Hepatocellular carcinoma frequently exhibits evasion of apoptosis, rendering the anti-apoptotic Bcl-2 protein a pertinent therapeutic target. Steroids from Talaromyces stipitatus were evaluated as Bcl-2 inhibitors using molecular docking, molecular dynamics simulation, MMGBSA free-energy estimation, ADMET prediction, and DFT descriptors. Docking prioritized CPD2 over Paclitaxel. It also indicated accommodation within a conserved pocket supported by hydrogen-bond and hydrophobic interactions. Molecular dynamics suggested sustained stability and compactness for the CPD2-Bcl-2 complex. In contrast, the reference complex exhibited comparatively larger conformational excursions. MMGBSA favored CPD2, with improved net association attributable primarily to a reduced solvation penalty. ADMET profiling indicated limited aqueous solubility and a shared hERG II liability, while predicting no hepatotoxicity alert for CPD2. DFT descriptors were consistent with higher electronic responsiveness for CPD2 relative to the reference. These findings suggest that CPD2 may serve as a promising scaffold for developing Bcl-2-targeted therapeutic strategies against HCC. Future in vitro and in vivo studies are required to validate these computational predictions and guide lead optimization.
Pancreatic cancer remains one of the most lethal malignancies worldwide due to late diagnosis and limited therapeutic response. Gemcitabine is widely used as a first-line chemotherapeutic agent, and SH3D21 has been identified as a gemcitabine sensitizer in pancreatic cancer cells. Here, we investigated whether rs34416442 polymorphism of SH3D21 is associated with overall survival in a cohort of Iranian patients with pancreatic cancer. Peripheral blood samples were collected from 26 patients, and genotyping was performed. Patients were followed and survival outcomes were analyzed using Kaplan-Meier curves and the log-rank test. Three genotypes-TTT/TTT, TTT/T, and T/T-were identified with frequencies of 38%, 54%, and 8%, respectively. Significant differences in survival were observed among genotypes (p = 0.004). Patients carrying the T/T genotype exhibited markedly shorter mean overall survival (135 days) compared with those harboring at least one TTT allele (395 and 450 days). A recessive model further confirmed the reduced survival associated with the homozygous T/T genotype (p = 0.001). Stratified analyses showed that this association persisted in both gemcitabine-received (p = 0.006) and not-received (p = 0.016) subgroups. While different genotype-based survival patterns were observed among patients of the two groups. The TTT/T genotype showed the best survival in patients receiving gemcitabine, while TTT/TTT genotype did so in patients not receiving gemcitabine. These findings suggest SH3D21 rs34416442 as a potential predictive biomarker for pancreatic cancer.
Sirtuin 1 (SIRT1), an NAD⁺-dependent deacetylase, is involved in glucose homeostasis, insulin signaling, and inflammatory regulation, making it a potential molecular target in type 2 diabetes mellitus (T2DM). This case-control study investigated the association between serum SIRT1 levels, the SIRT1 promoter polymorphism rs7895833, and metabolic parameters in 150 patients with T2DM and 150 age- and sex-matched healthy controls. Serum SIRT1 concentrations were measured by ELISA, and rs7895833 genotyping was performed using allele-specific PCR. Clinical and biochemical variables were also assessed. Serum SIRT1 levels were significantly lower in patients with T2DM than in controls (p < 0.001) and showed significant inverse correlations with fasting plasma glucose (p = 0.001) and HbA1c (p < 0.001). Genotypic analysis revealed a significant difference in the distribution of the rs7895833 AG genotype between the two groups (p = 0.03), and under the overdominant model (AG vs. AA + GG), the heterozygous AG genotype was significantly associated with T2DM risk (OR = 1.81, p = 0.011), whereas no significant association was found between SIRT1 genotypes and circulating SIRT1 levels. These findings suggest that reduced SIRT1 is associated with hyperglycemia and poor glycemic control in T2DM. Overall, SIRT1 may serve as a potential biomarker and molecular mediator in T2DM pathogenesis. This study provides original data from a Middle Eastern population and may help inform future mechanistic and comparative studies.
The tribe Arabideae includes various species worldwide with ornamental features; however, it has undergone taxonomic revisions and has been reclassified into different genera. Despite the available literature, the taxonomic assignment of some taxa requires further consideration. This study therefore addresses the true taxonomic position of Arabis verna (L.) W.T.Aiton, which is not phylogenetically nested within other Arabis species but is instead closely related to Aubrieta Adans,. The species is naturally distributed in Southwest Asia, North Africa, and South Europe, and its taxonomic delimitation has remained unresolved. Phylogenetic evidence from previous authorities, together with our morphological observations, supports the distinct status of A. verna from the genus Aubrieta. Consequently, A. verna is excluded from Aubrieta and transferred to a newly established genus, Pseudoarabis A.R. Khosravi & A. Eslami-Farouji gen. nov., and the new combination, P. verna (L.) A.R. Khosravi & A. Eslami-Farouji comb. nov. is proposed.
Psoriasis patients were 4- 5 times more likely to have S. aureus colonize their skin. Psoriasis is caused by staphylococcal infection-induced keratinocyte death, which is maintained by elevated cytokine production of TNF-α and IFN-γ. The study sought to determine the association between the influence of gene expression of certain genes in psoriasis infections in the presence of S. aureus and their effect in Skin Cutaneous Melanoma infections. GEO with accession number (GSE207390) was used to acquire the data. The microarray test was used to perform this investigation. Six sets of keratinocytes, IL-17A, and TNF-α were cultivated together. Several kinds of bioinformatics tools were employed to fulfill the study's objective. Gene hub analysis of 34284 genes was scanned. Six genes demonstrated high expression rates were expressed during the metastatic stage: CCL27, IL19, PAPPA2, UHRF1, IFNAR2, and GLS2. IFNAR2 and UHRF1 had the highest levels of expression. The expression of the COL4A4 gene rose in response to sun exposure, but the expression of the other genes remained same. The existence of cytokine groups with S. aureus in keratinocytes influences the expression difference compared to the other groups. This work adds to our understanding of the molecular alterations that occur in the epidermis of psoriasis patients, as well as their relationship to comorbidities.
Recent molecular phylogenetic analyses within the tribe Arabideae (Brassicaceae) have uncovered unresolved lineages that challenge current generic boundaries. In this study, we incorporate molecular data with morphological evidence to resolve a long-standing taxonomic ambiguity, resulting in the description of a new monophyletic genus, Hafezia gen. nov., together with two new combinations, H. aucheri (Boiss.) A.R. Khosravi & A. Eslami-Farouji and H. parvula (Dufour ex DC.) A.R. Khosravi & A. Eslami-Farouji. Integrative taxonomy and phylogenetic insights, such as indels and substitution nucleotide variants, confirm the distinct assignment of these taxa, previously misassigned to Arabis L. Morphological reassessment, including traits such as simple, long setaceous hairs, notched petals, winged stamens, not compressed, not subtorulose or torulose fruits, supports their separation. The new genus naturally grows in the Mediterranean and west of the Irano-Turanian floristic regions. Our findings highlight the significance of integration of taxonomic investigations with the molecular investigations in clarifying evolutionary relationships and provide a revised key for accurate identification within Arabideae.
The effect of 4-OH-Coumarin, a warfarin derivate, on the cellular characteristics and metastasis of SH-SY5Y neuroblastoma cells and HUVEC cells was aimed to determine. After IC50 concentrations were detected wound healing and hematoxylin-eosin assays were performed on both cell lines. Ki-67, hTERT, PI3K, AKT, mTOR, HIF-1α, PINK1, Parkin, Cyt C, p53 gene expressions and piR-651, piR-823, miR-126 expressions were determined by RT-PCR. The proliferation, wound closure and survival decreased after 4-OH-Coumarin treatment (p<0.001). Ki-67, hTERT, PI3K, mTOR, HIF-1α, PINK1, Parkin, Cyt C and piR-823 expressions were decreased, while AKT, p53, piR-651, and miR-126 increased on SH-SY5Y (p<0.001). AKT (p<0.05), Parkin, and piR-651 expressions increased on only HUVEC cells (p<0.001). We believe that the study of various molecules that are secondary metabolites such as 4-OH-Coumarin may provide valuable data to observe the effects and mechanisms of new therapeutics that have the potential to be used for cancer treatment.
Colorectal cancer (CRC) remains a major global health concern, especially given its increasing incidence among younger individuals. While genome-wide association studies (GWAS) have identified numerous CRC-associated polymorphisms, their spatial distribution and functional implications are not fully understood. This study examined the locations of 1,346 CRC-linked polymorphisms across chromosomal bands. The results revealed significant nonrandom clustering across thirteen chromosomal bands: 1q41, 6p21, 8q24, 9q34, 10p14, 10q25, 11q12, 12p13, 15q13, 18q21, 19q13, 20p12, and 20q13. Functional enrichment analysis of genes within these bands revealed several Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Reciprocal chromosomal enrichment confirmed that many of these terms and pathways were not randomly localized within the same bands, highlighting their potential biological significance. Survival analysis using TCGA data identified three KEGG pathways and 33 GO terms mapped to nine of the thirteen bands that were significantly associated with poor prognosis. Notably, the 8q24 and 20q13 regions were enriched for differentially expressed genes and survival-associated terms yet showed no significant enrichment for genes with high somatic mutation rates. These results imply that 8q24 and 20q13 act as regulatory hotspots rather than mutation-driven regions. Overall, this integrative approach identified functionally and clinically relevant genomic regions that may contribute to inherited CRC risk and progression, providing valuable targets for the development of diagnostic and prognostic biomarkers.
Abnormal expression levels of microRNAs are associated with numerous diseases in the female reproductive tract. A small subset of human endogenous retroviruses (HERVs) genes have retained open reading frames (ORFs) that serve beneficial functions for the host. Syncytin-1 (HERV-W) and Syncytin-2 (HERV-FRD) play crucial roles in mammalian development and are expressed in placental trophoblasts. The miRNAs associated with HERV-W and HERV-FRD in spontaneous abortion and endometriosis have not been elucidated. The present study aimed to identify potential miRNAs that affect the regulation of Syncytin-1 and Syncytin-2 in endometriosis and miscarriage using bioinformatics tools. Complete CDS of Syncytin-1 (ERVW-1) and Syncytin-2 (ERVFRD-1) genes were collected from the gene bank database. Several target prediction algorithms were utilized, such as TargetScan, DIANA, miRDB, and miRWalk. Complete CDS of Syncytin-1 (ERVW-1) and Syncytin-2 (ERVFRD-1) genes were collected from the gene bank database. By integrating data from these diverse bioinformatics databases, miR-509-3p and miR-625-5p were consistent across multiple platforms, ensuring robust selection criteria. These tools facilitate the identification of differentially expressed miRNAs, understanding their roles in cellular processes, and potentially utilizing them as biomarkers for disease diagnosis and prognosis. Validation of the identified miRNAs in experimental models or clinical samples is needed to confirm their roles in endometriosis and miscarriage.
Nuclear factor Y (NF-Y) is a heterotrimeric transcription factor essential for regulating genes involved in lipid metabolism, including fatty acid synthase (Fasn). Although NF-Y activity is known to be dynamically regulated during adipocyte differentiation, the amino acid residues responsible for its transcriptional function remain unclear. In this study, we examined the contribution of nuclear factor Ya (NF-Ya) to DNA-binding activity and transcriptional regulation in 3T3-L1 adipocytes. Using deletion constructs and adenoviral expression systems, we identified a region spanning amino acid residues 184-347 of NF-Ya as critical for acquiring DNA-binding ability during differentiation. Electrophoretic mobility shift assays revealed that NF-Ya undergoes modification within this region, conferring stage-specific DNA-binding activity to the Fasn promoter. These findings suggest that post-translational modification of NF-Ya is a key mechanism regulating NF-Y function in adipogenesis. Our work provides novel insights into transcriptional control of lipogenic genes and their relevance to metabolic regulation.
Prior studies have shown that conditioned media derived from Wharton's jelly mesenchymal stem cells (WJ-CM) have anti-cancer properties. This research investigated the impact of WJ-CM on HT-29 colorectal adenocarcinoma cells by examining autophagy biomarkers and the AMPK/mTOR pathway. The HT-29 cells were subjected to WJ-CM and an AMPK activator (AICAR). Autophagy and levels of AMPK and mTOR proteins were investigated. WJ-CM increased the expression of phosphorylated AMPK while reducing the level of phosphorylated mTOR in HT-29 cells. WJ-CM treatment elevated the LC3B/LC3A ratio and ATG7, ATG5, and Beclin-1 expression. However, there was a parallel drop in p62 expression, which indicates autophagy induction. AICAR increased the influence of WJ-CM on viability, as well as the levels of biomarkers associated with autophagy, phosphorylated AMPK, and phosphorylated mTOR in the HT-29 cells. WJ-CM inhibits colorectal cancer cell growth via activating AMPK/mTOR-mediated autophagy.
Formaldehyde (FA) is a known human carcinogen for the upper respiratory tract. However, its hematotoxicity remains unclear. This study was performed to assess probable effects of FA on blood parameters and to determine the common polymorphisms in the detoxification enzymes GSTM1 and GSTT1 as biomarkers of susceptibility. Sixty-four workers with high occupational FA exposure and 57 non-exposed controls were studied. Complete blood count was performed. Also, GSTM1/GSTT1 genotypes were determined. After adjusting for potential confounding variables, FA exposure was only associated with the levels of hemoglobin, mean corpuscular hemoglobin concentration, and reticulocytes. Notably, workers with homozygous deletions of GSTM1 or GSTT1 had hematological parameters similar to those with active genes. In conclusion, very high FA exposure resulted in only slight alterations in MCHC and no overt hematotoxicity was observed. These findings suggest that even at high exposure levels, FA may not reach the bone marrow in sufficient amounts to cause hematotoxicity. Also, it seems that GSTM1/GSTT1 polymorphisms do not influence the workers' susceptibility to FA-related blood effects.
Farnesyltransferase plays a critical role in the post-translational modification of mammalian proteins, including the Ras oncogene, which is strongly associated with cancer development. Essential oils from Syzygium cumini have demonstrated promising therapeutic effects, particularly in cancer treatment, potentially through the inhibition of farnesyltransferase activity. This study employed integrative computational approaches to investigate the anticancer potential of essential oils derived from S. cumini. Various compounds were screened for toxicity, biological activities, membrane permeability, gene expression profiles, and survival correlations were conducted to investigate cancer-associated properties. Molecular docking and molecular dynamics (MD) simulations were performed to evaluate the binding interactions and stability of ligand-protein complexes involving farnesyltransferase. α-Humulene epoxide II exhibited antineoplastic activity, functioned as an apoptosis agonist, and inhibited cancer-related targets such as HIF1A and MMP9. Bornyl acetate showed potential as a JAK2 inhibitor. Both compounds demonstrated favorable membrane permeability, indicating high bioavailability and effective cellular uptake. Analysis of the farnesyltransferase (FNTB) gene revealed significantly higher expression in cancerous tissues and a positive correlation with pro-tumor immune cell infiltration. Molecular docking identified Tipifarnib as the strongest binder, serving as a positive control, while α-humulene epoxide II and bornyl acetate showed moderate to weaker binding affinities. However, MD simulations confirmed that both essential oil compounds exhibit binding stability comparable to that of Tipifarnib. Finally, α-humulene epoxide II and bornyl acetate from S. cumini exhibit favorable drug-like properties, high predicted safety margins, and a lack of organ-specific toxicity, underscoring their suitability for further drug development.
TRPV1 (Transient Receptor Potential Vanilloid 1) is a non-selective ion channel that responds to various thermal, chemical, mechanical, and ligand stimuli. It is expressed in various tissues, mainly in nociceptive neurons, adipocytes, and other cell types. This channel is involved in pain and temperature transition processes, although it has recently been implicated in adipocyte browning processes. That is why the study of this receptor has increased in recent years to understand the process of activation and inactivation by various stimuli. In this work, we focus on modeling a complete channel of human TRPV1 (hTRPV1), the structural changes, and especially the behavior of the pore when this protein is subjected to high temperatures (400 K). We report that when molecular dynamics simulate hTRPV1 at 400 K, it suffers an increase in the diameter of the two gates reported elsewhere in the pore, suggesting the opening of the channel. In this work, we describe the structural changes in the entire protein, concomitant to those in the pore, favoring this process, which might be associated with its biological activity.
Adjuvant chemotherapy with TMZ (Temozolomide) does not improve the survival of patients suffering from GBM (Glioblastoma). Given the importance of autophagy and UPR (Unfolding Protein Response) in chemotherapy resistance, as well as the role of Beclin-1, LC3IIβ, and P62 in the regulation of autophagy, we evaluated the effect of TMZ along with CPUK02 on U87 cells as a model of Glioblastoma cancer in this study. To achieve this goal, we treated the U87 cells with different doses of TMZ (50, 100, 200, 400, and 800 μM) and CPUK02 (1, 0.5, 0.25, 0.125, 0.06, 0.03, 0.01, and 0.007 μM); then, cell viability was assessed by MTT assay. The gene expression of Beclin1, P62, LC3IIβ, and XBP-1s was analyzed using quantitative real-time polymerase chain reaction. The comparison of the control group with the groups treated with the TMZ drug showed that, in 48 and 72 hours, doses of TMZ more than IC50 (100 μM) (p<0.001) significantly led to cell death. CPUK02 doses more than 0.125 (p<0.0001) significantly led to cell death. TMZ and CPUK02 combination therapy (100 and 0.03 μM, respectively) increased the expression of Beclin-1, LC3IIβ, and P62 and activated the IRE-1 arm of UPR by increasing the expression of XBP-1s. TMZ and CPUK02 treatment inhibits the autophagic flux (p62, LC3IIβ). Increased XBP-1s expression might contribute to the enhanced TMZ sensitivity. This combination therapy is promising for TMZ-resistant cancers, but it needs further investigation.
SPIN.DOC was discovered as a transcriptional co-repressor of wingless related integration site (WNT) pathway. However, it has been found to be upregulated in various types of cancer, including hepatocellular carcinoma, colorectal cancer, renal papillary cell carcinoma. Whether SPIN.DOC functions as an oncogene or tumour suppressor gene remains uncertain. Here, we report that ectopic expression of SPIN.DOC in normal NIH3T3 fibroblast cells promotes cell proliferation, colony formation, migration and invasion. Moreover, SPIN.DOC expressing NIH3T3 cells show increased spheroid formation, suggesting enhanced stemness and transformation potential. Immunofluorescence analysis using anti-β-Tubulin suggests that SPIN.DOC may induce, formation of tubulin-based microtentacles (McTNs), indicating epithelial-to-mesenchymal (EMT) transition. In conclusion, our study helps in establishing that SPIN.DOC can function as an oncogene.
Colorectal cancer (CRC), which has high mortality and increasing morbidity is a major concern worldwide. The autophagy pathway plays a crucial role in carcinogenesis and drug resistance in this disease. Epigenetic modification is one of the main regulatory mechanisms for this pathway. This study aimed to investigate the impact of promoter methylation as one of the epigenetic modifications on the expression of autophagy-associated genes (ATGs) (ATG2B, ATG4D, ATG9A, and ATG9B) in 21 CRC patients from southern Iran. The tissue DNA and RNA were extracted by standard phenol-chloroform extraction method and A BIOZOL RNA isolation kit, respectively. The methylation status and transcript levels of desired genes were ascertained using the methylation-specific PCR and quantitative real-time PCR methods, respectively. In the majority of studied patients, the relative mRNA expressions of ATGs were significantly higher in CRC tissues compared to normal ones. There was no significant relationship between the methylation of the ATG genes and clinicopathological features of CRC patients. Interestingly, in most of the patients, the promoter hypermethylation of the ATG2B, ATG4D, ATG9A and ATG9B genes led to their high mRNA expression. Although promoter hypermethylation usually suppresses gene expression, the cancer type, stage, and compensatory mechanisms may reverse this association. This highlights the complexity of the epigenetic regulation of ATG2B, ATG4D, ATG9A and ATG9B genes in CRC. Further large-scale studies will contribute to discovering the exact influences of ATG methylation in CRC carcinogenesis and thereby may thereby provide novel targets and biomarkers for this lethal illness.
Colony Stimulating Factor-1 Receptor (CSF1R) is a tyrosine kinase transmembrane receptor that plays a vital role in innate immunity and neurogenesis and controls the differentiation and maintenance of most tissue-resident macrophages. CSF1R mutations have been linked with many neurodegenerative diseases. In this work, we aim to identify the functional and structural impact of deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) mutations on CSF1R, which could help understand the consequences of these mutational changes. A consensus-based prediction approach was used to screen the and FATHMM. SNPs found to be deleterious by more than five out of six tools were subjected to further analysis, such as protein secondary structure and domain architecture analysis by PSIPRED and NCBI-CDD, respectively. Mutant models of highly deleterious SNPs were modeled using PyMol, followed by energy minimization and Root Mean Square Deviation (RMSD) analysis and molecular dynamic (MD) simulation by YASARA, TM-ALIGN, and WebGro, respectively. Out of 780 missense SNPs screened, we found the four most deleterious SNPs (L301S, A770P, I775N, and F849S) that decreased the protein stability because of their presence in the conserved regions of wild-type CSF1R. Structural and functional studies revealed that these mutations could disrupt the protein's core and surface interactions, leading to destabilization and functional impairment. Moreover, the mutated proteins exhibited enhanced conformational flexibility and instability, as confirmed by MD simulation analysis.
