Non-cancerous Cells Research Articles

Untargeted metabolic analysis of Epaltes mexicana by LC-QTOF-MS: Terpenes with activity against human cancer cell lines

Epaltes mexicana is a plant widely used in traditional medicine and as a food in Mexico; however, its phytochemical and pharmacological studies are limited. This study aimed to identify the active secondary metabolites of Epaltes mexicana and determine its cytotoxic activity on cancer cell lines. Three organic extracts were obtained by maceration using n-hexane, dichloromethane, and methanol. The n-hexane extract was fractioned by simple column chromatography. Eight terpenes were annotated in collection 6 (C6) by LC-QTOF-MS using a gradient elution and Electrospray Ionization (ESI) in positive ion mode: 1) Gibberellin A15, 2) farfugin A, 3) dehydromyodesmone, 4) eremopetasitenin A1, 5) hydroxyisonobilin, 6) anhydrocinnzeylanine, 7) nigakilactone H and 8) taxodione. On the other hand, C6 showed a concentration-dependent cytotoxic effect on cancer cell lines MCF-7 (Emax = 74.69 ± 6.19 % and IC50 = 6.31 μg/mL), MDA-MB-231 (Emax = 79.28 ± 12.12 % and IC50 = 124.21 μg/mL), and SiHa (Emax = 82.96 ± 6.02 % and IC50 = 124.31 μg/mL). The C6 did not show a cytotoxic effect against DU-145 and non-cancerous cells from the mammary glands MCF-10A. These results indicate cytotoxic specificity on cancer cell lines and support the hypothesis that terpenes identified in E. mexicana must be investigated and developed for non-clinical and clinical trials as potential anti-cancer drugs.

Decreased PANK1 expression in kidney renal clear cell carcinoma: impact on cell apoptosis, invasion, migration, and epithelial-mesenchymal transition

ObjectiveTo investigate pantothenate kinases 1 (PANK1) expression in kidney renal clear cell carcinoma (KIRC) tissues, analyze its correlation with clinicopathological features and prognosis, and explore its impact on invasion, migration, and apoptosis in KIRC cells.MethodsGEPIA (gene expression profiling interactive analysis), UALCAN and LinkedOmics, were employed to analyze PANK1 expression in KIRC tissues and its correlation with clinical characteristics. Comparative analyses were performed between KIRC (Caki-1 and 786-O) and noncancerous renal cells (HK-2 and RPTEC). Transfection with PANK1 activation particles was conducted, followed by Wound healing, Transwell assay, Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) staining, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and Western blotting.ResultsPANK1 was down-regulated in KIRC tissues and cells compared to normal tissues and noncancerous cells. Correlation analyses linked PANK1 expression with clinicopathological features in KIRC, with high PANK1 expression associated with a favorable outcome. High PANK1 expression correlated positively with E-cadherin (CDH1), tight junction protein 1 (TJP1), Fas cell surface death receptor (FAS), caspase-8 (CASP8), and CASP9, while showing a negative correlation with vimentin (VIM), snail family transcriptional repressor 1 (SNAIL1), twist family BHLH transcription factor 1 (TWIST1), and TWIST2. PANK1 overexpression increased CDH1, TJP1, FAS, CASP8, and CASP9 while downregulating SNAIL1, VIM, TWIST1, and TWIST2, inhibiting invasion and migration, and promoting apoptosis in KIRC cells.ConclusionPANK1 down-regulation in KIRC tissues correlated with clinicopathological features and prognosis. Its overexpression modulated epithelial-mesenchymal transition (EMT)-related gene, inhibited invasion, promoted apoptosis in KIRC cells, highlighting its role in disease progression and therapeutic potential.

Parkinsonia praecox bark as a new source of antibacterial and anticancer compounds

IntroductionParkinsonia praecox is used in traditional medicine to treat various diseases; however, the antibacterial and anticancer properties from its bark have not been reported. Thus, this study aimed to evaluate the antibacterial activity, cytotoxicity and chemical study of methanolic extract of Parkinsonia praecox bark (PpBM). MethodsThe PpBM antibacterial activity was determined against pathogen strains using the broth microdilution method, the cytotoxic effect was assessed on cancerous (HepG2, SKOV-3 and HeLa) and non-cancerous (J774A.1 and HaCaT) cells using the crystal violet assay, the in vitro hemotoxicity was evaluated using the hemolysis assay on human erythrocytes and the identification of major compounds derived from PpBM was performed by 1H and 13C NMR and 2D NMR experiments. ResultsPpBM (2000 µg/mL) demonstrated antibacterial activity against Listeria monocytogenes, a potential breakthrough in the fight against this pathogen. PpBM decreased cell viability of HepG2 liver cancer cells (IC50, 104.56 µg/mL) with a selectivity index of 1.38 regarding J774A.1 macrophages and 2.04 to HaCaT keratinocytes, suggesting a selective anticancer potential. On the other hand, PpBM did not cause hemolysis to high concentrations (1000 µg/mL) or alterations in the morphology of human erythrocytes at doses lower than 200 µg/mL. For the first time, lupenone, germanicone, 3-oxo-oleanane-18-en-28-ol, and combretol were identified in P. praecox. PpBM showed antibacterial, selective anticancer, and non-hemotoxic properties. These activities may be related to the major compounds, such as lupenone. ConclusionP. praecox bark is a new option for obtaining bioactive compounds, further in vitro and in vivo studies are required to confirm their efficacy and safety.

The association between histopathological growth patterns with tumor budding and poorly differentiated clusters in colorectal liver metastasis treated with preoperative systemic therapy.

The liver's unique cellular structure makes it a frequent site for metastatic cancer. In colorectal liver metastasis (CRLM), surgical resection is essential for long-term survival. Histopathological growth patterns (HGPs) in CRLM, including desmoplastic and nondesmoplastic patterns, provide critical prognostic information. Tumor budding (TB) and poorly differentiated clusters (PDCs), indicators of aggressive cancer behavior, are evaluated using standardized histological scoring systems and are linked to epithelial-mesenchymal transition. This study explored the correlation between HGPs, TB, and PDCs in CRLM. Archived data from Thammasat University Hospital, including resected CRLM specimens, were analyzed. This study evaluated 51 CRLM resection specimens treated with preoperative systemic therapy, finding most to be nondesmoplastic with low TB and grade 1 PDC. Desmoplastic growth was significantly more prevalent in cases receiving preoperative chemotherapy than those that did not. Higher 3-year mortality was noted in nondesmoplastic groups and those with higher TB and tumor regression grade (TRG) scores. Significant correlations were observed between HGPs, TB, and PDCs, despite challenges in assessing these parameters due to issues with noncancer cells, extracellular mucin, bile ductular proliferation, and retraction artifacts. This study underscores the prognostic significance of HGPs, TB, PDCs, and TRG scores in CRLM, highlighting the need for precise histopathological evaluation for more accurate prognostic implications.

Significant enhancement of anticancer effect of iridium (III) complexes encapsulated in liposomes

In this study, the ligand EIPP (5-ethoxy-2-(1H-imidazo[4,5-f] [1,10] phenanthrolin-2-yl)phenol) and [Ir(ppy)2(EIPP)](PF6)] (5a, ppy = 2-phenylpyridine) and [Ir(piq)2(EIPP)](PF6)] (5b, piq = 1-phenylisoquinoline) were synthesized and they were entrapped into liposomes to produce 5alipo and 5blipo. 5a and 5b were characterized via HRMS, NMR, UV–vis and IR. The cytotoxicity of 5a, 5b, 5alipo and 5blipo on cancer and non-cancer cells was estimated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). MTT assay demonstrated that 5a and 5b did not show any significant cellular activity but their liposome-encapsulated 5alipo and 5blipo had significant toxic effects. The mechanism of 5alipo, 5blipo-inducing apoptosis was explored by studying cellular uptake, mitochondrial localization, mitochondrial membrane potential, cytochrome C, glutathione (GSH), malondialdehyde (MDA) and protein immunoblotting. The results demonstrated that 5alipo and 5blipo caused a release of cytochrome C, downregulated the expression of Bcl-2, upregulated the expression of BAX, activated caspase 3, and downregulated PARP expression. It was shown that 5alipo and 5blipo could inhibit cancer cell proliferation in G2/M phase by regulating p53 and p21 proteins. Additionally, 5alipo and 5blipo induced autophagy through an adjustment from LC3-I to LC3-II and caused ferroptosis. The in vivo antitumor activity of 5alipo was examined in detail

The role of LPA receptor signaling in modulating cellular responses of colon cancer cells co-cultured with lymphoid endothelial cells under hypoxic stress

Solid tumors are formed by cancer cells and the surrounding non-cancer stromal cells under hypoxic conditions, collectively referred to as the tumor microenvironment (TME). Lysophosphatidic acid (LPA) receptor (LPA1 to LPA6) signaling is crucial in regulating tumor progression. This study investigated the impact of LPA receptor signaling on the biological behaviors of colon cancer DLD-1 cells co-cultured with lymphatic endothelial SVEC4–10 cells under hypoxic conditions. Expression levels of LPAR1, LPAR2 and LPAR5 genes were significantly higher in DLD-1 cells co-cultured with SVEC4–10 cells compared to those cultured alone. Co-culturing with SVEC4–10 cells increased the motility of DLD-1 cells at 21 % O2. LPA stimulated the motility of DLD-1 cells co-cultured with SVEC4–10 cells but had no effect on DLD-1 cells cultured alone. Furthermore, under 1 % O2 conditions, expression levels of LPAR1, LPAR2, and LPAR5 genes were markedly elevated in DLD-1 cells co-cultured with SVEC4–10 cells compared to 21 % O2. The motility of DLD-1 cells co-cultured with SVEC4–10 cells was enhanced under 1 % O2 conditions. Viability of DLD-1 cells to fluorouracil (5-FU) in SVEC4–10 cell supernatants increased at 21 % O2 and decreased at 1 % O2. Additionally, the LPA2 agonist GRI-977143 increased viability to 5-FU. These findings indicate that LPA receptor signaling plays a critical role in regulating the biological behaviors of DLD-1 cells co-cultured with SVEC4–10 cells under hypoxic conditions.

NO- and H2S- releasing nanomaterials: A crosstalk signaling pathway in cancer

The gasotransmitters nitric oxide (NO) and hydrogen sulfide (H2S) play important roles not only in maintaining physiological functions, but also in pathological conditions and events. Importantly, these molecules show a complex interplay in cancer biology, demonstrating both tumor-promoting and anti-tumor activities depending on their concentration, flux, and the environmental redox state. Additionally, various cell types respond differently to NO and H2S. These gasotransmitters can be synergistically combined with traditional anticancer treatments such as radiotherapy, immunotherapy, chemotherapy, and phototherapy. Notably, NO, and more recently H2S, have been shown to reverse multidrug resistance. Nanomaterials to deliver NO donors and, to a lesser extent, H2S donors, have emerged as a promising approach for targeted delivery of these gasotransmitters. Nanotechnology has advanced the delivery of anticancer drugs, enhancing efficiency and reducing side effects on non-cancerous cells. This review highlights recent progress in the design of NO and H2S-releasing nanomaterials for anticancer effects. It also explores the interactions between NO and H2S, which are crucial for developing combined therapies and nanomedicines with minimal side effects.

Unveiling the anticancer potential of Pestalotioprolide E, an unexplored macrolide: Targeting TRXR1-TRX1-ASK1-P38 signaling cascade in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is highly aggressive and metastatic in nature. Existing treatment modalities for TNBC are associated with severe side effects. Thioredoxin reductase (TRXR), the pivotal component of the thioredoxin system, remains overexpressed in various cancer cells including TNBC; promotes cell growth, proliferation, and metastasis, and inhibits apoptosis. Pestalotioprolide E is one of the potent macrolides, a class of secondary metabolites derived from an endophytic fungus Pestalotiopsis microspora with relatively unexplored biological activities. Our study revealed increased expression and activity of TRXR1 in MDA-MB-231 cells compared to the non-cancerous cells. In silico docking analysis and in vitro activity assay demonstrated that Pestalotioprolide E directly interacts with TRXR1 and inhibits its enzymatic activity. This inhibition induces apoptosis via TRX1/ASK1/P38MAPK death signaling cascade and retards metastasis through modulating VEGF, MMP-2, MMP-9, E-cadherin, N-cadherin in MDA-MB-231 cells. Taken together present study establishes TRXR1 as a molecular target for Pestalotioprolide E and its anticancer effect can be attributed to the inhibition of TRXR1 activity in MDA-MB-231.

Integrating high mannose-binding aptamer and CRISPR/Cas12a machinery for the remote detection of cell surface high mannose

High mannose is overexpressed on the cell surface during carcinogenesis; however, there are currently no efficient techniques for its detection. Herein, we propose an assay called RADAR (remote high mannose detection on cell surface with CRISPR) for the quantification of high mannose, leveraging the integration of high mannose-binding aptamer and CRISPR technique. The high mannose-binding aptamer is hybridized with a locker, which is released upon specific binding to high mannose. The released locker then activates CRISPR/Cas12a to produce a fluorescence signal. The "remote" concept in RADAR refers to the recognition of high mannose occurring on the cell surface, while signal generation takes place in a solution separate from the target. This feature makes RADAR suitable for the detection of suspended bio-samples without the need for sophisticated imaging. RADAR can detect high mannose Man9 with a limit of detection of 2.5 nM, distinguish cancer cells from non-cancerous cells, and profile high mannose level in human serum for potential non-small cell lung cancer (NSCLC) diagnosis. This work represents the first attempt to integrate CRISPR technology into the aptasensing of high mannose, which may serve as a synthetic biology-enabled tool in glycochemistry and glycobiology.

Gouregine, an α-Gem-Dimethyltetradehydrocularine Alkaloid, and Other Aporphinoid Alkaloids from the Bark of Guatteria olivacea (Annonaceae) and Their In Vitro Cytotoxic Activities.

Guatteria olivacea R.E. Fries is an Amazonian species known as 'envira-bobó' and 'envira-fofa' and is common in the states of Amazonas, Acre, and Pará. Recently, the essential oil from the leaves of this species has shown promising antitumor activity both in vitro and in vivo. The presence of isoquinoline-derived alkaloids, including aporphinoids and tetrahydroprotoberberine alkaloids, has also been previously reported. In our ongoing search for bioactive compounds from Annonaceae Amazonian plants, the bark of G. olivacea was investigated via classical chromatography techniques, which revealed nine compounds, eight isoquinoline-derived alkaloids, a rare alkaloid with a α-gem-dimethyltetradehydrocularine structure known as gouregine, seven known aporphinoid alkaloids: isopiline, O-methylisopiline, melosmine, 9-hydroxyiguattescine, dihydromelosmine, lysicamine, and guattouregidine, and one known pimaradiene diterpene: acanthoic acid. All the isolated compounds were described for the first time in the bark of G. olivacea, and their structures were elucidated by extensive analyses of their 1D and 2D NMR spectra in combination with MS data. The NMR data of the alkaloids isopiline, O-methylisopiline, melosmine, dihydromelosmine, and guattouregidine were revised due to incomplete data in the literature and some ambiguities. The in vitro cytotoxic activities of the isolated compounds were evaluated against human cancer (HepG2, KG-1a, and HCT116) and noncancerous (MRC-5) cell lines via the Alamar blue assay after 72 h of incubation. Among the compounds evaluated against human cancer cell lines, the most active was the oxoaporphine alkaloid lysicamine, which has strong activity against HCT116 cells, with an IC50 value of 6.64 µg/mL (22.79 µmol/L). Melosmine had a moderate effect on HCT116 cells, with an IC50 value of 16.77 µg/mL (49.70 µmol/L), whereas acanthoic acid had moderate effects on HepG2 and HCT116 cells, with IC50 values of 14.63 µg/mL (48.37 µmol/L) and 21.25 µg/mL (70.25 µmol/L), respectively.

Anticancer potential of NSAID-derived tris(pyrazolyl)methane ligands in iron(II) sandwich complexes.

Tris(pyrazolyl)methane (tpm), 2,2,2-tris(pyrazolyl)ethanol (tpmOH) and its esterification derivatives with ibuprofen and flurbiprofen (tpmIBU and tpmFLU) were used as ligands to obtain complexes of the type [Fe(tpmX)2]Cl2 (1-4). The tpmIBU and tpmFLU ligands and corresponding complexes 3 and 4 were characterized by IR and multinuclear NMR spectroscopy, and the structure of tpmIBU was elucidated by single crystal X-ray diffraction. Complexes 1-4 were also assessed for their behaviour in aqueous media (solubility in D2O, octanol/water partition coefficient, stability in physiological-like conditions). The antiproliferative activity of ligands and complexes was determined on A2780, A2780cis and A549 cancer cell lines and the non-cancerous HEK 293T and BJ cell lines. The ligands and complexes were investigated for their ability to inhibit COX-2 (cyclooxygenase) and HNE (4-hydroxynonenal) enzymes. Complexes 3 and 4 exhibited cytotoxicity that may be attributed predominantly to their bioactive fragments, while DNA binding and enhancement of ROS production do not appear to play any significant role.

Endocytosis Pathways of Graphene Quantum Dots

Graphene quantum dots (GQDs) have emerged as a forerunner of carbon nanbiootechnology due to their multifunctional delivery and imaging capabilities as they exhibit fluorescence in the visible and near-infrared, high biocompatibility, and water solubility. These properties put GQDs forward as a compelling drug delivery platform that has already been utilized in a variety of applications including the delivery of chemotherapeutics, antibiotics as well as siRNA and CRISPR-based gene therapy. However, cellular entry pathways of this nanomaterial still remain largely undefined. In a number of studies describing GQD cellular internalization different and, often, conflicting results have been presented due to surveying only few endocytosis inhibitors and disregarding their potential off-target pathways. Understanding the cell internalization routes of GQDs is crucial while delivering drugs in different types of cell lines. Herein, we performed a holistic approach to cell uptake studies on GQDs of different charges by the comparative study of their preferred endocytosis paths in non-cancerous (HEK-293) and cancerous (HeLa) cell lines. The concentration and cell viability of GQDs were determined by MTT assays, while their endocytosis paths were investigated through confocal fluorescence microscopy on cells treated for up to 24 hours. The potential for GQD interactions with the cell membrane was also examined via zeta (ζ) potential measurements. Our findings provide insights into the internalization mechanisms of the GQDs into cell membranes of healthy and cancer cells. The optimization of these mechanisms can serve for the enhancement of a variety of novel GQD applications in biomedicine including therapeutic delivery, disease detection through sensing as well as diagnostic imaging.

Enhancing Bioactivity of N,N,N-Chelating Rhodium(III) Complexes with Ionic Liquids: Toward Targeted Cancer Therapy.

This study investigates the potential of using ionic liquids as cosolvents to enhance the solubility and activity of poorly soluble rhodium(III) complexes, particularly those with diene, pyridine derivatives, and camphor-derived bis-pyrazolylpyridine ligands, in relation to 5'-GMP, CT-DNA, and HSA as well as their biological activity. Findings indicate that ionic liquids significantly increase the substitution activity of these complexes toward 5'-GMP while only marginally affecting DNA/HSA binding affinities with molecular docking, further confirming the experimental results. Lipophilicity assessments indicated good lipophilicity. Notably, cytotoxicity studies show that Rh2 is selectively effective against HeLa cancer cells, with IL1 and IL10 modulating the cytotoxic effects. Redox evaluations indicate that rhodium complexes induce oxidative stress in cancerous cells while maintaining redox balance in noncancerous cells. By elucidating the role of ionic liquids in modulating these effects, the study proposes a promising avenue for augmenting the efficacy and selectivity of cancer treatments, thus opening new horizons in cancer therapeutics.

Tailored amino acid-derived ionic Liquids: Precision chemotherapy for tumors

A set of fourteen imidazolium ionic liquids, each derived from L-amino acids and featuring distinct hydrophobic and hydrophilic components, were synthesized and physicochemically characterized. Thermal analysis showed transition temperatures remaining below 100 °C, being the rigid solid to elastic solid transition temperatures between −27 °C to + 57 °C. The aggregation studies investigated by fluorescence in water and buffered media showed two critical micellar concentrations (CMC) in aqueous media for compounds 7, 8 and 9, with the formation of well-defined aggregates in the second step. The synthesized ILs were assessed for their effects on two cancer cell lines, namely human lung adenocarcinoma A-549 and colon adenocarcinoma HT-29, under both physiological and acidic pH conditions. Furthermore, the influence of the ILs on embryonic kidney cells (HEK-293) was investigated to assess their effect on non-cancerous cells. This study demonstrates that the manipulation of various design vectors allowed for the precise tuning of the structure of ILs, resulting in IC50 values within the micromolar range. ILs featuring a NC12 alkyl side chain in the amide consistently exhibited low IC50 values and a high degree of selectivity against non-tumoral cells under acidic pH conditions. Subsequent investigations were carried out to gain insights into the cellular-level mechanisms of action. These findings provide strong evidence that by meticulously adjusting the molecular structure of these functionalized ILs, it is possible to design potent and selective chemotherapeutic agents.

Bromelain-facilitated GNPs: A strategic innate anticancer delivery system for methotrexate into osteosarcoma cells

Osteosarcoma is the most common malignant bone tumor in children and adolescents during rapid bone growth. Traditional chemotherapy has markedly improved patient outcomes but suffers from nonspecific side effects due to nonspecific drug distribution, highlighting the need for targeted therapies. Methotrexate, although effective, poses toxicity concerns and prompts exploration into advanced drug delivery systems like nanoparticles. Here, we developed a novel method of synthesizing gold nanoparticles using bromelain (G-BNPs) as a reducing and capping agent, and we conjugated G-BNPs with methotrexate (G-B-MNPs) via 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide (EDC/NHS) as crosslinker. Our meticulous characterization, which included UV–visible spectroscopy, Transmission electron microscopy (TEM), Dynamic light scattering (DLS), Zeta potential, and Fourier-transform infrared spectroscopy (FTIR) analyses confirmed the successful fabrication and drug conjugation of the G-BNPs. We then evaluated the cytotoxicity of the G-BNPs (sized ∼ 21 nm) and G-B-MNPs (sized ∼ 24 nm) on the osteosarcoma cell lines, Saos-2 and MG-63, as well as the non-cancerous primary osteoblast cells. Our findings revealed that G-B-MNPs significantly increased the cytotoxic impact on osteosarcoma cells compared to methotrexate alone while showing minimal toxicity toward primary osteoblast cells. Importantly, using 4`,6-diamidino-2-phenylindole(DAPI), we demonstrated that G-B-MNPs were delivered directly into the nucleus of the cells without encountering lysosomes. G-B-MNPs can be considered a potential drug delivery method for osteosarcoma treatment by improving effectiveness and reducing adverse effects, thereby enhancing patient prognosis.

Abstract Tu105: Inhibition of Queuine tRNA-Ribosyltransferase 1 Ameliorates Heaptic Lipogenesis and Atherosclerosis

Background: Atherosclerosis threatens cardiovascular health, which is featured by abnormal lipid metabolism and chronic inflammation in arterial wall. Queuine tRNA-Ribosyltransferase 1 (QTRT1) , is an enzyme responsible for tRNA modification at the wobble base. Research Questions: It is unclear whether the function of QTRT1 is involved in metabolism of non-cancer cells and tissues, especially lipid metabolism mainly orchestrated by liver. Aims: We aimed to explore the role of QTRT1 deficiency in hyperlipidemia, liver steatosis and atherosclerosis. Methods: Transgenic mice such as Qtrt1fl/flAlb-iCre+/- (Qtrt1LKO), Qtrt1fl/fl(WT), ApoE-/-, and gain of function of PCSK9 by adeno-associated virus gene transfer were used to determine the functional significance of QTRT1 in atherosclerosis. Synthesis, transportation and oxidation of lipids in livers and hepatocytes were examined by quantitative real-time polymerase chain reaction. Moreover, primary hepatocytes with overexpression and downregulation of QTRT1 were followed by RNA sequencing to identify downstream targets. Results: Deficiency of hepatic QTRT1 significantly attenuated hyperlipidemia, liver steatosis and atherosclerotic burden, but increased plaque stability in the aorta of mice. Depletion of QTRT1 markedly downregulated de novo lipogenesis (DNL) without influence on lipoprotein transportation and fatty acid oxidation. Qtrt1LKO mice on a high-carbohydrate diet displayed relatively reduced hyperlipidemia and alleviation of DNL. RNA-seq indicated that odorant binding protein 2A (OBP2A) was upregulated in Qtrt1LKO hepatocytes, which reversed the promotion of DNL by QTRT1 in hepatocytes. Conclusion: Inhibition of QTRT1 in hepatocytes ameliorates hepatic lipogenesis and atherosclerosis in mice. Targeting of QTRT1 is a promising strategy to improve therapeutic effectiveness in both hyperlipidemia and atherosclerosis.

Selective induction of senescence in cancer cells through near-infrared light treatment via mitochondrial modulation.

Photobiomodulation, utilising non-ionising light in the visible and near-infrared (NIR) spectrum, has been suggested as a potential method for enhancing tissue repair, reducing inflammation and possibly mitigating cancer-therapy-associated side effects. NIR light is suggested to be absorbed intracellularly, mainly by chromophores within the mitochondria. This study examines the impact of 734 nm NIR light on cellular senescence. Cancer (MCF7 and A549) and non-cancer (MCF10A and IMR-90) cell populations were subjected to 63 mJ/cm2 NIR-light exposure for 6 days. Senescence levels were quantified by measuring active senescence-associated beta-galactosidase. Exposure to NIR light significantly increases senescence levels in cancer (10.0%-203.2%) but not in non-cancer cells (p > 0.05). Changes in senescence were associated with significant modulation of mitochondrial homeostasis, including increased levels of reactive oxygen species (p < 0.05) and mitochondrial membrane potential (p < 0.05) post-NIR-light treatment. These results suggest that NIR light modulates cellular chemistry, arresting the proliferation of cancer cells via senescence induction while sparing non-cancer cells.

Hypermethylation of genes on chromosome 3p as a biomarker for nasopharyngeal carcinoma diagnosis: A Vietnamese case-control study.

The crucial event driving nasopharyngeal tumorigenesis is the hypermethylation of chromosome 3p-located tumor suppressor genes. This case-control study aims to investigate the methylation characteristics of RASSF1A, Blu, ADAMTS9, and DLEC1 to potentially develop effective diagnostic biomarkers for nasopharyngeal carcinoma, either individually or in combination. The methylation of RASSF1A, Blu, ADAMTS9, and DLEC1 in the collection of 93 biopsy samples and 100 healthy swab specimens were evaluated by Nested methylation-specific polymerase chain reaction. The strength of the correlation between candidate genes and nasopharyngeal carcinoma was estimated by the evaluation of odds ratios (ORs). Promoter hypermethylation of RASSF1A, Blu, ADAMTS9, and DLEC1 were found in 60.22%, 80.65%, 62.37%, and 74.19%, respectively, in nasopharyngeal carcinoma tumors. A significant association between the methylation status of candidate genes with nasopharyngeal carcinoma was reported. The methylation of candidate genes significantly increased the risk of nasopharyngeal carcinoma in cancerous samples compared with control samples (OR > 1). Based on the value of the methylation index, methylation of at least one gene was found in 95.70% of nasopharyngeal tumors. Additionally, the methylation index among 93 tumors significantly correlated with advanced stage nasopharyngeal tumors. The study explored a higher frequency of hypermethylation at least one candidate gene. Methylation of a panel of potential genes can be utilized to discriminate between nasopharyngeal carcinoma and non-cancer cells, particularly in the advanced stages of nasopharyngeal carcinoma. Thus, it could serve as a valuable marker for the diagnosis and monitoring of nasopharyngeal carcinoma.

Cheminformatics-Guided Exploration of Synthetic Marine Natural Product-Inspired Brominated Indole-3-Glyoxylamides and Their Potentials for Drug Discovery.

Marine natural products (MNPs) continue to be tested primarily in cellular toxicity assays, both mammalian and microbial, despite most being inactive at concentrations relevant to drug discovery. These MNPs become missed opportunities and represent a wasteful use of precious bioresources. The use of cheminformatics aligned with published bioactivity data can provide insights to direct the choice of bioassays for the evaluation of new MNPs. Cheminformatics analysis of MNPs found in MarinLit (n = 39,730) up to the end of 2023 highlighted indol-3-yl-glyoxylamides (IGAs, n = 24) as a group of MNPs with no reported bioactivities. However, a recent review of synthetic IGAs highlighted these scaffolds as privileged structures with several compounds under clinical evaluation. Herein, we report the synthesis of a library of 32 MNP-inspired brominated IGAs (25-56) using a simple one-pot, multistep method affording access to these diverse chemical scaffolds. Directed by a meta-analysis of the biological activities reported for marine indole alkaloids (MIAs) and synthetic IGAs, the brominated IGAs 25-56 were examined for their potential bioactivities against the Parkinson's Disease amyloid protein alpha synuclein (α-syn), antiplasmodial activities against chloroquine-resistant (3D7) and sensitive (Dd2) parasite strains of Plasmodium falciparum, and inhibition of mammalian (chymotrypsin and elastase) and viral (SARS-CoV-2 3CLpro) proteases. All of the synthetic IGAs tested exhibited binding affinity to the amyloid protein α-syn, while some showed inhibitory activities against P. falciparum, and the proteases, SARS-CoV-2 3CLpro, and chymotrypsin. The cellular safety of the IGAs was examined against cancerous and non-cancerous human cell lines, with all of the compounds tested inactive, thereby validating cheminformatics and meta-analyses results. The findings presented herein expand our knowledge of marine IGA bioactive chemical space and advocate expanding the scope of biological assays routinely used to investigate NP bioactivities, specifically those more suitable for non-toxic compounds. By integrating cheminformatics tools and functional assays into NP biological testing workflows, we can aim to enhance the potential of NPs and their scaffolds for future drug discovery and development.

Development and validation of 3D printed anthropomorphic head phantom with eccentric holes for medical LINAC quality assurance testing in stereotactic radiosurgery

Stereotactic Radiosurgery (SRS) for brain tumors using Medical Linear Accelerator (LINAC) demands high precision and accuracy. A specific Quality Assurance (QA) is essential for every patient undergoing SRS to protect nearby non-cancerous cells by ensuring that the X-ray beams are targeted according to tumor position. In this work, a water-filled generic anthropomorphic head phantom consisting of two removable parts with eccentric holes was developed using Additive Manufacturing (AM) process for performing QA in SRS. In the patient specific QA, the planned radiation dose using Treatment Planning System (TPS) was compared with the dose measured in the phantom. Also, the energy consistency of radiation beams was tested at 200 MU for different energy beams at the central and eccentric holes of the phantom using an ionization chamber. Experimentally examined results show that planned doses in TPS are reaching the target within a 5% deviation. The ratio of the dose delivered in the eccentric hole to the dose delivered to the central hole shows variations of less than 2% for the energy consistency test. The designed, low-cost water-filled anthropomorphic phantom is observed to improve positioning verification and accurate dosimetry of patient-specific QA in SRS treatment.