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Frontiers in Bioscience (Landmark... Jun 2024The endoplasmic reticulum (ER) played an important role in the folding, assembly and post-translational modification of proteins. ER homeostasis could be disrupted by... (Review)
Review
The endoplasmic reticulum (ER) played an important role in the folding, assembly and post-translational modification of proteins. ER homeostasis could be disrupted by the accumulation of misfolded proteins, elevated reactive oxygen species (ROS) levels, and abnormal Ca2+ signaling, which was referred to ER stress (ERS). Ferroptosis was a unique programmed cell death model mediated by iron-dependent phospholipid peroxidation and multiple signaling pathways. The changes of mitochondrial structure, the damage of glutathione peroxidase 4 (GPX4) and excess accumulation of iron were the main characteristics of ferroptosis. ROS produced by ferroptosis can interfere with the activity of protein-folding enzymes, leading to the accumulation of large amounts of unfolded proteins, thus causing ERS. On the contrary, the increase of ERS level could promote ferroptosis by the accumulation of iron ion and lipid peroxide, the up-regulation of ferroptosis related genes. At present, the studies on the relationship between ferroptosis and ERS were one-sided and lack of in-depth studies on the interaction mechanism. This review aimed to explore the molecular mechanism of cross-talk between ferroptosis and ERS, and provide new strategies and targets for the treatment of liver diseases.
Topics: Ferroptosis; Humans; Endoplasmic Reticulum Stress; Liver Diseases; Reactive Oxygen Species; Animals; Signal Transduction; Iron; Lipid Peroxidation; Endoplasmic Reticulum
PubMed: 38940044
DOI: 10.31083/j.fbl2906221 -
Frontiers in Bioscience (Landmark... Jun 2024This study investigated the mechanism by which tazarotene-induced gene 1 (TIG1) inhibits melanoma cell growth. The main focus was to analyze downstream genes regulated...
BACKGROUND
This study investigated the mechanism by which tazarotene-induced gene 1 (TIG1) inhibits melanoma cell growth. The main focus was to analyze downstream genes regulated by TIG1 in melanoma cells and its impact on cell growth.
METHODS
The effects of TIG1 expression on cell viability and death were assessed using water-soluble tetrazolium 1 (WST-1) mitochondrial staining and lactate dehydrogenase release assays. RNA sequencing and Western blot analysis were employed to investigate the genes regulated by TIG1 in melanoma cells. Additionally, the correlation between expression and its downstream genes was analyzed in a melanoma tissue array.
RESULTS
TIG1 expression in melanoma cells was associated with decreased cell viability and increased cell death. RNA-sequencing (RNA-seq), quantitative reverse transcription PCR (reverse RT-QPCR), and immunoblots revealed that TIG1 expression induced the expression of Endoplasmic Reticulum (ER) stress response-related genes such as Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 (HERPUD1), Binding immunoglobulin protein (BIP), and DNA damage-inducible transcript 3 (DDIT3). Furthermore, analysis of the melanoma tissue array revealed a positive correlation between expression and the expression of , , and . Additionally, attenuation of the ER stress response in melanoma cells weakened the impact of TIG1 on cell growth.
CONCLUSIONS
TIG1 expression effectively hinders the growth of melanoma cells. TIG1 induces the upregulation of ER stress response-related genes, leading to an increase in caspase-3 activity and subsequent cell death. These findings suggest that the ability of retinoic acid to prevent melanoma formation may be associated with the anticancer effect of TIG1.
Topics: Humans; Endoplasmic Reticulum Stress; Melanoma; Cell Line, Tumor; Cell Survival; Gene Expression Regulation, Neoplastic; Cell Death; Apoptosis; Cell Proliferation; Membrane Proteins
PubMed: 38940043
DOI: 10.31083/j.fbl2906233 -
Frontiers in Bioscience (Landmark... Jun 2024Mitochondrial DNA (mtDNA) is located in the mitochondrial matrix, in close proximity to major sources of reactive oxygen species (ROS) in the cell. This makes mtDNA one... (Review)
Review
Mitochondrial DNA (mtDNA) is located in the mitochondrial matrix, in close proximity to major sources of reactive oxygen species (ROS) in the cell. This makes mtDNA one of the most susceptible components to damage in the cell. The nuclear factor E2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway is an important cytoprotective mechanism. It is well-studied and described that Nrf2 can regulate the expression of mitochondrial-targeted antioxidant systems in the cell, indirectly protecting mtDNA from damage. However, the Nrf2/ARE pathway can also directly impact on the mtDNA repair processes. In this review, we summarize the existing data on the impact of Nrf2 on mtDNA repair, primarily base excision repair (BER), as it is considered the main repair pathway for the mitochondrial genome. We explore the crosstalk between Nrf2/ARE, BRCA1, and p53 signaling pathways in their involvement in maintaining mtDNA integrity. The role of other repair mechanisms in correcting mismatched bases and double-strand breaks is discussed. Additionally, the review addresses the role of Nrf2 in the repair of noncanonical bases, which contribute to an increased number of mutations in mtDNA and can contaminate the nucleotide pool.
Topics: NF-E2-Related Factor 2; DNA, Mitochondrial; Humans; DNA Repair; Signal Transduction; Antioxidant Response Elements; Animals; BRCA1 Protein; Tumor Suppressor Protein p53; DNA Damage
PubMed: 38940042
DOI: 10.31083/j.fbl2906218 -
Frontiers in Bioscience (Landmark... Jun 2024Dental pulp stem cells (DPSCs) have self-renewal and multidirectional differentiation potentials. As such, DPSCs have a wide range of clinical applications. Low-level...
BACKGROUND
Dental pulp stem cells (DPSCs) have self-renewal and multidirectional differentiation potentials. As such, DPSCs have a wide range of clinical applications. Low-level laser therapy (LLLT) has positive photobiostimulatory effects on cell proliferation, angiogenesis, osteogenic differentiation, bone regeneration, and fracture healing. However, there have been few studies on the effect of low-energy lasers on DPSC proliferation.
METHODS
DPSCs were obtained from dental pulp tissue. The effects of LLLT on the proliferation of DPSCs and the associated mechanisms were investigated by culture and laser irradiation.
RESULTS
LLLT with energy densities of 3.5 J/cm2 and 14 J/cm2promoted the proliferation of DPSCs. Differential protein expression studies suggested the stimulation of DPSC proliferation by LLLT involved the PI3K-Akt and Rap1 signaling pathways, as well as the apoptosis-related pathway.
CONCLUSION
This preliminary study demonstrated that low-energy lasers have a pro-proliferative effect on DPSCs, and identified possible associated mechanisms. Our findings provide a theoretical basis for the clinical application of DPSCs and suggest novel strategies for the treatment of related diseases.
Topics: Dental Pulp; Cell Proliferation; Humans; Stem Cells; Low-Level Light Therapy; Cells, Cultured; Signal Transduction; Apoptosis; Cell Differentiation
PubMed: 38940041
DOI: 10.31083/j.fbl2906211 -
Frontiers in Bioscience (Landmark... Jun 2024The inhibitors of mammalian target of rapapmycin (mTOR), everolimus, temsirolimus and rapamycin, have a wide range of clinical utility; however, as is inevitably the... (Review)
Review
The inhibitors of mammalian target of rapapmycin (mTOR), everolimus, temsirolimus and rapamycin, have a wide range of clinical utility; however, as is inevitably the case with other chemotherapeutic agents, resistance development constrains their effectiveness. One putative mechanism of resistance is the promotion of autophagy, which is a direct consequence of the inhibition of the mTOR signaling pathway. Autophagy is primarily considered to be a cytoprotective survival mechanism, whereby cytoplasmic components are recycled to generate energy and metabolic intermediates. The autophagy induced by everolimus and temsirolimus appears to play a largely protective function, whereas a cytotoxic function appears to predominate in the case of rapamycin. In this review we provide an overview of the autophagy induced in response to mTOR inhibitors in different tumor models in an effort to determine whether autophagy targeting could be of clinical utility as adjuvant therapy in association with mTOR inhibition.
Topics: Humans; Autophagy; TOR Serine-Threonine Kinases; MTOR Inhibitors; Animals; Neoplasms; Signal Transduction; Antineoplastic Agents; Cytoprotection; Sirolimus
PubMed: 38940039
DOI: 10.31083/j.fbl2906231 -
Frontiers in Bioscience (Landmark... Jun 2024Gastric cancer (GC) is a leading cause of cancer-associated death worldwide. Its molecular mechanisms, especially concerning autophagy and various signaling pathways,...
BACKGROUND
Gastric cancer (GC) is a leading cause of cancer-associated death worldwide. Its molecular mechanisms, especially concerning autophagy and various signaling pathways, are not fully understood. Fatty Acid Binding Protein 6 () and RE1 Silencing Transcription Factor () emerge as potential key players in this context. This study sought to analyze the functional relationship of and concerning autophagy and their implications on the Akt/mTOR signaling pathway within GC cells.
METHODS
A comprehensive bioinformatics approach was used to identify key prognostic markers in GC. The effects of and on autophagy along with Akt/mTOR signaling pathways were analyzed by techniques including Western blotting (WB), flow cytometry, Transwell assay, dual luciferase reporter assay, and others.
RESULTS
was identified as overexpressed in GC, linked with poor prognosis. silencing reduces GC cell proliferation, induces S- and G2-phase arrest, and downregulates cyclins CDK2 and CDK4. It also inhibited GC cell invasion/migration and autophagy, effects that were counteracted by MG132. When combined with PI3K inhibitor LY294002c, knockdown showed synergistic anti-proliferative effects, modulating the Akt/mTOR pathway. Besides, the transcription factor has been shown to directly regulate expression, affecting autophagy and the Akt/mTOR signaling pathway in a -dependent manner.
CONCLUSIONS
positively regulates autophagy and negatively affects the Akt/mTOR signaling pathway in GC cells in a FABP6-dependent manner, providing valuable insights into regulatory networks involving and .
Topics: Humans; Stomach Neoplasms; TOR Serine-Threonine Kinases; Autophagy; Proto-Oncogene Proteins c-akt; Signal Transduction; Cell Line, Tumor; Fatty Acid-Binding Proteins; Cell Proliferation; Gene Expression Regulation, Neoplastic
PubMed: 38940038
DOI: 10.31083/j.fbl2906212 -
Frontiers in Bioscience (Landmark... Jun 2024L-Theanine, a nonproteinogenic amino acid derived from green tea, is being recognized as an anti-cancer candidate. However, it's roles in the development of cancer...
BACKGROUND
L-Theanine, a nonproteinogenic amino acid derived from green tea, is being recognized as an anti-cancer candidate. However, it's roles in the development of cancer chemoresistance is still unknown and the molecular mechanism is urgently to be explored.
METHODS
The effects of L-Theanine on lung cancer chemoresistance were validated by Cell Counting Kit-8 (CCK-8) assay, transwell assay, and tumor spheroid formation assay; the expression of proteins was detected by using polymerase chain reaction (PCR) and western blotting. RNA-sequencing (RNA-seq) and bioinformatics analysis were used to identify differentially expressed genes induced by L-Theanine. knockdown and overexpression were constructed by using a lentivirus-mediated transfection system.
RESULTS
L-Theanine improved the chemoresistance to -diamminedichloroplatinum (DDP) and inhibited stemness of DDP-resistant lung cancer cells but not non-resistant lung cancer cells. The results from RNA-seq analysis showed that STAT3/NOTCH1 pathway was a potential dominant signaling involved in L-Theanine improving the chemoresistance in DDP-resistant lung cancer. Mechanistically, L-Theanine impeded migration and stemness activation of DDP-resistant lung cancer cells via regulating the expression of STAT3/NOTCH1/BMAL1 signaling-induced stemness markers as well as inhibiting the expression levels of drug resistance-related genes. In addition, a combination of L-Theanine and Stat3 blockade synergistically improved the chemoresistance in DDP-resistant lung cancer.
CONCLUSION
L-Theanine improves the chemoresistance by regulating STAT3/NOTCH1/BMAL1 signaling, reducing stemness, and inhibiting the migration of DDP-resistant lung cancer cells. The finding might provide some evidence for therapeutic options in overcoming the chemoresistance in cancers, including lung cancer.
Topics: Humans; Glutamates; Drug Resistance, Neoplasm; Lung Neoplasms; Cisplatin; STAT3 Transcription Factor; Signal Transduction; Receptor, Notch1; Cell Line, Tumor; ARNTL Transcription Factors; Antineoplastic Agents; Gene Expression Regulation, Neoplastic; A549 Cells; Cell Movement
PubMed: 38940036
DOI: 10.31083/j.fbl2906226 -
Frontiers in Bioscience (Landmark... May 2024Lung cancer is the primary cause of cancer-related deaths, with one of the highest incidence and mortality rates of all malignant tumors. Dysregulated expression of...
BACKGROUND
Lung cancer is the primary cause of cancer-related deaths, with one of the highest incidence and mortality rates of all malignant tumors. Dysregulated expression of DEPDC1B has been reported to occur in various tumor types. However, the functional implications of this alteration in lung adenocarcinoma (LUAD) and the underlying molecular mechanism remains unclear. In this study, we investigated the role and clinical significance of DEPDC1B in LUAD.
METHODS
The expression of DEPDC1B in LUAD and its relationship with prognosis were systematically evaluated in several publically available datasets. The effects of DEPDC1B knockdown on the proliferation and motility of LUAD cells were assessed using the JULI Stage Real-time Cell History Recorder, while the effect of knockdown on the cell cycle was studied by flow cytometry. Furthermore, RNA-Sequencing (RNA-Seq) analysis was conducted to identify the downstream target genes and pathways regulated by DEPDC1B. Correlations between the expression of DEPDC1B and immune cell infiltration, immunotherapy resistance, and chemoresistance were also examined. Additionally, molecular biological methods were used to explore the regulatory mechanism of B-Myb on DEPDC1B expression.
RESULTS
DEPDC1B was found to be upregulated in LUAD patients and this was associated with poor clinical outcomes. Knockdown of inhibited cell growth, migration and motility, as well as cell cycle progression. Knockdown also resulted in the down-regulation of several downstream genes, including , , and , as well as the inactivation of multiple critical pathways, such as the ERK and PI3K-AKT pathways. Analysis of the tumor immuno-environment in LUAD revealed that high DEPDC1B expression was associated with an abundance of activated CD4+ memory T cells, M0 macrophages, M1 macrophages, and CD8+ T cells. Moreover, these tumors responded poorly to immunotherapy. Analysis of chemo-drug sensitivity showed that LUADs with high DEPDC1B expression were more responsive to frontline chemotherapeutic drugs such as Vinorelbine, Cisplatin, and Etoposide. Additionally, mechanistic investigations revealed that DEPDC1B is a direct target gene of B-Myb, and that its knockdown attenuated the proliferation and motility effects of B-Myb.
CONCLUSIONS
In summary, our findings indicate that DEPDC1B is a critical regulator during the malignant progression of LUAD. DEPDC1B could therefore be a promising prognostic marker and therapeutic target in LUAD diagnosis and treatment.
Topics: Humans; Adenocarcinoma of Lung; GTPase-Activating Proteins; Lung Neoplasms; Cell Proliferation; Cell Movement; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Disease Progression; Cell Cycle Proteins; Prognosis; Drug Resistance, Neoplasm; Male; Gene Knockdown Techniques; Signal Transduction; Neoplasm Proteins; Trans-Activators
PubMed: 38940035
DOI: 10.31083/j.fbl2906204 -
Frontiers in Bioscience (Landmark... Jun 2024Existing animal models for testing therapeutics in the skin are limited. Mouse and rat models lack similarity to human skin in structure and wound healing mechanism....
BACKGROUND
Existing animal models for testing therapeutics in the skin are limited. Mouse and rat models lack similarity to human skin in structure and wound healing mechanism. Pigs are regarded as the best model with regards to similarity to human skin; however, these studies are expensive, time-consuming, and only small numbers of biologic replicates can be obtained. In addition, local-regional effects of treating wounds that are closely adjacent to one-another with different treatments make assessment of treatment effectiveness difficult in pig models. Therefore, here, a novel nude mouse model of xenografted porcine hypertrophic scar (HTS) cells was developed. This model system was developed to test if supplying hypo-pigmented cells with exogenous alpha melanocyte stimulating hormone (α-MSH) will reverse pigment loss .
METHODS
Dyschromic HTSs were created in red Duroc pigs. Epidermal scar cells (keratinocytes and melanocytes) were derived from regions of hyper-, hypo-, or normally pigmented scar or skin and were cryopreserved. Dermal fibroblasts (DFs) were isolated separately. Excisional wounds were created on nude mice and a grafting dome was placed. DFs were seeded on day 0 and formed a dermis. On day 3, epidermal cells were seeded onto the dermis. The grafting dome was removed on day 7 and hypo-pigmented xenografts were treated with synthetic α-MSH delivered with microneedling. On day 10, the xenografts were excised and saved. Sections were stained using hematoxylin and eosin hematoxylin and eosin (H&E) to assess xenograft structure. RNA was isolated and quantitative real-time polymerase chain reaction (qRT-PCR) was performed for melanogenesis-related genes , , and .
RESULTS
The seeding of HTSDFs formed a dermis that is similar in structure and cellularity to HTS dermis from the porcine model. When hyper-, hypo-, and normally-pigmented epidermal cells were seeded, a fully stratified epithelium was formed by day 14. H&E staining and measurement of the epidermis showed the average thickness to be 0.11 ± 0.07 µm 0.06 ± 0.03 µm in normal pig skin. Hypo-pigmented xenografts that were treated with synthetic α-MSH showed increases in pigmentation and had increased gene expression of , , and compared to untreated controls (TYR: 2.7 ± 1.1 0.3 ± 1.1; TYRP1: 2.6 ± 0.6 0.3 ± 0.7; DCT 0.7 ± 0.9 0.3 ± 1-fold change from control; n = 3).
CONCLUSIONS
The developed nude mouse skin xenograft model can be used to study treatments for the skin. The cells that can be xenografted can be derived from patient samples or from pig samples and form a robust dual-skin layer containing epidermis and dermis that is responsive to treatment. Specifically, we found that hypo-pigmented regions of scar can be stimulated to make melanin by synthetic α-MSH .
Topics: Animals; Mice, Nude; Cicatrix, Hypertrophic; Mice; Disease Models, Animal; Swine; alpha-MSH; Humans; Skin; Fibroblasts; Melanocytes; Keratinocytes; Transplantation, Heterologous; Wound Healing; Skin Pigmentation
PubMed: 38940034
DOI: 10.31083/j.fbl2906230 -
Frontiers in Bioscience (Landmark... May 2024Phosphine resistance in challenges grain storage. This study investigates the impact of cytochrome P450 (CYP) enzymes and CYP346 family genes on phosphine resistance in...
BACKGROUND
Phosphine resistance in challenges grain storage. This study investigates the impact of cytochrome P450 (CYP) enzymes and CYP346 family genes on phosphine resistance in Indian Tribolium castaneum populations.
METHODS
Seven field populations of were compared with Lab- susceptible population for their resistance to phosphine. The levels of cytochrome P450 enzyme and expression of certain CYP346 family genes were tracked in these populations.
RESULTS
The highly resistant Patiala population showed significantly increased CYP450 activity (11.26 ± 0.14 nmol/min/mg protein, 7.41-fold higher) compared to the lab-susceptible population (1.52 ± 0.09 nmol/min/mg protein) when assayed using 8 mM p-nitroanisole as the substrate. The mRNA expression was measured relative to the standard gene and revealed significant upregulation of and in highly resistant populations Moga and Patiala (: 12.09 ± 2.19 to 21.74 ± 3.82; : 59.097 ± 10.265 to 50.148 ± 8.272). Patiala's exhibited an impressive 685.76-fold change, and Moga's showed a 361.893-fold change compared to lab-susceptible. Linear regression confirmed robust fits for each gene (R2: 0.693 to 0.756). Principal component analysis (PCA) demonstrated a strong positive correlation between genes expression; and cytochrome P450 activity. Patiala, Moga, and Hapur populations showed conformity, associating higher resistance with increased P450 activity and CYP346 gene expression. Cluster analysis highlighted a potential correlation between , , and and P450 activity, with Patiala and Moga clustering together.
CONCLUSIONS
Variability in and in strong resistance populations may contribute to adaptation and resistance mechanisms. The study provides insights into specific CYP346 family genes associated with phosphine resistance, emphasizing the intricate interaction between CYP450 detoxifying enzymes, CYP346 family genes, and resistance mechanisms. The upregulation of genes suggests a survival advantage for against phosphine, diminishing phosphine's efficacy as a pest control measure.
Topics: Tribolium; Cytochrome P-450 Enzyme System; Insecticide Resistance; Phosphines; Insecticides; India; Animals
PubMed: 38940033
DOI: 10.31083/j.fbl2906203