Expression of brain-derived neurotrophic factor and formation of migrasome increases in the glioma cells induced by the adipokinetic hormone.

OBJECTIVE: It has been previously shown that brain-derived neurotrophic factor is linked with various types of cancer. Brain-derived neurotrophic factor is found to be highly expressed in multiple human cancers and associated with tumor growth, invasion, and metastasis. Adipokinetic hormones are functionally related to the vertebrate glucagon, as they have similar functionalities that manage the nutrient-dependent secretion of these two hormones. Migrasomes are new organelles that contain numerous small vesicles, which aid in transmitting signals between the migrating cells. Therefore, the aim of this study was to investigate the effects of Anax imperator adipokinetic hormone on brain-derived neurotrophic factor expression and ultrastructure of cells in the C6 glioma cell line. METHODS: The rat C6 glioma cells were treated with concentrations of 5 and 10 Anax imperator adipokinetic hormone for 24 h. The effects of the Anax imperator adipokinetic hormone on the migrasome formation and brain-derived neurotrophic factor expression were analyzed using immunocytochemistry and transmission electron microscope. RESULTS: The rat C6 glioma cells of the 5 and 10 µM Anax imperator adipokinetic hormone groups showed significantly high expressions of brain-derived neurotrophic factor and migrasomes numbers, compared with the control group. CONCLUSION: A positive correlation was found between the brain-derived neurotrophic factor expression level and the formation of migrasome, which indicates that the increased expression of brain-derived neurotrophic factor and the number of migrasomes may be involved to metastasis of the rat C6 glioma cell line induced by the Anax imperator adipokinetic hormone. Therefore, the expression of brain-derived neurotrophic factor and migrasome formation may be promising targets for preventing tumor proliferation, invasion, and metastasis in glioma.

The interactions of subcellular organelles in pulmonary fibrosis induced by carbon black nanoparticles: a comprehensive review.

Owing to the widespread use and improper emissions of carbon black nanoparticles (CBNPs), the adverse effects of CBNPs on human health have attracted much attention. In toxicological research, carbon black is frequently utilized as a negative control because of its low toxicity and poor solubility. However, recent studies have indicated that inhalation exposure to CBNPs could be a risk factor for severe and prolonged pulmonary inflammation and fibrosis. At present, the pathogenesis of pulmonary fibrosis induced by CBNPs is still not fully elucidated, but it is known that with small particle size and large surface area, CBNPs are more easily ingested by cells, leading to organelle damage and abnormal interactions between organelles. Damaged organelle and abnormal organelles interactions lead to cell structure and function disorders, which is one of the important factors in the development and occurrence of various diseases, including pulmonary fibrosis. This review offers a comprehensive analysis of organelle structure, function, and interaction mechanisms, while also summarizing the research advancements in organelles and organelle interactions in CBNPs-induced pulmonary fibrosis.

Nivalenol affects spindle formation and organelle functions during mouse oocyte maturation.

Oocyte maturation is essential for fertilization and early embryo development, and proper organelle functions guarantee this process to maintain high-quality oocytes. The type B trichothecene nivalenol (NIV) is a mycotoxin produced by Fusarium oxysporum and is commonly found in contaminated food. NIV intake affect growth, the immune system, and the female reproductive system. Here, we investigated NIV toxicity on mouse oocyte quality. Transcriptome analysis results showed that NIV exposure altered the expression of multiple genes involved in spindle formation and organelle function in mouse oocytes, indicating its toxicity on mouse oocyte maturation. Further analysis indicated that NIV exposure disrupted spindle structure and chromosome alignment, possibly through tubulin acetylation. NIV exposure induced aberrant mitochondria distribution and reduced mitochondria number, mitochondria membrane potential (MMP), and ATP levels. In addition, NIV caused the abnormal distribution of the Golgi apparatus and altered the expression of the vesicle trafficking protein Rab11. ER distribution was also disturbed under NIV exposure, indicating the effects of NIV on protein modification and transport in oocytes. Thus, our results demonstrated that NIV exposure affected spindle structure and organelles function in mouse oocytes.

Synthesis and biological activity of novel 4-aminoquinoline/1,2,3-triazole hybrids against Leishmania amazonensis.

Quinoline and 1,2,3-triazoles are well-known nitrogen-based heterocycles presenting diverse pharmacological properties, although their antileishmanial activity is still poorly exploited. As an effort to contribute with studies involving these interesting chemical groups, in the present study, a series of compounds derived from 4-aminoquinoline and 1,2,3-triazole were synthetized and biological studies using L. amazonensis species were performed. The results pointed that the derivative 4, a hybrid of 4-aminoquinoline/1,2,3-triazole exhibited the best antileishmanial action, with inhibitory concentration (IC50) values of ~1 µM against intramacrophage amastigotes of L. amazonensis , and being 16-fold more active to parasites than to the host cell. The mechanism of action of derivative 4 suggest a multi-target action on Leishmania parasites, since the treatment of L. amazonensis promastigotes caused mitochondrial membrane depolarization, accumulation of ROS products, plasma membrane permeabilization, increase in neutral lipids, exposure of phosphatidylserine to the cell surface, changes in the cell cycle and DNA fragmentation. The results suggest that the antileishmanial effect of this compound is primarily altering critical biochemical processes for the correct functioning of organelles and macromolecules of parasites, with consequent cell death by processes related to apoptosis-like and necrosis. No up-regulation of reactive oxygen and nitrogen intermediates was promoted by derivative 4 on L. amazonensis -infected macrophages, suggesting a mechanism of action independent from the activation of the host cell. In conclusion, data suggest that derivative 4 presents selective antileishmanial effect, which is associated with multi-target action, and can be considered for future studies for the treatment against disease.

Recent progress in nanomedicine for enhanced cancer chemotherapy.

As one of the most important cancer treatment strategies, conventional chemotherapy has substantial side effects and leads easily to cancer treatment failure. Therefore, exploring and developing more efficient methods to enhance cancer chemotherapy is an urgently important problem that must be solved. With the development of nanotechnology, nanomedicine has showed a good application prospect in improving cancer chemotherapy. In this review, we aim to present a discussion on the significant research progress in nanomedicine for enhanced cancer chemotherapy. First, increased enrichment of drugs in tumor tissues relying on different targeting ligands and promoting tissue penetration are summarized. Second, specific subcellular organelle-targeted chemotherapy is discussed. Next, different combinational strategies to reverse multidrug resistance (MDR) and improve the effective intracellular concentration of therapeutics are discussed. Furthermore, the advantages of combination therapy for cancer treatment are emphasized. Finally, we discuss the major problems facing therapeutic nanomedicine for cancer chemotherapy, and propose possible future directions in this field.

Plant defence mechanisms against mycotoxin Fumonisin B1.

Fumonisin B1 (FB1) is the most harmful mycotoxin which prevails in several crops and affects the growth and yield as well. Hence, keeping the alarming consequences of FB1 under consideration, there is still a need to seek other more reliable approaches and scientific knowledge for FB1-induced cell death and a comprehensive understanding of the mechanisms of plant defence strategies. FB1-induced disturbance in sphingolipid metabolism initiates programmed cell death (PCD) through various modes such as the elevated generation of reactive oxygen species, lipid peroxidation, cytochrome c release from the mitochondria, and activation of specific proteases and nucleases causing DNA fragmentation. There is a close interaction between sphingolipids and defence phytohormones in response to FB1 exposure regulating PCD and defence. In this review, the model plant Arabidopsis and various crops have been presented with different levels of susceptibility and resistivity exposed to various concentration of FB1. In addition to this, regulation of PCD and defence mechanisms have been also demonstrated at the physiological, biochemical and molecular levels to help the understanding of the role and function of FB1-inducible molecules and genes and their expressions in plants against pathogen attacks which could provide molecular and biochemical markers for the detection of toxin exposure.

Organelle-Targeted Photosensitizers for Precision Photodynamic Therapy.

Subcellular organelles are the cornerstones of cells, and destroying them will cause cell dysfunction and even death. Therefore, realizing precise organelle targeting of photosensitizers (PSs) can help reduce PS dosage, minimize side effects, avoid drug resistance, and enhance therapeutic efficacy in photodynamic therapy (PDT). Organelle-targeted PSs provide a new paradigm for the construction of the next generation of PSs and may provide implementable strategies for future precision medicine. In this Review, the recent targeting strategies of different organelles and the corresponding design principles of molecular and nanostructured PSs are summarized and discussed. The current challenges and opportunities in organelle-targeted PDT are also presented.

Ethylene glycol butyl ether deteriorates oocyte quality via impairing mitochondrial function.

Ethylene glycol butyl ether (EGBE) is a ubiquitous environmental pollutant that is commonly used in maquillage, industrial, and household products. EGBE has been shown to cause blood toxicity, carcinogenicity, and organ malformations. However, little is known about the impact of EGBE on the female reproductive system, especially oocyte quality. Here, we reported that EGBE influenced oocyte quality by showing the disturbed oocyte meiotic capacity, fertilization potential, and early embryonic development competency. Specifically, EGBE exposure impaired spindle/chromosome structure, microtubule stability, and actin polymerization to result in the oocyte maturation arrest and aneuploidy. In addition, EGBE exposure compromised the dynamics of cortical granules and their component ovastacin, leading to the failure of sperm binding and fertilization. Last, single-cell transcriptome analysis revealed that EGBE-induced oocyte deterioration was caused by mitochondrial dysfunction, which led to the accumulation of ROS and occurrence of apoptosis. Altogether, our study illustrates that mitochondrial dysfunction and redox perturbation is the major cause of the poor quality of oocytes exposed to EGBE.

Effect of luteinizing hormone concentration on transcriptome and subcellular organelle phenotype of ovarian granulosa cells.

RESEARCH QUESTION: Granulosa cells (GCs) surrounding oocytes are crucial for follicular growth, oocyte development, ovulation, and luteinization under the dynamic co-stimulation of follicle stimulating hormone (FSH) and luteinizing hormone (LH). This study aimed to investigate the effect of LH levels on GCs in preovulatory follicles under gonadotropin releasing hormone antagonist-based ovarian stimulation. In vitro experiments were also conducted to study the direct effect of LH on GCs. METHODS: Twelve infertile women were divided into low (L), medium (M), and high (H) LH groups according to their serum LH levels during ovarian stimulation. RNA-sequencing (RNA-seq) was conducted to examine the transcriptome profiles of GCs obtained from the above patients during the oocyte retrieval. The activity of mitochondrial dehydrogenase was measured under the stimulation of recombinant LH (rLH) concentration gradient combined with recombinant FSH. The ultrastructures of subcellular organelles were observed. RESULTS: Bioinformatic analyses showed that compared with the M group, molecule and pathway changes in the L group and in the H group were similar. In cultured GCs, both insufficient and excessive rLH impaired the activity of mitochondrial dehydrogenase. With the medium rLH concentration, numerous cell connections and abundant mitochondria and liposomes were observed. Compared with the medium concentration, GCs showed smaller and rounder mitochondria, more autophagosomes, and massive organelles damages with excessive rLH, and swollen, circular, or forked mitochondria were observed with inadequate rLH. CONCLUSIONS: RNA-seq provided a novel spectrum of transcriptome characteristics of GCs potentially affected by serum LH levels during ovarian stimulation. In vitro, rLH could directly affect GCs at the subcellular level.

D2O-Probed Raman Microspectroscopy Distinguishes the Metabolic Dynamics of Macromolecules in Organellar Anticancer Drug Response.

To profile the metabolic dynamics responding to drugs at the single-cell/organelle resolution, rapid and economical mechanism-revealing methods are required. Here, we introduced D2O-probed Raman microspectroscopy in combination with the multivariate curve resolution-alternating least squares (MCR-ALS or MCR) algorithm. Exploiting MCR to deconvolute each macromolecular component specifically, the method is able to track and distinguish changes in lipid and protein metabolic activities in a human cancer cell line (MCF-7) and in Saccharomyces cerevisiae, in response to the metabolism-inhibitory effect of rapamycin, which inhibits the mammalian/mechanistic target of rapamycin (mTOR) signaling. Under rapamycin, in the lipid bodies of cancer cells, metabolic activities of both protein and lipid are suppressed; in the nucleus, protein synthesis remains active, whereas lipid synthesis is inhibited; in the cytoplasm, syntheses of protein and lipid are both dose- and duration-dependent. Thus, rapamycin differentially influences protein and lipid synthesis in mTOR signaling. Moreover, the strong correlation between macromolecular-specific components of yeast and those in MCF-7 cytoplasm, nucleus, and lipid bodies revealed similarity in rapamycin response. Notably, highly metabolically active cancer cells after high-dosage rapamycin exposure (500 or 5000 × IC50) were revealed, which escape detection by population-level cytotoxicity tests. Thus, by unveiling macromolecule-specific metabolic dynamics at the organelle level, the method is valuable to mechanism-based rapid screening and dissection of drug response.

The water-soluble non-starch polysaccharides from natural resources against excessive oxidative stress: A potential health-promoting effect and its mechanisms.

The water-soluble non-starch polysaccharides isolated from natural resources have become research hotpots in the field of food science and human health due to widely distributed in nature and low toxicity. It has indicated that the health-promoting effect of water-soluble non-starch polysaccharides were partly attributable to against excessive oxidative stress. Indeed, excessive oxidative stress in the body has been reported in occurrence of disease. The water-soluble non-starch polysaccharides from natural resources exhibit antioxidant activity to against oxidative stress via scavenging free radicals promoting antioxidant enzymes activity and/or regulating antioxidant signaling pathways. In this review, the water-soluble non-starch polysaccharides as medicine agent and the factor affecting antioxidant as well as the relationship between oxidative stress and disease are summarized, and the mechanisms of water-soluble non-starch polysaccharides therapy in disease are also discussed. It will provide a theoretical basis for natural polysaccharides used for the treatment of diseases.

Activatable Dual ROS-Producing Probe for Dual Organelle-Engaged Photodynamic Therapy.

Photodynamic therapy (PDT) necessitates approaches capable of increasing antitumor effects while decreasing nonspecific photodamage. We herein report an activatable probe (Glu-PyEB) comprising two distinct photosensitizers with mutually suppressed photodynamics. Activation by tumor-associated γ-glutamyltranspeptidase gives rise to a generator of superoxide radical (O2-•) accumulated in lysosomes and a producer of singlet oxygen (1O2) enriched in mitochondria. This enables light-irradiation-triggered damage of lysosomes and mitochondria, robust cell death, and tumor retardation in vivo, showing the use of paired photosensitizers subjected to reciprocally suppressed photodynamics for activatable PDT.

A novel progress of drug delivery system for organelle targeting in tumour cells.

At present, malignant tumours have become one of the most serious diseases that endanger human health. According to a survey on causes of death in Chinese population in early 1990s, the malignant tumours were the second leading cause of death. In the treatment of tumours, the ideal situation is that drugs should target and accumulate at tumour sites and destroy tumour cells specifically, without affecting normal cells and stem cells with regenerative capacity. This requires drugs to be specifically transported to the target organs, tissues, cells, and even specific organelles, like mitochondria, nuclei, lysosomes, endoplasmic reticulum (ER), and Golgi apparatus (GA). The nano drug delivery system can not only protect drugs from degradation but also facilitate functional modification and targeted drug delivery to the tumour site. This article mainly reviews the targeting of nano drug delivery systems to tumour cytoplasmic matrix, nucleus, mitochondria, ER, and lysosomes. Organelle-specific drug delivery system will be a major mean of targeting drug delivery with lower toxicity, less dosage and higher drug concentration in tumour cells.

Soil PAHs contamination effect on the cellular and subcellular organelle changes of Phragmites australis Cav.

The concentrations of ∑16 priority polycyclic aromatic hydrocarbons (PAHs) for soils, roots, and above-ground parts of reed (Phragmites australis Cav.) were determined on different monitoring plots located near the city of Kamensk-Shakhtinsky, southern Russia, where historically received industrial sewage and sludge. The total PAHs concentration in monitoring soil plots was significantly higher than those in the background site which situated at the distance of 2 km from the contamination source. Accordingly, the maximum accumulation was found for phenanthrene and chrysene among the 16 priority PAHs in most of the plant samples collected in the impact zone. The effects of PAHs' pollution on changes of Phragmites australis Cav. cellular and subcellular organelles in the studied monitoring sites were also determined using optical and electron microscopy, respectively. The obtained data showed that increasing of PAHs contamination negatively affected the ultrastructural changes of the studied plants. Phragmites australis Cav. showed a high level of adaptation to the effect of stressors by using tissue and cell levels. In general, the detected alterations under the PAHs effect were possibly connected to changes in biochemical and histochemical parameters as a response for reactive oxygen species and as a protective response against oxidative stress. The obtained results introduce innovative findings of cellular and subcellular changes in plants exposed to ∑16 priority PAHs as very persistent and toxic contaminants.

Zebra-like bodies in COVID-19: is phospholipidosis evidence of hydroxychloroquine induced acute kidney injury?

COVID-19 (from SARS-CoV-2) is the cause of an ongoing pandemic, with an increasing number of cases and significant mortality worldwide. Clinical trials and extensive studies are being conducted on a large scale for a better understanding of the pathophysiology of this disease and its effect on different organs. Several experimental treatment protocols have been introduced, in which hydroxychloroquine (HCQ) was one of the first drugs used. While patients can develop many side effects of HCQ, studies have documented a rare association of long-term HCQ treatment with zebra-like bodies in the ultrastructural examination of kidney biopsies, a finding typically seen in Fabry's disease, as well as in association with chronic HCQ use, among other drugs. We present a similar finding in the postmortem examination of a male in his early seventies with COVID-19 infection, who received five days of HCQ treatment before stopping the medication due to cardiac and renal toxicity.

An Organelle-Specific Nanozyme for Diabetes Care in Genetically or Diet-Induced Models.

The development of nanozymes has made active impact in diagnosis and therapeutics. However, understanding of the full effects of these nanozymes on biochemical pathways and metabolic homeostasis remains elusive. Here, it is found that iron oxide nanoparticles (Fe3 O4 NPs), a type of well-established nanozyme, can locally regulate the energy sensor adenosine 5'-monophosphate-activated protein kinase (AMPK) via their peroxidase-like activity in the acidic lysosomal compartment, thereby promoting glucose metabolism and insulin response. Fe3 O4 NPs induce AMPK activation and enhance glucose uptake in a variety of metabolically active cells as well as in insulin resistant cell models. Dietary Fe3 O4 NPs display therapeutic effects on hyperglycemia and hyperinsulinemia in Drosophila models of diabetes induced by genetic manipulation or high-sugar diet. More importantly, intraperitoneal administration of Fe3 O4 NPs stimulates AMPK activities in metabolic tissues, reduces blood glucose levels, and improves glucose tolerance and insulin sensitivity in diabetic ob/ob mice. The study reveals intrinsic organelle-specific properties of Fe3 O4 NPs in AMPK activation, glycemic control, and insulin-resistance improvement, suggesting their potential efficacy in diabetes care.

In vitro effect of a novel protease inhibitor cocktail on Toxoplasma gondii tachyzoites.

Toxoplasmosis is a zoonotic disease and a global food and water-borne infection. The disease is caused by the parasite Toxoplasma gondii, which is a highly successful and remarkable pathogen because of its ability to infect almost any nucleated cell in warm-blooded animals. The present study was done to demonstrate the effect of protease inhibitors cocktail (PIC), which inhibit both cysteine and serine proteases, on in vitro cultured T. gondii tachyzoites on HepG2 cell line. This was achieved by assessing its effect on the invasion of the host cells and the intracellular development of T.gondii tachyzoites through measuring their number and viability after their incubation with PIC. Based on the results of the study, it was evident that the inhibitory action of the PIC was effective when applied to tachyzoites before their cultivation on HepG2 cells. Pre-treatment of T.gondii tachyzoites with PIC resulted in failure of the invasion of most of the tachyzoites and decreased the intracellular multiplication and viability of the tachyzoites that succeeded in the initial invasion process. Ultrastructural studies showed morphological alteration in tachyzoites and disruption in their organelles. This effect was irreversible till the complete lysis of cell monolayer in cultures. It can be concluded that PIC, at in vitro levels, could prevent invasion and intracellular multiplication of Toxoplasma tachyzoites. In addition, it is cost effective compared to individual protease inhibitors. It also had the benefit of combined therapy as it lowered the concentration of each protease inhibitor used in the cocktail. Other in vivo experiments are required to validate the cocktail efficacy against toxoplasmosis. Further studies may be needed to establish the exact mechanism by which the PIC exerts its effect on Toxoplasma tachyzoites behavior and its secretory pathway.

Interface Engineering in Multiphase Systems toward Synthetic Cells and Organelles: From Soft Matter Fundamentals to Biomedical Applications.

Synthetic cells have a major role in gaining insight into the complex biological processes of living cells; they also give rise to a range of emerging applications from gene delivery to enzymatic nanoreactors. Living cells rely on compartmentalization to orchestrate reaction networks for specialized and coordinated functions. Principally, the compartmentalization has been an essential engineering theme in constructing cell-mimicking systems. Here, efforts to engineer liquid-liquid interfaces of multiphase systems into membrane-bounded and membraneless compartments, which include lipid vesicles, polymer vesicles, colloidosomes, hybrids, and coacervate droplets, are summarized. Examples are provided of how these compartments are designed to imitate biological behaviors or machinery, including molecule trafficking, growth, fusion, energy conversion, intercellular communication, and adaptivity. Subsequently, the state-of-art applications of these cell-inspired synthetic compartments are discussed. Apart from being simplified and cell models for bridging the gap between nonliving matter and cellular life, synthetic compartments also are utilized as intracellular delivery vehicles for nuclei acids and nanoreactors for biochemical synthesis. Finally, key challenges and future directions for achieving the full potential of synthetic cells are highlighted.

Cell Senescence, Multiple Organelle Dysfunction and Atherosclerosis.

Atherosclerosis is an age-related disorder associated with long-term exposure to cardiovascular risk factors. The asymptomatic progression of atherosclerotic plaques leads to major cardiovascular diseases (CVD), including acute myocardial infarctions or cerebral ischemic strokes in some cases. Senescence, a biological process associated with progressive structural and functional deterioration of cells, tissues and organs, is intricately linked to age-related diseases. Cell senescence involves coordinated modifications in cellular compartments and has been demonstrated to contribute to different stages of atheroma development. Senescence-based therapeutic strategies are currently being pursued to treat and prevent CVD in humans in the near-future. In addition, distinct experimental settings allowed researchers to unravel potential approaches to regulate anti-apoptotic pathways, facilitate excessive senescent cell clearance and eventually reverse atherogenesis to improve cardiovascular function. However, a deeper knowledge is required to fully understand cellular senescence, to clarify senescence and atherogenesis intertwining, allowing researchers to establish more effective treatments and to reduce the cardiovascular disorders' burden. Here, we present an objective review of the key senescence-related alterations of the major intracellular organelles and analyze the role of relevant cell types for senescence and atherogenesis. In this context, we provide an updated analysis of therapeutic approaches, including clinically relevant experiments using senolytic drugs to counteract atherosclerosis.

4-hydroxynonenal and oxidative stress in several organelles and its damaging effects on cell functions.

This review aims to describe the action sites of the oxidative stress products for 4-hydroxy-2E-nonenal, on subcellular fractions of eukaryotic cells from several tissues. Described also are; the detoxification mechanisms from derivatives of 4-hydroxy-2E-nonenal. All dangerous compounds for subcellular fractions are metabolites of a respiratory chain that can give stable products of oxidative compounds and are intermediates of other oxidation reaction chains. Finally, the balancing among the illustrated processes to identify the relative oxidative power of several metabolic chains useful to make evident subcellular damages or detoxification processes is discussed.