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Pharmaceutics Dec 2021Cancer has been identified as a leading cause of death worldwide, and the increasing number of cancer cases threatens to shorten the average life expectancy of people....
Cancer has been identified as a leading cause of death worldwide, and the increasing number of cancer cases threatens to shorten the average life expectancy of people. Recently, we reported a 3-azido-3-deoxythymidine (AZT)-based amphipathic small molecule, ADG-2e that revealed a notable potency against tumor metastasis. To evaluate the anticancer potential of ADG-2e, we assessed its anticancer potency in vitro and in vivo. Anticancer screening of ADG-2e against cervical cancer cells, HeLa CCL2, and BT549 mammary gland ductal carcinoma showed significant inhibition of cancer cell proliferation. Furthermore, mechanistic investigations revealed that cancer cell death presumably proceeded through an oncosis mechanistic pathway because ADG-2e treated cells showed severe damage on the plasma membrane, a loss of membrane integrity, and leakage of -tubulin and -actin. Finally, evaluation of the antitumorigenic potential of ADG-2e in mouse xenograft models revealed that this compound potentially inhibits cancer cell proliferation. Collectively, these findings suggest that ADG-2e can evolve as an anticancer agent, which may represent a model for nucleoside-based small molecule anticancer drug discovery.
PubMed: 34959352
DOI: 10.3390/pharmaceutics13122071 -
Folia Neuropathologica 2021Migraine is considered not only as a separate clinical entity but also as a symptom of various brain disorders, including cerebral small vessel diseases. Since...
INTRODUCTION
Migraine is considered not only as a separate clinical entity but also as a symptom of various brain disorders, including cerebral small vessel diseases. Since cerebral small vessel diseases are usually general angiopathies, evaluation of biopsy material other than brain tissue may help in their diagnosis in vivo. In patients with migraine, brain magnetic resonance imaging (MRI) often shows hyperintense changes in the cerebral white matter. Such changes may indicate the symptomatic nature of migraine and coexisting structural or biochemical vascular abnormalities.
MATERIAL AND METHODS
To verify the hypothesis of the symptomatic nature of migraine in patients with abnormal brain neuroimaging, we performed an ultrastructural examination of skin and skeletal muscle vessels in biopsy material from 40 patients with clinically diagnosed migraine and hyperintense white matter lesions on MRI.
RESULTS
In 80% of the examined patients, ultrastructural examination showed various pathological changes in the microvessels including abnormalities characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and elastin disorders, as well as less specific changes such as thickening of the basal lamina, narrowing of the vessel lumen, degeneration of the vessel wall cells, endothelial activation, oncosis-like changes, and the presence of various types of deposits in the vessel wall. In 20% of the examined cases, ultrastructural examination of the vessels was normal.
CONCLUSIONS
Patients with migraine and hyperintense cerebral white matter changes on MRI have an increased risk of concomitant microangiopathy. In this group of patients, skin-muscle biopsy allows the identification of cases with coexisting vessel abnormalities.
Topics: Brain; CADASIL; Humans; Magnetic Resonance Imaging; Migraine Disorders; White Matter
PubMed: 34628791
DOI: 10.5114/fn.2021.108582 -
Scientific Reports Aug 2021Hepatocellular carcinoma (HCC) still presents poor prognosis with high mortality rate, despite of the improvement in the management. The challenge for precision...
Hepatocellular carcinoma (HCC) still presents poor prognosis with high mortality rate, despite of the improvement in the management. The challenge for precision treatment was due to the fact that little targeted therapeutics are available for HCC. Recent studies show that metabolic and circulating peptides serve as endogenous switches for correcting aberrant cellular plasticity. Here we explored the antitumor activity of low molecular components in human umbilical serum and identified a high abundance peptide VI-13 by peptidome analysis, which was recognized as the part of glutamyltransferase signal peptide. We modified VI-13 by inserting four arginines and obtained an analog peptide VI-17 to improve its solubility. Our analyses showed that the peptide VI-17 induced rapid context-dependent cell death, and exhibited a higher sensitivity on hepatoma cells, which is attenuated by polyethylene glycol but not necrotic inhibitors such as z-VAD-fmk or necrostatin-1. Morphologically, VI-17 induced cell swelling, blebbing and membrane rupture with release of cellular ATP and LDH into extracellular media, which is hallmark of oncotic process. Mechanistically, VI-17 induced cell membrane pore formation, degradation of α-tubulin via influx of calcium ion. These results indicated that the novel peptide VI-17 induced oncosis in HCC cells, which could serve as a promising lead for development of therapeutic intervention of HCC.
Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Death; Cell Line, Tumor; Fetal Blood; Humans; Liver Neoplasms; Peptides
PubMed: 34389740
DOI: 10.1038/s41598-021-93055-5 -
Biological & Pharmaceutical Bulletin Oct 2021The "dextran-magnetic layered double hydroxide-fluorouracil" (DMF) drug delivery system is a new type of pharmaceutic preparation that can cause cancer cell oncosis. In...
The "Dextran-Magnetic Layered Double Hydroxide-Fluorouracil" Drug Delivery System Exerts Its Anti-tumor Effect by Inducing Lysosomal Membrane Permeability in the Process of Cell Death.
The "dextran-magnetic layered double hydroxide-fluorouracil" (DMF) drug delivery system is a new type of pharmaceutic preparation that can cause cancer cell oncosis. In the present study, we used different experimental methods such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cycle assay, reactive oxygen species (ROS) assay, Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI), Giemsa stainings, transmission electron microscopy, immunofluorescence staining and Western blotting to study the mechanism of expansion death by using Hydroxychloroquine (HCQ) as a positive control and 5-Fluorouracil (5-Fu) as reference. The results showed that DMF exhibited a better anti-tumor effect than 5-Fu in the process of cell death, and the pharmacological mechanism of 5-Fu was changed by its preparation DMF. The mechanism of cancer cell death induced by DMF was similar to that of HCQ. But DMF intervention did not cause a large amount of accumulation of mitochondrial reactive oxygen species, and the location of lysosomotropic LysoTracker Red (LTR) staining induced by DMF was closer to the nucleus or nuclear membrane. Lysosomal membrane permeability (LMP) and its subsequent the explosive death of cancer cells may be mainly related to the direct action of DMF with different organelles.
Topics: Adenocarcinoma; Antineoplastic Agents; Azure Stains; Blotting, Western; Cell Death; Cell Line, Tumor; Dextrans; Drug Delivery Systems; Fluorescent Antibody Technique; Fluorouracil; Humans; Lymphatic Metastasis; Lysosomes; Magnetic Iron Oxide Nanoparticles; Microscopy, Electron, Transmission; Permeability; Stomach Neoplasms
PubMed: 34305072
DOI: 10.1248/bpb.b21-00297 -
Journal of Healthcare Engineering 2021With the continuous popularization of smart medicine, the protective effect of silibinin in the liver has attracted much attention. This study mainly explores the liver...
With the continuous popularization of smart medicine, the protective effect of silibinin in the liver has attracted much attention. This study mainly explores the liver protection mechanism and absorption promotion technology of silybin based on intelligent medical analysis. Refining of silibinin: accurately weigh 1.0 g of silibinin in a three-necked flask; gradually add 50 mL of anhydrous methanol, reflux and filter the precipitated solid; and weigh it after drying. ICR male mice were taken as experimental subjects and randomly divided into groups of 10 each. The mice in the normal group and the model group were given intragastrically with 0.5% CMC-Na solution; the mice in the silibinin group were given intragastrically with SB/CMC-Na suspension; the mice in the remaining groups were given low, medium, and high-dose suspensions to their stomachs, and silibinin 23 acylate/CMC-Na suspension was administered at a dose of 10 mL/kg for 7 consecutive days. After that, the mice were fasted for 12 hours. After 6 hours of fasting (18 hours after modeling), the blood cells from their orbits were taken, placed in a 37°C water bath for 30 minutes, and centrifuged at 4000 rpm for 10 minutes, and then the serum was taken; the activity equivalent of AST and ALT in serum was measured; serum determination Medium AST and ALT vitality. The mice were killed by decapitation, fresh liver tissue was immediately collected, and part of it was frozen in liquid nitrogen for the RT-PCR test. The hepatocyte expansion and death were observed using a transmission electron microscope, and the oncosis index (OI) was calculated. Another part of the liver tissue was fixed in 4% paraformaldehyde solution, embedded in paraffin, dehydrated, and sliced at 4 m. Some sections were stained with conventional HE, and the pathological changes of liver cells were observed under light microscope; some sections were subjected to immunohistochemistry. Only one mouse died when 240 mg/kg of silibinin was given 10 minutes after the model was modeled. However, when 240 mg/kg silibinin was given to the mice 20 minutes after modeling, the mortality rate of the mice rose to 50%, and the therapeutic effect was significantly weakened. This research is helpful to advance the research of silybin in liver protection.
Topics: Animals; Humans; Liver; Male; Mice; Mice, Inbred ICR; Random Allocation; Silybin; Technology
PubMed: 34285784
DOI: 10.1155/2021/9968016 -
Advanced Science (Weinheim,... Sep 2021Oncosis, depending on DNA damage and mitochondrial swelling, is an important approach for treating cancer and other diseases. However, little is known about the behavior...
Oncosis, depending on DNA damage and mitochondrial swelling, is an important approach for treating cancer and other diseases. However, little is known about the behavior of mitochondria during oncosis, due to the lack of probes for in situ visual illumination of the mitochondrial membrane and mtDNA. Herein, a mitochondrial lipid and mtDNA dual-labeled probe, MitoMN, and a continuous add-on assay, are designed to image the dynamic process of mitochondria in conditions that are unobservable with current mitochondrial probes. Meanwhile, the MitoMN can induce oncosis in a light-activated manner, which results in the enlargement of mitochondria and the death of cancer cells. Using structured illumination microscopy (SIM), MitoMN-stained mitochondria with a dual-color response reveals, for the first time, how swelled mitochondria interacts and fuses with each other for a nonlinear enlargement to accelerate oncosis into an irreversible stage. With this sign of irreversible oncosis revealed by MitoMN, oncosis can be segregated into three stages, including before oncosis, initial oncosis, and accelerated oncosis.
Topics: Cell Death; Cells, Cultured; DNA, Mitochondrial; Equipment Design; Light; Microscopy; Mitochondria; Mitochondrial Membranes
PubMed: 34197052
DOI: 10.1002/advs.202004566 -
Experimental and Molecular Pathology Aug 2021This review explores the developments leading up to the establishment of the cell theory and cellular pathology and their subsequent refinements and applications while... (Review)
Review
This review explores the developments leading up to the establishment of the cell theory and cellular pathology and their subsequent refinements and applications while focusing on the individuals who have made seminal advances in the field. The links between cell biology, cell pathology and cell injury research are emphasized. Recognition also is given to the importance of technological advances in microscopy, histology, biochemical and molecular methods for discovery in cell biology and cell pathology. Particular attention is focused on the work of Rudolph Virchow and his former students in the formulation of the cell theory in biology and pathology and John F. R. Kerr and colleagues who identified and developed a comprehensive characterization of apoptosis, thereby giving impetus to the contemporary field of cell injury research. Cell injury research remains an important and fruitful field of ongoing inquiry and discovery.
Topics: Animals; Biology; Cell Death; Humans; Medicine; Necrosis
PubMed: 34116021
DOI: 10.1016/j.yexmp.2021.104660 -
Journal of Clinical Medicine Apr 2021Ischemic Stroke precedes depression. Post-stroke depression (PSD) is a major driver for poor recovery, negative quality of life, poor rehabilitation outcomes and poor... (Review)
Review
Ischemic Stroke precedes depression. Post-stroke depression (PSD) is a major driver for poor recovery, negative quality of life, poor rehabilitation outcomes and poor functional ability. In this systematic review, we analysed the inflammatory basis of post-stroke depression, which involves bioenergetic failure, deranged iron homeostasis (calcium influx, Na influx, potassium efflux etc), excitotoxicity, acidotoxicity, disruption of the blood brain barrier, cytokine-mediated cytotoxicity, reactive oxygen mediated toxicity, activation of cyclooxygenase pathway and generation of toxic products. This process subsequently results in cell death, maladapted, persistent neuro-inflammation and deranged neuronal networks in mood-related brain regions. Furthermore, an in-depth review likewise reveals that anatomic structures related to post-stroke depression may be localized to complex circuitries involving the cortical and subcortical regions.
PubMed: 33919670
DOI: 10.3390/jcm10081674 -
Frontiers in Cell and Developmental... 2020In stroke and other neurological diseases, Transient Receptor Potential Melastatin 4 (TRPM4) has been reported to cause oncotic cell death which is due to an excessive...
In stroke and other neurological diseases, Transient Receptor Potential Melastatin 4 (TRPM4) has been reported to cause oncotic cell death which is due to an excessive influx of sodium ions. Following stroke, hypoxia condition activates TRPM4 channel, and the sodium influx via TRPM4 is further enhanced by an increased TRPM4 expression. However, the effect of TRPM4 inhibition on oncotic cell death, particularly during the acute stage, remains largely unknown. Recently, we have developed a polyclonal antibody M4P that specifically inhibits TRPM4 channel. M4P blocks the channel via binding to a region close to the channel pore from extracellular space. Using M4P, we evaluated the acute effect of blocking TRPM4 in neurons, astrocytes, and vascular endothelial cells. In a rat stroke model, M4P co-localized with neuronal marker NeuN and endothelial marker vWF, whereas few GFAP positive astrocytes were stained by M4P in the ipsilateral hemisphere. When ATP was acutely depleted in cultured cortical neurons and microvascular endothelial cells, cell swelling was induced. Application of M4P significantly blocked TRPM4 current and attenuated oncosis. TUNEL assay, PI staining and western blot on cleaved Caspase-3 revealed that M4P could ameliorate apoptosis after 24 h hypoxia exposure. In contrast, acute ATP depletion in cultured astrocytes failed to demonstrate an increase of cell volume, and application of M4P or control IgG had no effect on cell volume change. When TRPM4 was overexpressed in astrocytes, acute ATP depletion successfully induced oncosis which could be suppressed by M4P treatment. Our results demonstrate that comparing to astrocytes, neurons, and vascular endothelial cells are more vulnerable to hypoxic injury. During the acute stage of stroke, blocking TRPM4 channel could protect neurons and vascular endothelial cells from oncotic cell death.
PubMed: 33195194
DOI: 10.3389/fcell.2020.562584 -
Frontiers in Pharmacology 2020Artemisinin and its derivatives have shown broad-spectrum antitumor activities and . Furthermore, outcomes from a limited number of clinical trials provide encouraging... (Review)
Review
Artemisinin and its derivatives have shown broad-spectrum antitumor activities and . Furthermore, outcomes from a limited number of clinical trials provide encouraging evidence for their excellent antitumor activities. However, some problems such as poor solubility, toxicity and controversial mechanisms of action hamper their use as effective antitumor agents in the clinic. In order to accelerate the use of ARTs in the clinic, researchers have recently developed novel therapeutic approaches including developing novel derivatives, manufacturing novel nano-formulations, and combining ARTs with other drugs for cancer therapy. The related mechanisms of action were explored. This review describes ARTs used to induce non-apoptotic cell death containing oncosis, autophagy, and ferroptosis. Moreover, it highlights the ARTs-caused effects on cancer metabolism, immunosuppression and cancer stem cells and discusses clinical trials of ARTs used to treat cancer. The review provides additional insight into the molecular mechanism of action of ARTs and their considerable clinical potential.
PubMed: 33117153
DOI: 10.3389/fphar.2020.529881