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ObjectivesDetermine the role of apolipoprotein M (ApoM) in anthracycline (Dox) cardiotoxicity.BackgroundApoM binds the cardioprotective sphingolipid sphingosine-1-phosphate (S1P). Circulating ApoM is inversely associated with mortality in human heart failure (HF).MethodsIn the Penn HF Study (PHFS), we tested the relationship between ApoM and mortality in a subset with anthracycline-induced cardiomyopathy. We measured ApoM in humans and mice treated with Dox and utilized hepatic ApoM transgenic (ApomTG), ApoM knockout (ApomKO), ApoM knock-in mice with impaired S1P binding, and S1P receptor 3 (S1PR3) knockout mice in Dox cardiotoxicity. We assayed autophagy in left ventricular tissue from anthracycline-induced HF patients versus donor controls.ResultsApoM was inversely associated with mortality in PHFS, and Dox reduced circulating ApoM in mice and breast cancer patients.ApomTGmice were protected from Dox-induced cardiac dysfunction and loss of left ventricular mass.ApomTGattenuated Dox-induced impairment in autophagic flux in vivo and accumulation of insoluble p62, which was also observed in the myocardium of patients with anthracycline-induced HF. In vehicle-treated mice, ApoM negatively regulated transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis. The effect of ApoM on TFEB required both S1P binding and S1PR3. In the presence of Dox, ApoM preserved TFEB and cardiomyocyte lysosomal abundance assessed as lysosomal associated membrane protein 1 positive structures in vivo, while S1P mimetic pretreatment of cardiomyocytes prevented Dox-induced changes in lysosomal pH.ConclusionsApoM attenuates Dox cardiotoxicity via the autophagy-lysosome pathway. The association between ApoM and reduced mortality may be explained by its role in sustaining autophagy.HighlightsCirculating ApoM is inversely associated with survival in human anthracycline-induced cardiomyopathyAnthracycline treatment reduces circulating ApoM in humans and miceIncreasing ApoM attenuates doxorubicin cardiotoxicity, lysosomal injury and preserves myocardial autophagic flux, but does not impact doxorubicin anti-neoplastic efficacyAutophagic impairment is characteristic of human anthracycline cardiomyopathy

There is a resurgence of interest in understanding the role of the mevalonate pathway in cancer. The on-target anti-cancer effects of the clinical mevalonate inhibitors, statins, are plentiful and diverse across several cancer models. As pan-cancer approaches have not identified a unifying theory for the observed mevalonate pathway dependence in cancers, we focus on blood cancers which have collectively demonstrated the greatest sensitivity to mevalonate pathway inhibition. In blood cancers, it is widely published that statins induce the non-inflammatory cell death modality, apoptosis. The success of apoptosis induction in blood cancers using inhibitors of BCL2 Homology 3 (BH3) domains of pro-survival BCL2 family members known as BH3 mimetics provides an impetus and means to understand the apoptotic mechanisms of mevalonate dependence. Herein, we describe mechanisms by which mevalonate pathway inhibitors sensitize to BH3 mimetics in blood cancers and our efforts to understand the mevalonate pathway outputs that promote blood cancer survival.

Background: Stress induces secretion of cathecolamines and glucocorticoids, which may produce liver injury. Followed by the production of inflammatory mediators, it causes apoptosis. Centella asiatica (CeA) has anti-inflammatory and hepatoprotective effects. The present study aims to determine the role of CeA in the attenuation of liver pro-inflammatory mediator expression in rats with electrical foot shock stress model. Materials and Methods: Twenty-four Sprague-Dawley rats were randomized into four groups consisted of six rats each: (1) Control group, (2) CeA-treated group, (3) Stress group, and (4) CeA + stress group. Reverse transcriptase PCR of inflammatory and apoptosis markers as well as Real-Time PCR of β2-adrenergic receptor were performed from liver tissues. Results: Electrical foot shock stress induced up-regulation of NFκB and TNF-α mRNA expressions as pro-inflammatory mediators, compared to control group. This alteration was followed by up-regulation of BAX and β2-adrenergic receptor, as well as the down-regulation of BCl2 compared to control. CeA treatment prevented enhancement of NFκB, TNF-α, TLR-4 and β-adrenergic receptor mRNA expressions, which was followed by down-regulation of BAX and up-regulation of BCl-2, compared to stress group. Conclusion: CeA prevents secretion of pro-inflammatory chemokines and cytokines as well as apoptotic markers in liver cells through the activation of β2-adrenergic receptor.

Background: Temozolomide (TMZ) resistance plays a critical role in the treatment of glioma. This research tries to explore how circRNAs affect the chemosensitivity of glioma cells. Materials and Methods: In this study, the authors performed gene sequencing and selected circRNAs specifically expressed in TMZ-R cells and used them as target genes for subsequent studies. By knocking out the target gene, the authors clarify its effect on TMZ-R glioma proliferation, invasion, migration, and cell apoptosis; and through tumor-burdened animals, the authors explore the effect of the target gene in an in vivo environment. Results: In this research, the authors revealed that circ-GLIS3 was significantly upregulated in TMZ-R glioma cells. Functionally, knocking down circ-GLIS3 could inhibit proliferation, invasion, and migration abilities of TMZ-R glioma cells. Moreover, downregulation of circ-GLIS3 could induce cell cycle arrest and apoptosis, while miR-548m inhibition and MED31 mRNA could reverse this progress. In the in vivo condition, silencing of circ-GLIS3 could induce cell apoptosis and suppressed tumor growth. Mechanistically, circ-GLIS3 positively upregulated MED31 expression by sponging miR-548m. Conclusions: All these research findings demonstrate that circ-GLIS3 accelerates TMZ-R glioma progression through the miR-548m/MED31 axis.

Low molecular weight heparins (LMWHs) have been used for the treatment for recurrent pregnancy loss (RPL) for a long time. We aimed to investigate the efficacy of the LMWHs on angiogenesis and apoptosis during placentation. A total of twenty-four rats were randomly divided into three groups each containing 8 rats: normal saline; enoxaparine sodium 0.4 ml, and enoxaparine sodium 0.8 ml were given to the Group 1, 2 and 3, respectively. Normal saline and enoxaparine sodium 0.4 ml or 0.8 ml were given to the rats beginning on the day the pregnancy was detected and continued until the 15th day of the pregnancy. The tissues containing placental decidual zone were immunostained for vascular endothelial growth factor A (VEGF-A) and caspase 7. The decidual and placental VEGF-A and the decidual caspase 7 immunostaining scores of all of the groups were high, however, there were no statistically significant differences among the groups (p>0.05). On the other hand, the placental caspase 7 immunostaining scores of the normal saline group were significantly lower than those of the enoxaparine sodium 0.4 and the enoxaparine sodium 0.8 groups (p

Background: Colorectal cancer (CRC) is the third most common malignancy worldwide. Matrine can act as a potential antitumor drug, and its antitumor activities have been tested in various cancers, including CRC. However, the effect of matrine and the related mechanisms on CRC cells remains poorly defined. Materials and Methods: CRC cells were treated with different concentrations of matrine, and then MTT, flow cytometric, and transwell assays were used to assess cell proliferation, apoptosis, invasion, and migration. MiR-10b-5p and Phosphatase and tensin homolog (PTEN) expression levels were measured by quantitative real-time polymerase chain reaction and western blot assay. The binding interaction of miR-10b-5p and PTEN were predicted by TargetScan and verified by a dual-luciferase reporter and RIP assay. The effect of matrine, miR-10b-5p, and PTEN on CRC cell proliferation, apoptosis, migration, and invasion was detected by MTT, flow cytometric, and transwell assays severally. Results: Matrine notably restrained proliferation, invasion, and migration and boosted apoptosis of CRC cells, as well as downregulated miR-10b-5p expression and upregulated PTEN protein level. PTEN was a direct target of miR-10b-5p in CRC cells. MiR-10b-5p knockdown and matrine treatment inhibited cell proliferation, migration, and invasion and induced apoptosis, and reintroduction of si-PTEN partly regained the inhibiting effect. Besides, MiR-10b-5p knockdown and matrine treatment repressed CRC growth in vivo. Conclusion: Matrine could suppress proliferation, migration, and invasion and induce apoptosis of CRC cells via the miR-10b/PTEN pathway, providing the potential molecular mechanism of matrine in blocking CRC progression.

It is necessary to develop a new strategy for treatment of lung cancer since it is the main cause of cancer death. Tanshinone IIA (Tan IIA), an active ingredient of a commonly used traditional Chinese herb Salvia miltiorrhiza, provides a new direction to develop a new strategy for the treatment. It has been found that Tan IIA could inhibit lung cancer in vitro and in vivo by inducing autophagic apoptosis. Tan IIA increased apoptotic cells and the expression of cleaved caspase 3 and cleaved caspase 9, decreased B-cell lymphoma-2 (Bcl-2)/Bcl-2 associated X protein (Bax) ratio in human non-small cell lung cancer (NSCLC) cell lines, which was promoted by an autophagy activator Rapamycin, and weaken by autophagy inhibitor 3-methyladenine (3-MA). In addition, Tan IIA induced more autophagosomes, up-regulated light chain 3β (LC-3B) I and LC-3B II conversion and less sequestosome 1 (SQSTM1/p62) expression, which cannot be weakened by the caspase 3 antagonist. Moreover, overexpression of LC-3B gene (LC3B) and downregulation of autophagic gene 5 (ATG5) further confirmed that Tan IIA induced autophagic apoptosis in NSCLC cell lines. Beclin-1 gene (BECN1) overexpression and silence attenuated the effects of Tan IIA, suggesting autophagic apoptosis that Tan IIA induced was dependent on Beclin-1. Overall, our study demonstrated a new treatment mechanism of Tan IIA and suggested that Tan IIA is a potential new anti-cancer therapeutic option.

Background: Endometrial cancer (EC) is an intractable gynecological cancer with increasing incidence and mortality worldwide. Accumulating studies indicated that long noncoding RNA nuclear enriched...

Lichens, algae and fungi-based symbiotic associations, are sources of many important secondary metabolites, such as antibiotics, anti-inflammatory, antioxidants, and anticancer agents. Wide range of experiments based on in vivo and in vitro studies revealed that lichens are a rich treasure of anti-cancer compounds. Lichen extracts and isolated lichen compounds can interact with all biological entities currently identified to be responsible for tumor development. The critical ways to control the cancer development include induction of cell cycle arrests, blocking communication of growth factors, activation of anti-tumor immunity, inhibition of tumor-friendly inflammation, inhibition of tumor metastasis, and suppressing chromosome dysfunction. Also, lichen-based compounds induce the killing of cells by the process of apoptosis, autophagy, and necrosis, that inturn positively modulates metabolic networks of cells against uncontrolled cell division. Many lichen-based compounds have proven to possess potential anti-cancer activity against a wide range of cancer cells, either alone or in conjunction with other anti-cancer compounds. This review primarily emphasizes on an updated account of the repository of secondary metabolites reported in lichens. Besides, we discuss the anti-cancer potential and possible mechanism of the most frequently reported secondary metabolites derived from lichens.

In cancer, human cells lose the ability to properly control the series of events that occur constantly during cell growth and division, including protein expression, stability, and dynamics. Heat shock proteins (Hsps) are key molecules in these events, constitutively expressed at high levels and could furthermore be induced by the response to cancer-induced stress. In tumor cells, Hsps have been shown to be implicated in the regulation of apoptosis, immune responses, angiogenesis and metastasis; in some cases, they can be overexpressed and dysregulated, representing important cancer hallmarks. In the past few years, it has been demonstrated that Hsps can be released by tumor cells through several secreting pathways, including the extracellular vesicles (EVs), thus modulating the tumor microenvironment as well as long-distance intercellular communication and metastatization. In this review, we discuss the role of extracellular Hsps in cancer, with a particular interest in Hsps in EVs. We would also like to highlight the importance of fully understanding of the role of extracellular Hsps released by EVs and encourage further research in this field the use of Hsps as early cancer biomarkers and therapeutic targets.

Schizophrenia (SZ) is a mental disorder with a strong genetic basis as well as epigenetic aspects. Siblings of patients with SZ can share certain endophenotypes with the patients, suggesting that siblings may be important for distinguishing between trait and state markers. In the current study, we aimed to characterize the balance between pro-BDNF/mature BDNF and its receptors p75NTR/TrkB, which are tPA-BDNF pathways proteins and are thought to play a role in synaptic pruning, as a possible endophenotype of schizophrenia. Forty drug-naive patients with first-episode psychosis (FEP) matched for age, gender, and level of education, 40 unaffected siblings (UAS) of patients with FEP, and 67 healthy controls (HC) were included in the study. Blood samples were collected from all participants to determine BDNF, pro-BDNF, TrkB and p75NTR, PAI1, tPA, ACTH, and cortisol levels. We showed that levels of proteins of the tPA-BDNF pathway as well as the pro-BDNF/m-BDNF and p75NTR/TrkB ratios could successfully differentiate FEP and their siblings from the HCs by using ROC analysis. Plasma levels of m-BDNF were found to be the lowest in the healthy siblings and highest in the HCs with statistically significant differences between all 3 groups. The plasma level of pro-BDNF in the HC group was similar to the FEP patients, the same in the healthy siblings of the FEP patients. Our data support the hypothesis that imbalance between neurotrophic and apoptotic proteins might occur in SZ and this imbalance could be an endophenotype of the disease. University of (University of Health Sciences Turkey) Research Projects Unit

Background: Triple-negative breast cancer (TNBC) is the most serious subtype of breast cancer (BC) and has been a great health threat to females. Although chemotherapeutic agent contributes a lot to TNBC treatment, drug resistance has been a great obstacle for chemotherapies. Ursolic acid (UA), a pentacyclic triterpenoid compound, was reported to reverse paclitaxel resistance in BC. However, whether UA could affect the resistance of TNBC cells to other drugs such as doxorubicin (DOX) remains to be discovered. Materials and Methods: MTT assay, EdU assay, colony formation assay, and flow cytometry analysis were implemented to detect the viability, proliferation, and apoptosis of DOX-resistant MDA-MB-468 and MDA-MB-436 cells with or without UA treatment. Mechanism assays including RIP, RNA pull-down, and luciferase reporter assays verified the interaction between RNAs. Results: UA treatment hindered the growth and mitigated the DOX resistance of DOX-resistant MDA-MB-468 and MDA-MB-436 cells. Mechanistically, multidrug resistance-associated protein 1 (ABCC1) expression was downregulated by UA treatment. MiR-186-5p was verified to target ABCC1. Further, UA-inhibited ZEB1-AS1 (zinc finger E-box binding homeobox 1 antisense RNA 1) was verified as a competitive endogenous RNA (ceRNA) to upregulate ABCC1 through sponging miR-186-5p. Importantly, UA treatment impaired the malignant phenotypes of DOX-resistant MDA-MB-468 and MDA-MB-436 cells through ZEB1-AS1/ABCC1 axis. Conclusion: UA promotes TNBC cell sensitivity to DOX through inactivating ZEB1-AS1/miR-186-5p/ABCC1 signaling.

Background: Long non-coding RNA actin filament-associated protein1-antisense RNA 1 (AFAP1-AS1) was confirmed to be associated with tumorigenesis. However, the role of AFAP1-AS1 in breast cancer was...

Background: Upregulation of mitochondrial E3 ubiquitin ligase 1 (Mul1) contributes to brain injury in ischemic stroke due to disturbance of mitochondrial dynamics, and bioinformatics analysis predicts that Mul1 is a potential target of Dipsacoside B. Objective: The aim of the study was to explore whether Dipsacoside B can exert a beneficial effect on brain injury in the ischemic stroke rat via targeting Mul1. Methods: The SD rat brains or PC12 cells were subjected to 2 h-ischemia or 8 h-hypoxia plus 24 h-reperfusion or 24 h-reoxygenation to establish the ischemic stroke rat model in vivo or in vitro, which were treated with Dipsacoside B at different dosages. The brain or PC12 cell injury, relevant protein levels and mitochondrial functions were measured by methods of biochemistry, flow cytometry or Western blot. Results: The neurological dysfunction and brain injury (such as infarction and apoptosis) observed in the ischemic stroke rats were accompanied by increases in Mul1 and dynamin-related protein 1 (Drp1) levels along with decreases in mitofusin 2 (Mfn2) level and ATP production. These effects were attenuated by Dipsacoside B. Consistently, cell injury (necroptosis and apoptosis) occurred in the PC12 cells exposed to hypoxia concomitant with the upregulation of Mul1 and Drp1 along with downregulation of Mfn2 and mitochondrial functions (such as increases in reactive oxygen species production and mitochondrial fission and decreases in mitochondrial membrane potential and ATP production).These phenomena were reversed in the presence of Dipsacoside B. Conclusion: Dipsacoside B can protect the rat brain against ischemic injury via inhibition of Mul1 due to the improvement of mitochondrial function.

Background: Breast cancer is one of the most prevalent cancers that often occur in females. Long noncoding RNA differentiation antagonizing nonprotein coding RNA (DANCR) has been involved in the pathogenesis of various tumors, including breast cancer. This study aimed to investigate the role and underlying mechanism of DANCR in breast cancer. Materials and Methods: The level of DANCR was detected in breast cancer tissues and cells by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability was evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay. Cell apoptosis was assessed using flow cytometry. Cell migration and invasion were estimated by the Transwell assay. The relationship between DANCR, miR-4319, and vesicle-associated membrane protein-associated protein B (VAPB) was confirmed by bioinformatic analysis and dual-luciferase reporter assay. The level of microRNA-4319 (miR-4319) was tested by qRT-PCR. The expression of VAPB was measured by qRT-PCR or western blot assay. Results: DANCR and VAPB were upregulated, while miR-4319 was downregulated in breast cancer tissues and cells. Knockdown of DANCR hindered proliferation, migration, and invasion and promoted apoptosis of breast cancer cells. DANCR knockdown inhibited breast cancer development through regulating miR-4319. Inhibition of miR-4319 restrained breast cancer cell progression by targeting VAPB. Moreover, DANCR regulated VAPB expression by sponging miR-4319 in breast cancer cells. Conclusion: DANCR facilitated breast cancer cell progression through regulating the miR-4319/VAPB axis, indicating that DANCR might be a potential biomarker and therapeutic target for breast cancer treatment.

The Notch signaling pathway is an evolutionarily conserved pathway usually present in multicellular organisms, which plays a pivotal role in cell fate determination and proliferation. Due to this property, it is known to be highly oncogenic, especially in the dysregulated version of the Notch pathway, where apoptosis is inhibited and abnormal cell growth is supported. Notch receptors and ligand proteins play an essential role in cancers, such as myeloid leukemia, T-cell lymphoblastic leukemia, and organ-specific, i.e., breast, colon, pancreas, and skin cancers. Any type of cancer generates due to genetic defects, including epigenetic alterations and mutations. The researchers can use these alterations to find a promising diagnostic as well as therapeutic tool for cancer. The successful inhibition of the Notch pathway with the help of specific biomarkers or suppression of gene expression represents a new remedy in cancer research. This article focuses on the various remedies hidden within the Notch pathway's mechanism, primarily based on different patents published in recent years for assisting cancer diagnosis and succeeding treatment.

Programmed cell death (PCD) is an important pathologic process after spinal cord injury (SCI), and as a newly type of PCD, ferroptosis is also involved in the secondary SCI, however, the underlying molecular mechanisms remain unclear. Integrating animal experiment and bioinformatics, we validated the ferroptotic phenotype in SCI first, and then bioinformatic analyses, including Gene Ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, gene set enrichment analysis and protein-protein interaction analysis were performed to investigate the ferroptotic genes at 1 day, 3 days, 7 days, 14 days and 56 days post-SCI, finally, the ferroptotic genes in SCI were identified and expression of 5 key genes were validated by western blot. The ferroptotic symbols including iron overload, lipid peroxidation, shrunken mitochondria and ROS accumulation were detected in the acute and sub-acute phase of SCI. The outcomes of bioinformatics suggested that mTOR signaling pathway, HIF-1 signaling pathway, VEGF signaling pathway, Protein processing in endoplasmic reticulum were involved in ferroptotic regulation and ATF-3, XBP-1, HO-1, DDIT-3 and CHAC-1 were selected as the ferroptotic key genes in SCI. Besides, response to oxidative stress, amide metabolic process, cation transport and cytokine production were showed as the essential biological process in ferroptosis after SCI. The ferroptotic phenotype following SCI was validated and the ferroptotic genes and signaling pathways were identified. The results contribute to exploring the ferroptotic mechanism underlying secondary SCI and to providing potential target for clinical treatment.

Hand, foot and mouth disease (HFMD) is a serious threat to the health of infants, which can be caused by enterovirus 71 (EV71). The clinical symptoms are mostly self-limited, but some of them develop into aseptic meningitis with poor prognosis and even death. In this study, we screened Urolithin A (UroA), an intestinal metabolite of ellagic acid, significantly inhibited the replication of EV71 in cells. Further evaluation showed that UroA was better than ribavirin in CC50, IC50 and selection index (SI). Moreover, we found that UroA inhibits the proliferation of EV71 by promoting autophagy and apoptosis of infected cells. Therefore, UroA is a candidate drug for the treatment of EV71 infection.

Background: Cancer therapy is one of the most important challenges that human beings are facing. The abnormal activity of epidermal growth factor receptor tyrosine kinase (EGFR1) in tumors has been reported in many studies. Tyrosine kinase inhibitors are now commercially available for the treatment of a variety of cancers. Based on our previous studies, we assumed that a hybrid of aminopyrimidine derivatives as EGFR inhibitors and benzocheromen derivatives as cytotoxic agents can induce apoptosis in EGFR positive cancer cells. In the present study, the cytotoxic effect, ability of EGFR inhibition and apoptosis induction of some synthetic benzochromene pyrimidine derivatives were investigated on MDA-MB231, SKBR3 and PC3 cell lines. Methods: The EGFR inhibition activity was determined using cell-based EGFR ELISA kit. Cell viability was determined by MTT assay in 2D and 3D cultures. The apoptosis was confirmed through different methods such as fluorescent staining, annexin V– propidium iodide double staining, DNALadder assay, caspase-3 colorimetric assay, and nitric oxide assay. Results: The results of the MTT assay showed that derivatives with different substituents exhibited differential cytotoxicity in three cancer cell lines, although in MDA-MB231 the cytotoxicity effect of compounds is more obvious than the other cell lines. Production of nitric oxide, caspase-3 activity and DNA-fragmentation was significant in MDA-MB231 and PC3 cells. SKBR3 cells, despite having the lowest apoptosis among these three cell lines, showed a significant EGFR inhibition in the ELISA assay. Conclusion: In this research, we proved that hybrids of benzochromene and amino pyrimidine could be effective on growth inhibition of cancer cell lines and may be used as a drug candidate for cancer therapy in the future.

Background: Eryngium is a genus flowering plant in the Umbelliferae family, having pharmacological properties, such as anti-inflammatory and anti-diabetic. Given the nature of melanoma and breast cancers in recent years and the fact that the anti-cancer properties of Eryngium billardieri on mentioned cell lines have not been studied, the present study was conducted to explore these properties. Objective: The mechanisms of cytotoxicity and apoptosis of aerial parts of various extracts and fractions of E. billardieri on cancerous cells and normal cells were investigated. Methods: Samples were collected from natural habitats, dried and then extracted by Soxhlet apparatus with solvents of n-Hex, DCM and methanol, respectively. The cytotoxic effects of the extracts were investigated by the MTT method on MCF7, B16 and HFF-2 classes for 24 and 48 hours. Flow cytometry was also used to investigate the mechanism of cytotoxicity, and it has been confirmed by Real-time PCR of p53 and Bax genes as to which comprise the apoptosis regulatory proteins. Meanwhile, volatile compounds of extracts were identified by the GC-MS method. Results: The obtained data showed that the n-Hex extract of E. billardieri on B-16 and MCF7 cell lines and dichromethane extract on MCF7 cell line had the most significant cytotoxic effect compared to DMSO control (p-value Conclusion: Non-terpenoid compounds of E. billardieri can be responsible for exhibiting the most cytotoxic effects on MCF7 and B16 cell lines with apoptotic mechanism, and n-Hex extract was found to have the most significant inhibitory effect on cancerous cells compared to the HFF-2 control cells by employing the mechanism of apoptosis.

Apoptosis is a programmed cell death that occurs due to the production of several catabolic enzymes. During this process, several morphological and biochemical changes occur in mitochondria, the main organelle in the cell that participates in apoptosis and controls apoptotic pathways. During apoptosis, cytochrome c is released from mitochondria, and different proteins activate caspase cascades that carry out the cell towards the death process. Apoptosis mainly occurs due to p53 protein that allows the abnormal cells to proliferate. Bcl-2 and Bcl-xl are two anti-apoptotic members of the protein family that prevents apoptosis. The membrane potential of mitochondria decreases by the opening of the permeability transition pore (PTP). These PTP are formed by the binding of Bax with adenine nucleotide translocator (ANT) and cause depolarization in the membrane. The depolarization releases apoptogenic factors (cytochrome c) that result in the loss of oxidative phosphorylation. Knockdown in lactate dehydrogenase (LDH) is the cause of the decrease in mitochondrial membrane potential elevating the levels of reactive oxygen species (ROS) and Bax. Consequently, causing an increase in the release of cytochrome c that ultimately leads to apoptosis. In this review, we have summarized the combined effect of mitochondrial membrane potential and LDH enzyme that triggers apoptosis in cells and their role in the mechanism of apoptosis.

Fil: Saban, Melina. Hospital Británico. Unidad de Endocrinología, Metabolismo, Nutrición y Diabetes; Argentina Fil: Costilla, Melisa. Pontificia Universidad Católica Argentina. Instituto de Investigaciones Biomédicas; Argentina Fil: Klecha, Alicia Juana. Pontificia Universidad Católica Argentina. Instituto de Investigaciones Biomédicas; Argentina Fil: Di Cugno, Mariana. Hospital Británico. Unidad de Endocrinología, Metabolismo, Nutrición y Diabetes; Argentina Fil: Curriá, Marina Inés. Hospital Británico. Unidad de Endocrinología, Metabolismo, Nutrición y Diabetes; Argentina Fil: Cremaschi, Graciela A. Pontificia Universidad Católica Argentina. Instituto de Investigaciones Biomédicas; Argentina Fil: Barreiro Arcos, María Laura. Pontificia Universidad Católica Argentina. Instituto de Investigaciones Biomédicas; Argentina Abstract: Background: Graves’ disease is an autoimmune disorder characterised by excessive production of thyroid hormones, which induces increased cellular metabolism in most tissues and increased production of reactive oxygen species (ROS). The aim of this work was to analyse the effect of ROS on cell viability and the expression of catalase (CAT), glutathione peroxidase-1 (GPx1), superoxide dismutase (SOD-1) and DNA methyltransferase-1 (DNMT-1) in peripheral blood mononuclear cells (PBMC) from patients with newly diagnosed Graves’ disease or treated with methimazole. Patients and methods: For this study, women patients with newly diagnosed Graves’ disease (n = 18), treated with methimazole (n = 6) and healthy subjects (n = 15) were recruited. ROS were evaluated by flow cytometry, and the viability/apoptosis of PBMC was analysed by flow cytometry and fluorescence microscopy. Genomic expression of CAT, GPx-1, SOD-1 and DNMT-1 was quantified by real-time PCR. Results: We found high levels of ROS and increased expression of CAT, GPx-1, SOD-1 and DNMT-1 in PBMC from patients with newly diagnosed Graves’ disease. Methimazole treatment reversed these parameters. Cell viability was similar in all study groups. Conclusions: ROS induces the expression of CAT, GPx-1, and SOD-1. The activity of these enzymes may contribute to the protection of PBMC from the harmful effect of free radicals on cell viability. Increased expression of DNMT-1 may be associated with aberrant methylation patterns in immunoregulatory genes contributing to autoimmunity in Graves’ disease. Resumen: Antecedentes: La enfermedad de Graves es un trastorno autoinmune caracterizado por una producción excesiva de hormonas tiroideas, que induce un aumento del metabolismo celular en la mayoría de los tejidos y una mayor producción de especies reactivas de oxígeno (ROS). El objetivo de este trabajo fue analizar el efecto de las ROS sobre la viabilidad celular y la expresión de catalasa (CAT), glutatión peroxidasa-1 (GPx-1), superóxido dismutasa (SOD-1) y ADN metiltransferasa-1 (DNMT-1) en células mononucleares de sangre periférica (PBMC) de pacientes con enfermedad de Graves recién diagnosticada o tratados con metimazol. Pacientes y métodos: Se seleccionó a mujeres con enfermedad de Graves recién diagnosticada (n = 18), tratadas con metimazol (n = 6) y a sujetos sanos (n = 15). La producción de ROS fue evaluada por citometría de flujo. La viabilidad y apoptosis de las PBMC fue analizada por citometría de flujo y microscopía de fluorescencia. La expresión genómica de CAT, GPx-1, SOD-1 y DNMT-1 fue cuantificada por PCR en tiempo real. Resultados: Encontramos altos niveles de ROS y una mayor expresión de CAT, GPx-1, SOD-1 y DNMT-1 en PBMC de pacientes con enfermedad de Graves recién diagnosticada. El tratamiento con metimazol revirtió estos parámetros. La viabilidad celular fue similar en todos los grupos de estudio. Conclusiones: Las ROS inducen la expresión de CAT, GPx-1 y SOD-1. La actividad de estas enzimas podría contribuir a la protección de las PBMC del efecto nocivo de los radicales libres sobre la viabilidad celular. El aumento de la expresión de DNMT-1 podría estar asociado con patrones de metilación aberrantes en genes inmunorreguladores que contribuyen a la autoinmunidad en la enfermedad de Graves.

The caspase family is commonly involved in the pathophysiology of acute brain injury (ABI) through complex apoptotic, pyroptotic, and inflammatory pathways. Current translational strategies for caspase modulation in ABI primarily focus on caspase inhibitors. Because there are no caspase-inhibiting drugs approved for clinical use on the market, the development of caspase inhibitors remains an attractive challenge for researchers and clinicians. Therefore, we conducted the present review with the aim of providing a comprehensive introduction of caspases in ABI. In this review, we summarized the available evidence and potential mechanisms regarding the biological function of caspases. We also reviewed the therapeutic effects of caspase inhibitors on ABI and its subsequent complications. However, various important issues remain unclear, prompting further verification of the efficacy and safety regarding clinical application of caspase inhibitors. We believe that our work will be helpful to further understand the critical role of the caspase family and will provide novel therapeutic potential for ABI treatment.

Ultrasound stimulated microbubbles (USMB) are being investigated for their potential to promote the uptake of anticancer agents into tumor tissue by exploiting their ability to enhance microvascular permeability. At sufficiently high ultrasound transmit amplitudes it has also recently been shown that USMB treatments can, on their own, induce vascular damage, shutdown blood flow, and inhibit tumor growth. The objective of this study is to examine the antitumor effects of ‘antivascular’ USMB treatments in conjunction with chemotherapy, which differs from previous work which has sought to enhance drug uptake with USMBs by increasing vascular permeability. Conceptually this is a strategy similar to combining vascular disrupting agents with a chemotherapy, and we have selected the taxane docetaxel (Taxotere) for evaluating this approach as it has previously been shown to have potent antitumor effects when combined with small molecule vascular disrupting agents. Experiments were conducted on PC3 tumors implanted in athymic mice. USMB treatments were performed at a frequency of 1 MHz employing sequences of 50 ms bursts (0.00024 duty cycle) at 1.65 MPa. USMB treatments were administered on a weekly basis for 4 weeks with docetaxel (DTX) being given intravenously at a dose level of 5 mg/kg. The USMB treatments, either alone or in combination with DTX, induced an acute reduction in tumor perfusion which was accompanied at the 24 hour point by significantly enhanced necrosis and apoptosis. Longitudinal experiments showed a modest prolongation in survival but no significant growth inhibition occurred in DTX–only and USMB-only treatment groups relative to control tumors. The combined USMB-DTX treatment group produced tumor shrinkage in weeks 4–6, and significant growth inhibition and survival prolongation relative to the control (p

Background Glucocorticoid Modulatory Element-Binding protein 1 (GMEB1) suppresses caspase-mediated cell apoptosis. microRNA-320 (miR-320a) can inhibit tumor development by arresting tumor cell invasion. To our best knowledge, no previous study focused on the role of miR-320a andGMEB1 in colorectal cancer (CRC), which deserves our exploration. Methods GMEB1 expression was detected through immunohistochemistry and compared with the pathology of 60 CRC patients. Transwell and scratch healing experiments detected cell invasion and migration. Western blot was used to observe Epithelial-Mesenchymal Transition (EMT)-related proteins expression after silencing and overexpressing GMEB1 (oe-GMEB1). Online database search and dual-luciferase reporter assay identified the target relationship between miR-320a and GMEB1. qRT-PCR was conducted to compare the differences in the expression of miR-320a between normal and tumor tissues of CRC patients. Results GMEB1 is overexpressed in CRC tissues, and its high expression levels can be correlated with lymph node invasion, TNM stage, and differentiation degrees of CRC. The si-GMEB1 group showed a significant decrease in invasion and metastatic abilities, accompanied by a decline in the expression of N-cadherin and vimentin., but the expression of E-cadherin was increased, while an opposite trend was observed in the oe-GMEB1 group. Both cell and tissue tests verified that miR-320a mimic can downregulate the expression of GMEB1. Conclusion miR-320a can promote EMT phenotype changes by silencing the expression of GMEB1, which inhibits the invasion of CRC cells. This feature is a potential basis for the diagnosis and treatment of CRC at the genetic level.

Cancer is a multifactorial disease that constitutes a serious public health problem worldwide. Prostate cancer advanced stages are associated with the development of androgen-independent tumors and an apoptosis-resistant phenotype that progresses to metastasis. By studying androgen-independent lymphoid nodule carcinoma of the prostate (LNCaP) cells induced to apoptosis by serum elimination, we identified the activation of a non-selective cationic channel of 23pS conductance that promotes incoming Ca2+ currents, as well as apoptosis final stages. arp2cDNA was isolated and identified to be of the same cell type, and mRNA was expressed in Xenopus laevis oocytes, which was found to be associated with the activation of incoming Ca2+ currents and induction to apoptosis. cDNA, which encodes the ARP2 protein, was overexpressed in LNCaP cells and Chinese hamster ovary cells, which induced apoptosis. Our evidence suggests that protein ARP2 overexpression and transit to the cell membrane allows an increased Ca2+ incoming current that initiates the apoptosis process in epithelial-type cells whose phenotype shows resistance to programmed cell death.