Co-delivery of salinomycin and curcumin for cancer stem cell treatment by inhibition of cell proliferation, cell cycle arrest, and epithelial-mesenchymal transition

Malignant cancer is a devastating disease often associated with a poor clinical prognosis. For decades, modern drug discoveries have attempted to identify potential modulators that can impede tumor growth. Cancer stem cells however are more resistant to therapeutic intervention, which often leads to treatment failure and subsequent disease recurrence. Here in this study, we have developed a specific multi-target drug delivery nanoparticle system against breast cancer stem cells (BCSCs). Therapeutic agents curcumin and salinomycin have complementary functions of limiting therapeutic resistance and eliciting cellular death, respectively. By conjugation of CD44 cell-surface glycoprotein with poly(lactic-co-glycolic acid) (PLGA) nanoparticles that are loaded with curcumin and salinomycin, we investigated the cellular uptake of BCSCs, drug release, and therapeutic efficacy against BCSCs. We determined CD44-targeting co-delivery nanoparticles are highly efficacious against BCSCs by inducing G1 cell cycle arrest and limiting epithelial–mesenchymal transition. This curcumin and salinomycin co-delivery system can be an efficient treatment approach to target malignant cancer without the repercussion of disease recurrence

A robust approach to differentiate human monocyte-derived microglia from peripheral blood mononuclear cells

Microglia are implicated in most neurodegenerative diseases. Here, we present a robust and efficient protocol to differentiate monocyte-derived microglia-like cells (MDMi) from whole blood. The protocol consists of three parts. The first part will describe two methods for PBMC isolation. This will be followed by MDMi differentiation, and lastly, the characterization of MDMi by immunocytochemistry. MDMi can be used to investigate microglial-related responses in various age-related neurodegenerative diseases and can be applied to drug testing on a personalized basis. For complete details on the use and execution of this protocol, please refer to Quek et al

SPT6-driven error-free DNA repair safeguards genomic stability of glioblastoma cancer stem-like cells

Glioblastoma cancer-stem like cells (GSCs) display marked resistance to ionizing radiation (IR), a standard of care for glioblastoma patients. Mechanisms underpinning radio-resistance of GSCs remain largely unknown. Chromatin state and the accessibility of DNA lesions to DNA repair machineries are crucial for the maintenance of genomic stability. Understanding the functional impact of chromatin remodeling on DNA repair in GSCs may lay the foundation for advancing the efficacy of radio-sensitizing therapies. Here, we present the results of a high-content siRNA microscopy screen, revealing the transcriptional elongation factor SPT6 to be critical for the genomic stability and self-renewal of GSCs. Mechanistically, SPT6 transcriptionally up-regulates BRCA1 and thereby drives an error-free DNA repair in GSCs. SPT6 loss impairs the self-renewal, genomic stability and tumor initiating capacity of GSCs. Collectively, our results provide mechanistic insights into how SPT6 regulates DNA repair and identify SPT6 as a putative therapeutic target in glioblastoma.Danish Cancer Society R146-A9511Danish Cancer Society R148-A10151Danish Council for Independent ResearchDanish National Research Foundation (CARD)Lundbeck FoundationNovo Nordisk Foundation NNF17OC0026056Novo Nordisk Foundation NNF16OC0023146Swedish research counci

Low Dose Ionizing Radiation Responses and Knockdown of ATM Kinase Activity in Glioma Stem Cells

Genesis of new cells in the mammalian brain has previously been regarded as a negligible event; an assumption that long prevented our understanding in the development of neoplasias. The recent discovery of perpetual lineages derived from neural stem cells has resulted in a new approach to studying the cellular behaviour of potential cancer stem cells in the brain. Glioblastoma multiforme (GBM), the most aggressive and lethal brain tumour is derived from such a group of cancerous stem cells known as glioma stem cells. GBM cells are impervious to conventional therapies such as surgical resection and ionizing radiation because of their pluripotent and radioresistant properties. Thus in our study, we aim to investigate whether a combination of chemo- and radio- therapies is an effective treatment for glioma stem cells. The study utilizes a specific kinase inhibitor (ATMi) of the ATM (Ataxia-telangiectasia mutated) protein which is an essential protein in DNA-damage responses. In the presence of both low dose radiation and ATMi, glioma stem cells have rapid onset of cell death and reduction in growth. Since DNA damage can be inherited through cell division, accumulated DNA breaks in later generations may also lead to cell death. The limitation of conventional radiation therapy is that administration of fractionated (low) doses to reduce any potential harm to the surrounding healthy cells in the brain outweighs the benefits of high radiation doses to induce actual arrest in the propagation of malignant cells. Our study demonstrates a benefit in using low dose radiation combined with chemotherapy resulting in a reduction in malignancy of glioma stem cells

Active compound, antioxidant, antiproliferative and effect on STZ induced zebrafish of various crude extracts from Boletus qriseipurpureus

Boletus qriseipurpureus (gelam mushroom) is a mushroom used by locals in Tok Bali, Kelantan, Malaysia to treat diabetes, cervical cancer and breast cancer. The active compounds in B. qriseipurpureus remain unidentified. Therefore, in this study, we investigated the potential medicinal properties of B. qriseipurpureus extracts (hot water, cold water and methanol extracts) by conducting preliminary phytochemical screening, in vitro antioxidant, in vitro antiproliferative and in vivo antidiabetic test. Biochemical assays were performed to detect the presence of alkaloids, anthraquinones, flavonoids, reducing sugars, saponins, steroids and tannins in B. qriseipurpureus extracts. 1,1-diphenyl-2-picrylhydrazyl (DPPH) was used to evaluate the antioxidant capacity of B. qriseipurpureus extracts, while MTT cell proliferation assay (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) was used to investigate the extracts antiproliferative activity. The effects of B. qriseipurpureus extracts on streptozotocin (STZ) induced zebrafish were examined at the concentration of 45 mg/mL, 90 mg/mL and 135 mg/mL. The effect of extracts were measured by the regenerative growth rate of the amputated caudal fin for fourteen days post transection. Screening of the mushroom extracts for active compounds revealed the presence of alkaloids, flavonoids, saponins and tannins in all test extracts. Reducing sugars and anthraquinones are only detected in hot water and cold water of B. qriseipurpureus extracts. The half maximal inhibitory concentration (IC50) of DPPH by hot water, cold water and methanol extract of B. qriseipurpureus are 1.79 mg/mL, 1.97 mg/mL and 3.98 mg/mL respectively. The MTT assay indicated that all extracts exhibited significant antiproliferative effects on MCF-7 cell line after 72 hours with IC50 of 7.7 mg/mL for hot water extract, 8.2 mg/ mL for cold water extract and 16.1 mg/mL for methanol extract but do not display any significant cytotoxic effect. The STZ induced zebrafish treated with 135 mg/mL of hot water B. qriseipurpureus extract for 14 days showed the highest regeneration growth rate of caudal fin (5.04 ± 0.43%) compared to fish treated with metformin (5.72 ± 0.64 %). In this study, we showed the potential of hot water B. qriseipurpureus extracts as a potent therapeutic agent for diabetes and as an alternative natural source of antioxidant

The burden of cardiovascular disease in Asia from 2025 to 2050: a forecast analysis for East Asia, South Asia, South-East Asia, Central Asia, and high-income Asia Pacific regions.

Summary Background Given the rapidly growing burden of cardiovascular disease (CVD) in Asia, this study forecasts the CVD burden and associated risk factors in Asia from 2025 to 2050. Methods Data from the Global Burden of Disease 2019 study was used to construct regression models predicting prevalence, mortality, and disability-adjusted life years (DALYs) attributed to CVD and risk factors in Asia in the coming decades. Findings Between 2025 and 2050, crude cardiovascular mortality is expected to rise 91.2% despite a 23.0% decrease in the age-standardised cardiovascular mortality rate (ASMR). Ischaemic heart disease (115 deaths per 100,000 population) and stroke (63 deaths per 100,000 population) will remain leading drivers of ASMR in 2050. Central Asia will have the highest ASMR (676 deaths per 100,000 population), more than three-fold that of Asia overall (186 deaths per 100,000 population), while high-income Asia sub-regions will incur an ASMR of 22 deaths per 100,000 in 2050. High systolic blood pressure will contribute the highest ASMR throughout Asia (105 deaths per 100,000 population), except in Central Asia where high fasting plasma glucose will dominate (546 deaths per 100,000 population). Interpretation This forecast forewarns an almost doubling in crude cardiovascular mortality by 2050 in Asia, with marked heterogeneity across sub-regions. Atherosclerotic diseases will continue to dominate, while high systolic blood pressure will be the leading risk factor. Funding This was supported by the NUHS Seed Fund (NUHSRO/2022/058/RO5+6/Seed-Mar/03), National Medical Research Council Research Training Fellowship (MH 095:003/008-303), National University of Singapore Yong Loo Lin School of Medicine's Junior Academic Fellowship Scheme, NUHS Clinician Scientist Program (NCSP2.0/2024/NUHS/NCWS) and the CArdiovascular DiseasE National Collaborative Enterprise (CADENCE) National Clinical Translational Program (MOH-001277-01)

Asian Pacific Society of Cardiology Consensus Recommendations on Dyslipidaemia

The prevalence of dyslipidaemia has been increasing in the Asia-Pacific region and this is attributed to dietary changes and decreasing physical activity. While there has been substantial progress in dyslipidaemia therapy, its management in the region is hindered by limitations in awareness, adherence and healthcare costs. The Asian Pacific Society of Cardiology (APSC) developed these consensus recommendations to address the need for a unified approach to managing dyslipidaemia. These recommendations are intended to guide general cardiologists and internists in the assessment and treatment of dyslipidaemia and are hoped to pave the way for improving screening, early diagnosis and treatment. The APSC expert panel reviewed and appraised the evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Consensus recommendations were developed, which were then put to an online vote. The resulting consensus recommendations tackle contemporary issues in the management of dyslipidaemia, familial hypercholesterolaemia and lipoprotein(a) in the Asia-Pacific region

Вихретоковый анизотропный термоэлектрический первичный преобразователь лучистого потока

Представлена оригинальная конструкция первичного преобразователя лучистого потока, который может служить основой для создания приемника неселективного излучения с повышенной чувствительностью