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Cell Death & Disease Nov 2022Histone acetylation/deacetylation play an essential role in modifying chromatin structure and in regulating cell plasticity in eukaryotic cells. Therefore, histone...
Histone acetylation/deacetylation play an essential role in modifying chromatin structure and in regulating cell plasticity in eukaryotic cells. Therefore, histone deacetylase (HDAC) pharmacological inhibitors are promising tools in the therapy of fibrotic diseases and in cancer. Peritoneal fibrosis is a pathological process characterized by many cellular and molecular alterations, including the acquisition of invasive/pro-fibrotic abilities by mesothelial cells (MCs) through induction of mesothelial to mesenchymal transition (MMT). The aim of this study was to characterize the molecular mechanism of the antifibrotic role of HDAC1 inhibition. Specifically, treatment with MS-275, an HDAC1-3 inhibitor previously known to promote MMT reversal, induced the expression of several TGFBRI mRNA-targeting miRNAs. Among them, miR-769-5p ectopic expression was sufficient to promote MMT reversal and to limit MC migration and invasion, whereas miR-769-5p silencing further enhanced mesenchymal gene expression. These results were confirmed by HDAC1 genetic silencing. Interestingly, miR-769-5p silencing maintained mesenchymal features despite HDAC1 inhibition, thus indicating that it is necessary to drive MMT reversal induced by HDAC1 inhibition. Besides TGFBRI, miR-769-5p was demonstrated to target SMAD2/3 and PAI-1 expression directly. When analyzing molecular mechanisms underlying miR-769-5p expression, we found that the transcription factor Wilms' tumor 1 (WT1), a master gene controlling MC development, binds to the miR-769-5p promoter favoring its expression. Interestingly, both WT1 expression and binding to miR-769-5p promoter were increased by HDAC1 inhibition and attenuated by TGFβ1 treatment. Finally, we explored the significance of these observations in the cell-to-cell communication: we evaluated the ability of miR-769-5p to be loaded into extracellular vesicles (EVs) and to promote MMT reversal in recipient mesenchymal-like MCs. Treatment of fibrotic MCs with EVs isolated from miR-769-5p over-expressing MCs promoted the down-regulation of specific mesenchymal targets and the reacquisition of an epithelial-like morphology. In conclusion, we highlighted an HDAC1-WT1-miR-769-5p axis potentially relevant for therapies aimed at counteracting organ fibrosis.
Topics: Cell Movement; Epithelial-Mesenchymal Transition; Epithelium; MicroRNAs
PubMed: 36396626
DOI: 10.1038/s41419-022-05398-0 -
Frontiers in Cell and Developmental... 2019Mechanoreciprocity refers to a cell's ability to maintain tensional homeostasis in response to various types of forces. Physical forces are continually being exerted... (Review)
Review
Mechanoreciprocity refers to a cell's ability to maintain tensional homeostasis in response to various types of forces. Physical forces are continually being exerted upon cells of various tissue types, even those considered static, such as the brain. Through mechanoreceptors, cells sense and subsequently respond to these stimuli. These forces and their respective cellular responses are prevalent in regulating everything from embryogenic tissue-specific differentiation, programmed cell death, and disease progression, the last of which being the subject of extensive attention. Abnormal mechanical remodeling of cells can provide clues as to the pathological status of tissues. This becomes particularly important in cancer cells, where cellular stiffness has been recently accepted as a novel biomarker for cancer metastasis. Several studies have also elucidated the importance of cell stiffness in cancer metastasis, with data highlighting that a reversal of tumor stiffness has the capacity to revert the metastatic properties of cancer. In this review, we summarize our current understanding of extracellular matrix (ECM) homeostasis, which plays a prominent role in tissue mechanics. We also describe pathological disruption of the ECM, and the subsequent implications toward cancer and cancer metastasis. In addition, we highlight the most novel approaches toward understanding the mechanisms which generate pathogenic cell stiffness and provide potential new strategies which have the capacity to advance our understanding of one of human-kinds' most clinically significant medical pathologies. These new strategies include video-based techniques for structural dynamics, which have shown great potential for identifying full-field, high-resolution modal properties, in this case, as a novel application.
PubMed: 31637239
DOI: 10.3389/fcell.2019.00199 -
Cancers Jun 2022Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally... (Review)
Review
Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally advanced CRC, and 15% for patients with metastatic CRC (mCRC). In fact, most CRC patients are at an advanced stage at the time of diagnosis. Although chemotherapy, molecularly targeted therapy and immunotherapy have significantly improved patient survival, some patients are initially insensitive to these drugs or initially sensitive but quickly become insensitive, and the emergence of such primary and secondary drug resistance is a significant clinical challenge. The most direct cause of resistance is the aberrant anti-tumor drug metabolism, transportation or target. With more in-depth research, it is found that cell death pathways, carcinogenic signals, compensation feedback loop signal pathways and tumor immune microenvironment also play essential roles in the drug resistance mechanism. Here, we assess the current major mechanisms of CRC resistance and describe potential therapeutic interventions.
PubMed: 35740594
DOI: 10.3390/cancers14122928 -
Current Issues in Molecular Biology May 2024The many limitations of implementing anticancer strategies under the term "precision oncology" have been extensively discussed. While some authors propose promising... (Review)
Review
The many limitations of implementing anticancer strategies under the term "precision oncology" have been extensively discussed. While some authors propose promising future directions, others are less optimistic and use phrases such as illusion, hype, and false hypotheses. The reality is revealed by practicing clinicians and cancer patients in various online publications, one of which has stated that "in the quest for the next cancer cure, few researchers bother to look back at the graveyard of failed medicines to figure out what went wrong". The message is clear: Novel therapeutic strategies with catchy names (e.g., synthetic "lethality") have not fulfilled their promises despite decades of extensive research and clinical trials. The main purpose of this review is to discuss key challenges in solid tumor therapy that surprisingly continue to be overlooked by the Nomenclature Committee on Cell Death (NCCD) and numerous other authors. These challenges include: The impact of chemotherapy-induced genome chaos (e.g., multinucleation) on resistance and relapse, oncogenic function of caspase 3, cancer cell anastasis (recovery from late stages of apoptosis), and pitfalls of ubiquitously used preclinical chemosensitivity assays (e.g., cell "viability" and tumor growth delay studies in live animals) that score such pro-survival responses as "lethal" events. The studies outlined herein underscore the need for new directions in the management of solid tumors.
PubMed: 38920994
DOI: 10.3390/cimb46060322 -
Cell Death & Disease Jul 2022Chemoresistance remains the primary challenge of clinical treatment of gastric cancer (GC), making the biomarkers of chemoresistance crucial for treatment decision. Our...
Chemoresistance remains the primary challenge of clinical treatment of gastric cancer (GC), making the biomarkers of chemoresistance crucial for treatment decision. Our previous study has reported that p21-actived kinase 6 (PAK6) is a prognostic factor for selecting which patients with GC are resistant to 5-fluorouracil/oxaliplatin chemotherapy. However, the mechanistic role of PAK6 in chemosensitivity remains unknown. The present study identified PAK6 as an important modulator of the DNA damage response (DDR) and chemosensitivity in GC. Analysis of specimens from patients revealed significant associations between the expression of PAK6 and poorer stages, deeper invasion, more lymph node metastases, higher recurrence rates, and resistance to oxaliplatin. Cells exhibited chemosensitivity to oxaliplatin after knockdown of PAK6, but showed more resistant to oxaliplatin when overexpressing PAK6. Functionally, PAK6 mediates cancer chemoresistance by enhancing homologous recombination (HR) to facilitate the DNA double-strand break repair. Mechanistically, PAK6 moves into nucleus to promote the activation of ATR, thereby further activating downstream repair protein CHK1 and recruiting RAD51 from cytoplasm to the DNA damaged site to repair the broken DNA in GC. Activation of ATR is the necessary step for PAK6 mediated HR repair to protect GC cells from oxaliplatin-induced apoptosis, and ATR inhibitor (AZD6738) could block the PAK6-mediated HR repair, thereby reversing the resistance to oxaliplatin and even promoting the sensitivity to oxaliplatin regardless of high expression of PAK6. In conclusion, these findings indicate a novel regulatory mechanism of PAK6 in modulating the DDR and chemoresistance in GC and provide a reversal suggestion in clinical decision.
Topics: Ataxia Telangiectasia Mutated Proteins; Cell Line, Tumor; Drug Resistance, Neoplasm; Fluorouracil; Homologous Recombination; Humans; Oxaliplatin; Stomach Neoplasms; p21-Activated Kinases
PubMed: 35902562
DOI: 10.1038/s41419-022-05118-8 -
Bioengineering (Basel, Switzerland) Jul 2022Breast cancer (BC) is a highly metastatic multifactorial disease with various histological and molecular subtypes. Due to recent advancements, the mortality rate in BC... (Review)
Review
Breast cancer (BC) is a highly metastatic multifactorial disease with various histological and molecular subtypes. Due to recent advancements, the mortality rate in BC has improved over the past five decades. Detection and treatment of many cancers are now possible due to the application of nanomedicine in clinical practice. Nanomedicine products such as Doxil and Abraxane have already been extensively used for BC adjuvant therapy with favorable clinical outcomes. However, these products were designed initially for generic anticancer purposes and not specifically for BC treatment. With a better understanding of the molecular biology of BC, several novel and promising nanotherapeutic strategies and devices have been developed in recent years. In this context, multi-functionalized nanostructures are becoming potential carriers for enhanced chemotherapy in BC patients. To design these nanostructures, a wide range of materials, such as proteins, lipids, polymers, and hybrid materials, can be used and tailored for specific purposes against BC. Selective targeting of BC cells results in the activation of programmed cell death in BC cells and can be considered a promising strategy for managing triple-negative BC. Currently, conventional BC screening methods such as mammography, digital breast tomosynthesis (DBT), ultrasonography, and magnetic resonance imaging (MRI) are either costly or expose the user to hazardous radiation that could harm them. Therefore, there is a need for such analytical techniques for detecting BC that are highly selective and sensitive, have a very low detection limit, are durable, biocompatible, and reproducible. In detecting BC biomarkers, nanostructures are used alone or in conjunction with numerous molecules. This review intends to highlight the recent advances in nanomedicine in BC treatment and diagnosis, emphasizing the targeting of BC cells that overexpress receptors of epidermal growth factors. Researchers may gain insight from these strategies to design and develop more tailored nanomedicine for BC to achieve further improvements in cancer specificity, antitumorigenic effects, anti-metastasis effects, and drug resistance reversal effects.
PubMed: 35877371
DOI: 10.3390/bioengineering9070320 -
Free Radical Research 2022Plasma, the fourth state of matter could be artificially generated at room temperature under atmospheric pressure - termed as cold atmospheric plasma (CAP). The... (Review)
Review
Plasma, the fourth state of matter could be artificially generated at room temperature under atmospheric pressure - termed as cold atmospheric plasma (CAP). The reactive oxygen and nitrogen radicals emanated during plasma discharge accord manifold applications in medicine and have proven clinical applications in cancer treatment, dentistry, and dermatology. Developments in the field termed "Plasma medicine" has inclined research toward its prospects in immunotherapy. Controlled generation of reactive oxygen and nitrogen radicals during plasma formation produces oxidative stress on tissue of concern, selectively and activates a number of cytological and molecular reactions, triggering immunological response. Plasma treatment induces immunogenic cell death (ICD) in tumor cells and elicits enhanced adaptive and systemic immune response with memory cells, conferring better defense to cancer. HIV inactivation, reduced viral replication, reversal of latency in HIV-infected cells, and augmented infected cell opsonization has been observed with CAP treatment. Plasma-treated medium has shown to deactivate virus (HSV-1) in human corneal explants and epithelial cells, and lessen the severity of herpes simplex keratitis. Perception of cellular changes that triggers innate and adaptive immune response during CAP treatment is quintessential for understanding and expansion of research in this arena. This review mentions the inimitable properties of plasma that makes it a safe and sensitive immunotherapeutic tool. The methods of plasma generation relied for the purpose are elucidated. The cellular mechanism of immunological stimulation in cancer, HIV, and keratitis during CAP treatment is detailed. The future prospects and challenges are briefly addressed.HighlightsReactive oxygen and nitrogen radicals produced by cold atmospheric plasma (CAP) triggers oxidative stress in exposed cells.Cells in oxidative stress incite immunological response that could be suitably manipulated for immunotherapy.The role of reactive radicals and methods of plasma generation for immunotherapy is elucidated.The cellular and molecular cascade of reactions leading to immunological cell death in cancer cells is detailed.The mechanism of HIV inactivation and reduced infection; further, deactivation of HSV in Herpes keratitis in intact human corneal explants is also described.
Topics: Humans; Plasma Gases; Oxidative Stress; Immunotherapy; Oxygen; Nitrogen; HIV Infections
PubMed: 36282274
DOI: 10.1080/10715762.2022.2139691 -
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 -
Current Opinion in Virology Oct 2019HIV cure is impeded by the persistence of a strenuous reservoir of latent but replication competent infected cells, which remain unsusceptible to c-ART and unrecognized... (Review)
Review
HIV cure is impeded by the persistence of a strenuous reservoir of latent but replication competent infected cells, which remain unsusceptible to c-ART and unrecognized by the immune system for elimination. Ongoing progress in understanding the molecular mechanisms that control HIV transcription and latency has led to the development of strategies to either permanently inactivate the latent HIV infected reservoir of cells or to stimulate the virus to emerge out of latency, coupled to either induction of death in the infected reactivated cell or its clearance by the immune system. This review focuses on the currently explored and non-exclusive pharmacological strategies and their molecular targets that 1. stimulate reversal of HIV latency in infected cells by targeting distinct steps in the HIV-1 gene expression cycle, 2. exploit mechanisms that promote cell death and apoptosis to render the infected cell harboring reactivated virus more susceptible to death and/or elimination by the immune system, and 3. permanently inactivate any remaining latently infected cells such that c-ART can be safely discontinued.
Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; CpG Islands; DNA Methylation; Drug Development; Gene Expression Regulation, Viral; HIV Infections; HIV Long Terminal Repeat; HIV-1; Humans; Transcriptional Activation; Viral Load; Virus Activation; Virus Latency; Virus Replication
PubMed: 31323521
DOI: 10.1016/j.coviro.2019.06.001 -
Biological Research Dec 2023Atherosclerosis (AS), a significant contributor to cardiovascular disease (CVD), is steadily rising with the aging of the global population. Pyroptosis and apoptosis,...
BACKGROUND
Atherosclerosis (AS), a significant contributor to cardiovascular disease (CVD), is steadily rising with the aging of the global population. Pyroptosis and apoptosis, both caspase-mediated cell death mechanisms, play an essential role in the occurrence and progression of AS. The human pineal gland primarily produces melatonin (MT), an indoleamine hormone with powerful anti-oxidative, anti-pyroptotic, and anti-apoptotic properties. This study examined MT's anti-oxidative stress and anti-pyroptotic effects on human THP-1 macrophages treated with nicotine.
METHODS
In vitro, THP-1 macrophages were induced by 1 µM nicotine to form a pyroptosis model and performed 30 mM MT for treatment. In vivo, ApoE mice were administered 0.1 mg/mL nicotine solution as drinking water, and 1 mg/mL MT solution was intragastric administrated at 10 mg/kg/day. The changes in pyroptosis, apoptosis, and oxidative stress were detected.
RESULTS
MT downregulated pyroptosis, whose changes were paralleled by a reduction in reactive oxygen species (ROS) production, reversal of sirtuin3 (SIRT3), and Forkhead box O3 (FOXO3α) upregulation. MT also inhibited apoptosis, mainly caused by the interaction of caspase-1 and caspase-3 proteins. Vivo studies confirmed that nicotine could accelerate plaque formation. Moreover, mice treated with MT showed a reduction in AS lesion area.
CONCLUSIONS
MT alleviates pyroptosis by regulating the SIRT3/FOXO3α/ROS axis and interacting with apoptosis. Importantly, our understanding of the inhibitory pathways for macrophage pyroptosis will allow us to identify other novel therapeutic targets that will help treat, prevent, and reduce AS-associated mortality.
Topics: Mice; Humans; Animals; Melatonin; Pyroptosis; Reactive Oxygen Species; Sirtuin 3; Nicotine; Apoptosis; Atherosclerosis; Caspases
PubMed: 38041171
DOI: 10.1186/s40659-023-00479-6