitorum longus and soleus muscles, respectively. CONCLUSIONS: Insulin insufficiency due to β-cell dysfunction perturbs the structure and function of skeletal muscle. These adverse effects are rectified by insulin supplementation. 2024-02-01T00:00:00Z