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Frontiers in Cellular Neuroscience 2017A variety of experimental studies demonstrated that neurotransmitters are an important factor for the development of the central nervous system, affecting... (Review)
Review
A variety of experimental studies demonstrated that neurotransmitters are an important factor for the development of the central nervous system, affecting neurodevelopmental events like neurogenesis, neuronal migration, programmed cell death, and differentiation. While the role of the classical neurotransmitters glutamate and gamma-aminobutyric acid (GABA) on neuronal development is well established, the aminosulfonic acid taurine has also been considered as possible neuromodulator during early neuronal development. The purpose of the present review article is to summarize the properties of taurine as neuromodulator in detail, focusing on the direct involvement of taurine on various neurodevelopmental events and the regulation of neuronal activity during early developmental epochs. The current knowledge is that taurine lacks a synaptic release mechanism but is released by volume-sensitive organic anion channels and/or a reversal of the taurine transporter. Extracellular taurine affects neurons and neuronal progenitor cells mainly via glycine, GABA(A), and GABA(B) receptors with considerable receptor and subtype-specific affinities. Taurine has been shown to directly influence neurogenesis as well as neuronal migration . It provides a depolarizing signal for a variety of neuronal population in the immature central nervous system, thereby directly influencing neuronal activity. While in the neocortex, taurine probably enhance neuronal activity, in the immature hippocampus, a tonic taurinergic tone might be necessary to attenuate activity. In summary, taurine must be considered as an essential modulator of neurodevelopmental events, and possible adverse consequences on fetal and/or early postnatal development should be evaluated for pharmacological therapies affecting taurinergic functions.
PubMed: 29123472
DOI: 10.3389/fncel.2017.00328 -
Translational Stroke Research Feb 2014Encephalopathy consequent on perinatal hypoxia-ischemia occurs in 1-3 per 1,000 term births in the UK and frequently leads to serious and tragic consequences that... (Review)
Review
Encephalopathy consequent on perinatal hypoxia-ischemia occurs in 1-3 per 1,000 term births in the UK and frequently leads to serious and tragic consequences that devastate lives and families, with huge financial burdens for society. Although the recent introduction of cooling represents a significant advance, only 40% survive with normal neurodevelopmental function. There is thus a significant unmet need for novel, safe, and effective therapies to optimize brain protection following brain injury around birth. The Na⁺/H⁺ exchanger (NHE) is a membrane protein present in many mammalian cell types. It is involved in regulating intracellular pH and cell volume. NHE1 is the most abundant isoform in the central nervous system and plays a role in cerebral damage after hypoxia-ischemia. Excessive NHE activation during hypoxia-ischemia leads to intracellular Na⁺ overload, which subsequently promotes Ca²⁺ entry via reversal of the Na⁺/Ca²⁺ exchanger. Increased cytosolic Ca²⁺ then triggers the neurotoxic cascade. Activation of NHE also leads to rapid normalization of pHi and an alkaline shift in pHi. This rapid recovery of brain intracellular pH has been termed pH paradox as, rather than causing cells to recover, this rapid return to normal and overshoot to alkaline values is deleterious to cell survival. Brain pHi changes are closely involved in the control of cell death after injury: an alkalosis enhances excitability while a mild acidosis has the opposite effect. We have observed a brain alkalosis in 78 babies with neonatal encephalopathy serially studied using phosphorus-31 magnetic resonance spectroscopy during the first year after birth (151 studies throughout the year including 56 studies of 50 infants during the first 2 weeks after birth). An alkaline brain pHi was associated with severely impaired outcome; the degree of brain alkalosis was related to the severity of brain injury on MRI and brain lactate concentration; and a persistence of an alkaline brain pHi was associated with cerebral atrophy on MRI. Experimental animal models of hypoxia-ischemia show that NHE inhibitors are neuroprotective. Here, we review the published data on brain pHi in neonatal encephalopathy and the experimental studies of NHE inhibition and neuroprotection following hypoxia-ischemia.
Topics: Animals; Brain; Disease Models, Animal; Energy Metabolism; Female; Humans; Hydrogen-Ion Concentration; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Neurons; Sodium-Hydrogen Exchangers
PubMed: 24452957
DOI: 10.1007/s12975-013-0322-x -
Journal of Translational Medicine Oct 2011Tumour cells communicate with the cells of their microenvironment via a series of molecular and cellular interactions to aid their progression to a malignant state and... (Review)
Review
Tumour cells communicate with the cells of their microenvironment via a series of molecular and cellular interactions to aid their progression to a malignant state and ultimately their metastatic spread. Of the cells in the microenvironment with a key role in cancer development, tumour associated macrophages (TAMs) are among the most notable. Tumour cells release a range of chemokines, cytokines and growth factors to attract macrophages, and these in turn release numerous factors (e.g. VEGF, MMP-9 and EGF) that are implicated in invasion-promoting processes such as tumour cell growth, flicking of the angiogenic switch and immunosuppression. TAM density has been shown to correlate with poor prognosis in breast cancer, suggesting that these cells may represent a potential therapeutic target. However, there are currently no agents that specifically target TAM's available for clinical use.Bisphosphonates (BPs), such as zoledronic acid, are anti-resorptive agents approved for treatment of skeletal complication associated with metastatic breast cancer and prostate cancer. These agents act on osteoclasts, key cells in the bone microenvironment, to inhibit bone resorption. Over the past 30 years this has led to a great reduction in skeletal-related events (SRE's) in patients with advanced cancer and improved the morbidity associated with cancer-induced bone disease. However, there is now a growing body of evidence, both from in vitro and in vivo models, showing that zoledronic acid can also target tumour cells to increase apoptotic cell death and decrease proliferation, migration and invasion, and that this effect is significantly enhanced in combination with chemotherapy agents. Whether macrophages in the peripheral tumour microenvironment are exposed to sufficient levels of bisphosphonate to be affected is currently unknown. Macrophages belong to the same cell lineage as osteoclasts, the major target of BPs, and are highly phagocytic cells shown to be sensitive to bisphosphonates in model studies; In vitro, zoledronic acid causes increased apoptotic cell death; in vivo the drug has been shown to inhibit the production of pro-angiogenic factor MMP-9, as well as most recent evidence showing it can trigger the reversal of the TAMs phenotype from pro-tumoral M2 to tumoricidal M1. There is thus accumulating evidence supporting the hypothesis that effects on TAMs may contribute to the anti-tumour effect of bisphosphonates. This review will focus in detail on the role of tumour associated macrophages in breast cancer progression, the actions of bisphosphonates on macrophages in vitro and in tumour models in vivo and summarise the evidence supporting the potential for the targeting of tumour macrophages with bisphosphonates.
Topics: Animals; Antineoplastic Agents; Diphosphonates; Humans; Macrophages; Neoplasms; Neovascularization, Pathologic; Tumor Microenvironment
PubMed: 22005011
DOI: 10.1186/1479-5876-9-177 -
Antioxidants (Basel, Switzerland) Sep 2019In the last decade, immune therapies against human cancers have emerged as a very effective therapeutic strategy in the treatment of various cancers, some of which are... (Review)
Review
In the last decade, immune therapies against human cancers have emerged as a very effective therapeutic strategy in the treatment of various cancers, some of which are resistant to current therapies. Although the clinical responses achieved with many therapeutic strategies were significant in a subset of patients, another subset remained unresponsive initially, or became resistant to further therapies. Hence, there is a need to develop novel approaches to treat those unresponsive patients. Several investigations have been reported to explain the underlying mechanisms of immune resistance, including the anti-proliferative and anti-apoptotic pathways and, in addition, the increased expression of the transcription factor Yin-Yang 1 (YY1) and the programmed death ligand 1 (PD-L1). We have reported that YY1 leads to immune resistance through increasing HIF-1α accumulation and PD-L1 expression. These mechanisms inhibit the ability of the cytotoxic T-lymphocytes to mediate their cytotoxic functions via the inhibitory signal delivered by the PD-L1 on tumor cells to the PD-1 receptor on cytotoxic T-cells. Thus, means to override these resistance mechanisms are needed to sensitize the tumor cells to both cell killing and inhibition of tumor progression. Treatment with nitric oxide (NO) donors has been shown to sensitize many types of tumors to chemotherapy, immunotherapy, and radiotherapy. Treatment of cancer cell lines with NO donors has resulted in the inhibition of cancer cell activities via, in part, the inhibition of YY1 and PD-L1. The NO-mediated inhibition of YY1 was the result of both the inhibition of the upstream NF-κB pathway as well as the S-nitrosylation of YY1, leading to both the downregulation of YY1 expression as well as the inhibition of YY1-DNA binding activity, respectively. Also, treatment with NO donors induced the inhibition of YY1 and resulted in the inhibition of PD-L1 expression. Based on the above findings, we propose that treatment of tumor cells with the combination of NO donors, at optimal noncytotoxic doses, and anti-tumor cytotoxic effector cells or other conventional therapies will result in a synergistic anticancer activity and tumor regression.
PubMed: 31533363
DOI: 10.3390/antiox8090407 -
Frontiers in Physiology 2023Transition of arterial smooth muscle (ASM) from a quiescent, contractile state to a growth-promoting state is a hallmark of cardiovascular disease (CVD), a leading cause...
Transition of arterial smooth muscle (ASM) from a quiescent, contractile state to a growth-promoting state is a hallmark of cardiovascular disease (CVD), a leading cause of death and disability in the United States and worldwide. While many individual signals have been identified as important mechanisms in this phenotypic conversion, the combined impact of the transcription factors Smad3 and FoxO3 in ASM growth is not known. The purpose of this study was to determine that a coordinated, phosphorylation-specific relationship exists between Smad3 and FoxO3 in the control of ASM cell growth. Using a rat arterial injury model and rat primary ASM cell lysates and fractions, validated low and high serum models of respective quiescent and growth states, and adenoviral (Ad-) gene delivery for overexpression (OE) of individual and combined Smad3 and/or FoxO3, we hypothesized that FoxO3 can moderate Smad3-induced ASM cell growth. Key findings revealed unique cellular distribution of Smad3 and FoxO3 under growth conditions, with induction of both nuclear and cytosolic Smad3 yet primarily cytosolic FoxO3; Ad-Smad3 OE leading to cytosolic and nuclear expression of phosphorylated and total Smad3, with almost complete reversal of each with Ad-FoxO3 co-infection in quiescent and growth conditions; Ad-FoxO3 OE leading to enhanced cytosolic expression of phosphorylated and total FoxO3, both reduced with Ad-Smad3 co-infection in quiescent and growth conditions; Ad-FoxO3 inducing expression and activity of the ubiquitin ligase MuRF-1, which was reversed with concomitant Ad-Smad3 OE; and combined Smad3/FoxO3 OE reversing both the pro-growth impact of singular Smad3 and the cytostatic impact of singular FoxO3. A primary takeaway from these observations is the capacity of FoxO3 to reverse growth-promoting effects of Smad3 in ASM cells. Additional findings lend support for reciprocal antagonism of Smad3 on FoxO3-induced cytostasis, and these effects are dependent upon discrete phosphorylation states and cellular localization and involve MuRF-1 in the control of ASM cell growth. Lastly, results showing capacity of FoxO3 to normalize Smad3-induced ASM cell growth largely support our hypothesis, and overall findings provide evidence for utility of Smad3 and/or FoxO3 as potential therapeutic targets against abnormal ASM growth in the context of CVD.
PubMed: 37693008
DOI: 10.3389/fphys.2023.1136998 -
Viruses May 2022HIV-1 protease (PR) is a viral enzyme that cleaves the Gag and Gag-Pol polyprotein precursors to convert them into their functional forms, a process which is essential... (Review)
Review
HIV-1 protease (PR) is a viral enzyme that cleaves the Gag and Gag-Pol polyprotein precursors to convert them into their functional forms, a process which is essential to generate infectious viral particles. Due to its broad substrate specificity, HIV-1 PR can also cleave certain host cell proteins. Several studies have identified host cell substrates of HIV-1 PR and described the potential impact of their cleavage on HIV-1-infected cells. Of particular interest is the interaction between PR and the caspase recruitment domain-containing protein 8 (CARD8) inflammasome. A recent study demonstrated that CARD8 can sense HIV-1 PR activity and induce cell death. While PR typically has low levels of intracellular activity prior to viral budding, premature PR activation can be achieved using certain non-nucleoside reverse transcriptase inhibitors (NNRTIs), resulting in CARD8 cleavage and downstream pyroptosis. Used together with latency reversal agents, the induction of premature PR activation to trigger CARD8-mediated cell killing may help eliminate latent reservoirs in people living with HIV. This represents a novel strategy of utilizing PR as an antiviral target through premature activation rather than inhibition. In this review, we discuss the viral and host substrates of HIV-1 protease and highlight potential applications and advantages of targeting CARD8 sensing of HIV-1 PR.
Topics: CARD Signaling Adaptor Proteins; Fusion Proteins, gag-pol; HIV Protease; HIV-1; Humans; Neoplasm Proteins; Reverse Transcriptase Inhibitors
PubMed: 35746649
DOI: 10.3390/v14061179 -
Aging Dec 2023Recently, there has been a great deal interest in cuproptosis, a form of programmed cell death that is mediated by copper. The specific mechanism through which...
Integrative analysis of single-cell and bulk RNA seq to reveal the prognostic model and tumor microenvironment remodeling mechanisms of cuproptosis-related genes in colorectal cancer.
BACKGROUND
Recently, there has been a great deal interest in cuproptosis, a form of programmed cell death that is mediated by copper. The specific mechanism through which cuproptosis-related genes impact the development of colorectal cancer (CRC) remains unknown.
METHODS
Here, we combined bulk RNA-seq with scRNA-seq to investigate the CRGs functions within CRC. A number of 61 cuproptosis-related genes were chosen for further investigation. Nine prognostic CRGs were identified by Lasso-Cox. The RiskScore was created and the patients have been separated into two different groups, low- and high-RiskScore group. The CIBERSORT, ESTIMATE, MCP-counter, TIDE, and IPS have been employed to score the TME, and GSVA and GSEA were utilized to evaluate the pathway within the both groups. Further, we used cell communication analysis to explore the tumor microenvironment remodeling mechanisms of the COX17 and DLAT based on scRNA-seq. Finally, we used IHC and qPCR to validate the expression of COX17 and DLAT.
RESULTS
AOC3, CCS, CDKN2A, COX11, COX17, COX19, DLD, DLAT, and PDHB have been recognized as prognostic CRGs in CRC. The high-risk group exhibited the worst prognosis, an immune-deficient phenotype, and were more resistant to ICB treatment. Further, scRNA-seq analysis revealed that elevated expression of COX17 in CD4-CXCL13Tfh could contribute to the immune evasion while DLAT had the opposite effect, reversing T cell exhaustion and inducing pyroptosis to boost CD8-GZMKT infiltration.
CONCLUSIONS
The current investigation has developed a prognostic framework utilizing cuproptosis-related genes that is highly effective in predicting prognosis, TME type, and response to immunotherapy in CRC patients. Furthermore, our study reveals a novel finding that elevated levels of COX17 expression within CD4-CXCL13 T cells in CRC mediates T cell exhaustion and Treg infiltration, while DLAT has been found to facilitate the anti-tumor immunity activation through the T cell exhaustion reversal and the induction of pyroptosis.
Topics: Humans; RNA-Seq; Prognosis; Tumor Microenvironment; Genes, p16; Apoptosis; Copper; Colorectal Neoplasms
PubMed: 38078879
DOI: 10.18632/aging.205324 -
BioRxiv : the Preprint Server For... May 2023Proteotoxic stress drives numerous degenerative diseases. In response to misfolded proteins, cells adapt by activating the unfolded protein response (UPR), including...
Proteotoxic stress drives numerous degenerative diseases. In response to misfolded proteins, cells adapt by activating the unfolded protein response (UPR), including endoplasmic reticulum-associated protein degradation (ERAD). However persistent stress triggers apoptosis. Enhancing ERAD is a promising therapeutic approach for protein misfolding diseases. From plants to humans, loss of the Zn transporter ZIP7 causes ER stress, however the mechanism is unknown. Here we show that ZIP7 enhances ERAD and that cytosolic Zn is limiting for deubiquitination of client proteins by the Rpn11 Zn metalloproteinase as they enter the proteasome in Drosophila and human cells. ZIP7 overexpression rescues defective vision caused by misfolded rhodopsin in Drosophila. Thus ZIP7 overexpression may prevent diseases caused by proteotoxic stress, and existing ZIP inhibitors may be effective against proteasome-dependent cancers.
PubMed: 37292980
DOI: 10.1101/2023.05.22.541645 -
Frontiers in Oncology 2022Defective silencing of tumor suppressor genes through epigenetic alterations contributes to oncogenesis by perturbing cell cycle regulation, DNA repair or cell death... (Review)
Review
Defective silencing of tumor suppressor genes through epigenetic alterations contributes to oncogenesis by perturbing cell cycle regulation, DNA repair or cell death mechanisms. Reversal of such epigenetic changes including DNA hypermethylation provides a promising anticancer strategy. Until now, the nucleoside derivatives 5-azacytidine and decitabine are the sole DNA methyltransferase (DNMT) inhibitors approved by the FDA for the treatment of specific hematological cancers. Nevertheless, due to their nucleoside structure, these inhibitors directly incorporate into DNA, which leads to severe side effects and compromises genomic stability. Much emphasis has been placed on the development of less toxic epigenetic modifiers. Recently, several preclinical studies demonstrated the potent epigenetic effects of local anesthetics, which are routinely used during primary tumor resection to relief surgical pain. These non-nucleoside molecules inhibit DNMT activity, affect the expression of micro-RNAs and repress histone acetylation, thus exerting cytotoxic effects on malignant cells. The in-depth mechanistic comprehension of these epigenetic effects might promote the use of local anesthetics as anticancer drugs.
PubMed: 36110954
DOI: 10.3389/fonc.2022.849895 -
Advanced Science (Weinheim,... Apr 2024Photodynamic therapy (PDT) is a minimally invasive and controllable local cancer treatment for cholangiocarcinoma (CCA). However, the efficacy of PDT is hindered by...
Photodynamic therapy (PDT) is a minimally invasive and controllable local cancer treatment for cholangiocarcinoma (CCA). However, the efficacy of PDT is hindered by intratumoral hypoxia and the presence of an antioxidant microenvironment. To address these limitations, combining PDT with gas therapy may be a promising strategy to enhance tumor oxygenation. Moreover, the augmentation of oxidative damage induced by PDT and gas therapy can be achieved by inhibiting NRF2, a core regulatory molecule involved in the antioxidant response. In this study, an integrated nanotherapeutic platform called CMArg@Lip, incorporating PDT and gas therapies using ROS-responsive liposomes encapsulating the photosensitizer Ce6, the NO gas-generating agent L-arginine, and the NRF2 inhibitor ML385, is successfully developed. The utilization of CMArg@Lip effectively deals with challenges posed by tumor hypoxia and antioxidant microenvironment, resulting in elevated levels of oxidative damage and subsequent induction of ferroptosis in CCA. Additionally, these findings suggest that CMArg@Lip exhibits notable immunomodulatory effects, including the promotion of immunogenic cell death and facilitation of dendritic cell maturation. Furthermore, it contributes to the anti-tumor function of cytotoxic T lymphocytes through the downregulation of PD-L1 expression in tumor cells and the activation of the STING signaling pathway in myeloid-derived suppressor cells, thereby reprogramming the immunosuppressive microenvironment via various mechanisms.
Topics: Humans; Photochemotherapy; NF-E2-Related Factor 2; Antioxidants; Cholangiocarcinoma; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Tumor Microenvironment
PubMed: 38308097
DOI: 10.1002/advs.202307143