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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 -
Microbiology and Molecular Biology... Nov 2020Brucellosis is a bacterial disease of domestic animals and humans. The pathogenic ability of organisms relies on their stealthy strategy and their capacity to replicate... (Review)
Review
Brucellosis is a bacterial disease of domestic animals and humans. The pathogenic ability of organisms relies on their stealthy strategy and their capacity to replicate within host cells and to induce long-lasting infections. organisms barely induce neutrophil activation and survive within these leukocytes by resisting microbicidal mechanisms. Very few -infected neutrophils are found in the target organs, except for the bone marrow, early in infection. Still, induces a mild reactive oxygen species formation and, through its lipopolysaccharide, promotes the premature death of neutrophils, which release chemokines and express "eat me" signals. This effect drives the phagocytosis of infected neutrophils by mononuclear cells that become thoroughly susceptible to replication and vehicles for bacterial dispersion. The premature death of the infected neutrophils proceeds without NETosis, necrosis/oncosis, or classical apoptosis morphology. In the absence of neutrophils, the Th1 response exacerbates and promotes bacterial removal, indicating that -infected neutrophils dampen adaptive immunity. This modulatory effect opens a window for bacterial dispersion in host tissues before adaptive immunity becomes fully activated. However, the hyperactivation of immunity is not without a price, since neutropenic -infected animals develop cachexia in the early phases of the disease. The delay in the immunological response seems a requirement for the development of long-lasting brucellosis. This property may be shared with other pathogenic alphaproteobacteria closely related to We propose a model in which -infected polymorphonuclear neutrophils (PMNs) function as "Trojan horse" vehicles for bacterial dispersal and as modulators of the Th1 adaptive immunity in infection.
Topics: Animals; Apoptosis; Brucella; Brucellosis; Host-Pathogen Interactions; Humans; Immunity, Innate; Lipopolysaccharides; Neutrophils; Phagocytosis; Th1 Cells; Virulence
PubMed: 33055283
DOI: 10.1128/MMBR.00048-20 -
Frontiers in Physiology 2020Ouabain is of cardiotonic steroids (CTS) family that is plant-derived compounds and is known for many years as therapeutic and cytotoxic agents. They are specific... (Review)
Review
Ouabain is of cardiotonic steroids (CTS) family that is plant-derived compounds and is known for many years as therapeutic and cytotoxic agents. They are specific inhibitors of Na,K-ATPase, the enzyme, which pumps Na and K across plasma membrane of animal cells. Treatment of cells by CTS affects various cellular functions connected with the maintenance of the transmembrane gradient of Na and K. Numerous studies demonstrated that binding of CTS to Na,K-ATPase not only suppresses its activity but also induces some signal pathways. This review is focused on different mechanisms of two ouabain effects: their ability (1) to protect rodent cells from apoptosis through the expression of [Na]-sensitive genes and (2) to trigger death of non-rodents cells (so-called «oncosis»), possessing combined markers of «classic» necrosis and «classic» apoptosis. Detailed study of oncosis demonstrated that the elevation of the [Na]/[K] ratio is not a sufficient for its triggering. Non-rodent cell death is determined by the characteristic property of "sensitive" to ouabain α1-subunit of Na,K-ATPase. In this case, ouabain binding leads to enzyme conformational changes triggering the activation of p38 mitogen-activated protein kinases (MAPK) signaling. The survival of rodent cells with ouabain-«resistant» α1-subunit is connected with another conformational transition induced by ouabain binding that results in the activation of ERK 1/2 signaling pathway.
PubMed: 33013454
DOI: 10.3389/fphys.2020.01060 -
Inorganic Chemistry Aug 2020Platinum drugs are widely used in clinics to treat various types of cancer. However, a number of severe side effects induced by the nonspecific binding of platinum drugs...
Platinum drugs are widely used in clinics to treat various types of cancer. However, a number of severe side effects induced by the nonspecific binding of platinum drugs to normal tissues limit their clinical use. The conversion of platinum(II) drugs into more inert platinum(IV) derivatives is a promising strategy to solve this problem. Some platinum(IV) prodrugs, such as carboplatin-based tetracarboxylatoplatinum(IV) prodrugs, are not easily reduced to active platinum(II) species, leading to low cytotoxicity in vitro. In this study, we report the design and synthesis of a carboplatin-based platinum(IV) prodrug functionalized with a boron dipyrromethene (bodipy) ligand at the axial position, and the ligand acts as a photoabsorber to photoactivate the platinum(IV) prodrug. This compound, designated as BODI-Pt, is highly stable in the dark but quickly activated under irradiation to release carboplatin and the axial ligands. A cytotoxic study reveals that BODI-Pt is effective under irradiation, with cytotoxicity 11 times higher than that in the dark and 39 times higher than that of carboplatin in MCF-7 cells. Moreover, BODI-Pt has been proven to kill cancer cells by binding to the genomic DNA, arresting the cell cycle at the G/M phase, inducing oncosis, and generating ROS upon irradiation. In summary, we report a green-light-activatable and carboplatin-based Pt(IV) prodrug with improved cytotoxicity against cancer cells, and our strategy can be used as a promising way to effectively activate carboplatin-based platinum(IV) prodrugs.
Topics: Antineoplastic Agents; Boron Compounds; Carboplatin; Cell Line, Tumor; Drug Screening Assays, Antitumor; Fluorescent Dyes; Humans; Light; Prodrugs
PubMed: 32799491
DOI: 10.1021/acs.inorgchem.0c01880 -
American Journal of Physiology.... Sep 2020How low-level psychological stress and overnutrition interact in influencing cardiometabolic disease is unclear. Mechanistic overlaps suggest potential synergies;...
How low-level psychological stress and overnutrition interact in influencing cardiometabolic disease is unclear. Mechanistic overlaps suggest potential synergies; however, findings are contradictory. We test whether low-level stress and Western diet (WD) feeding synergistically influence homeostasis, mood, and myocardial ischemic tolerance. Male C57BL6/J mice were fed a control diet or WD (32%/57%/11% calories from fat/carbohydrates/protein) for 12 wk, with subgroups restrained for 30 min/day over the final 3 wk. Metabolism, behavior, tolerance of perfused hearts to ischemia-reperfusion (I/R), and cardiac "death proteins" were assessed. The WD resulted in insignificant trends toward increased body weight (+5%), glucose (+40%), insulin (+40%), triglycerides (+15%), and cholesterol (+20%) and reduced leptin (-20%) while significantly reducing insulin sensitivity [100% rise in homeostasis model assessment of insulin resistance (HOMA-IR), < 0.05]. Restraint did not independently influence metabolism while increasing HOMA-IR a further 50% (and resulting in significant elevations in insulin and glucose to 60-90% above control) in WD mice ( < 0.05), despite blunting weight gain in control and WD mice. Anxiogenesis with restraint or WD was nonadditive, whereas anhedonia (reduced sucrose consumption) only arose with their combination. Neuroinflammation markers (hippocampal TNF-α, Il-1b) were unchanged. Myocardial I/R tolerance was unaltered with stress or WD alone, whereas the combination worsened dysfunction and oncosis [lactate dehydrogenase (LDH) efflux]. Apoptosis (nucleosome accumulation) and death protein expression (BAK, BAX, BCL-2, RIP-1, TNF-α, cleaved caspase-3, and PARP) were unchanged. We conclude that mild, anxiogenic yet cardio-metabolically "benign" stress interacts synergistically with a WD to disrupt homeostasis, promote anhedonia (independently of neuroinflammation), and impair myocardial ischemic tolerance (independently of apoptosis and death protein levels).
Topics: Animals; Diet, High-Fat; Energy Intake; Heart; Homeostasis; Insulin Resistance; Mice, Inbred C57BL; Myocardial Ischemia; Myocardium; Obesity
PubMed: 32755463
DOI: 10.1152/ajpregu.00322.2019