TBX15 and SDHB expression changes in colorectal cancer serve as potential prognostic biomarkers.

Alterations in the expression of certain genes could be associated with both patient mortality rates and drug resistance. This study aimed to identify genes in colorectal cancer (CRC) that potentially serve as hub genes influencing patient survival rates. RNA-Seq data were downloaded from the cancer genome atlas database, and differential expression analysis was performed between tumors and healthy controls. Through the utilization of univariate and multivariate Cox regression analyses, in combination with the MCODE clustering module, the genes whose expression changes were related to survival rate and the hub genes related to them were identified. The mortality risk model was computed using the hub genes. CRC samples and the RT-qPCR method were utilized to confirm the outcomes. PharmacoGx data were employed to link the expression of potential genes to medication resistance and sensitivity. The results revealed the discovery of seven hub genes, which emerged as independent prognostic markers. These included HOXC6, HOXC13, HOXC8, and TBX15, which were associated with poor prognosis and overexpression, as well as SDHB, COX5A, and UQCRC1, linked to favorable prognosis and downregulation. Applying the risk model developed with the mentioned genes revealed a markedly higher incidence of deceased patients in the high-risk group compared to the low-risk group. RT-qPCR results indicated a decrease in SDHB expression and an elevation in TBX15 levels in cancer samples relative to adjacent healthy tissue. Also, PharmacoGx data indicated that the expression level of SDHB was correlated with drug sensitivity to Crizotinib and Dovitinib. Our findings highlight the potential association between alterations in the expression of genes such as HOXC6, HOXC13, HOXC8, TBX15, SDHB, COX5A, and UQCRC1 and increased mortality rates in CRC patients. As revealed by the PPI network, these genes exhibited the most connections with other genes linked to survival.

Exploring the role of interleukin 11 in cancer progression, patient survival, and therapeutic insights.

BACKGROUND: The Interleukin (IL)-11 gene, which is one of the members of the cytokine family, has an oncogenic role in some cancers. The main goal of this study is to analyze IL-11 expression level in 14 prevalent cancers and highlights its role in patients' survival, drug resistance, and sensitivities. Also, an association of this gene with metastasis and inflammation pathways has been investigated. METHODS AND RESULTS: Using the cancer genome atlas (TCGA) data, the level of IL-11 expression and its role in prognosis and survival rate were evaluated in 13 common cancers. Then, confirming the obtained in-silico outcomes, the relative expression level of this gene in colorectal cancer (CRC) samples and their adjusted tissues were assayed by the RT-qPCR method. Furthermore, to examine the association between IL-11 expression and drug resistance and sensitivity, PharmacoGX data was applied. The co-expression network was used to recognize the pathways in which IL-11 was involved. The results from the TCGA dataset indicated that the expression level of IL-11 increased significantly in 13 prevalence cancers compared to the control groups. Interestingly, this enhanced expression level is associated with a high rate of mortality in patients with bladder, stomach, colorectal, and endometrial cancers. Also, the co-expression network analysis showed a strong correlation between IL-11 and the genes of metastasis pathway and the genes related to the inflammation process. Finally, regarding drug sensitivity, IL-11 expression level can be introduced as a remarkable biomarker for cancer detection due to area under curve (AUC). CONCLUSION: Altered expression of the IL-11 gene is observed in 13 common cancers and is associated with prognosis and mortality rate in patients. Moreover, this gene can be considered a prognostic biomarker in different types of cancer, such as CRC.

Biomechanical evaluation of a sheep tracheal scaffold.

Tissue engineering is a set of techniques for producing or reconstructing tissue that primarily aims to restore or improve the function of tissues in the human body. The aim of the present study was to evaluate the mechanical and histological characteristics of decellularized tracheal scaffolds prepared in comparison with fresh trachea for use in tracheal repair. In order to prepare the scaffold, sheep's trachea was prepared and after cleaning the waste tissues, they were decellularized. Then decellularized scaffolds were evaluated histologically and laboratory and numerical study of the nonlinear mechanical behavior of tracheal tissue and scaffold and their comparison. Examining the results of histological evaluations showed that the decellularization of the scaffolds was completely done. These results were confirmed by hematoxylin-eosin staining. Also, the exact hyperelastic properties of tracheal tissue and scaffold were used in biomechanical models, and according to the presented results, the five-term Mooney-Rivlin strain energy density function became a suitable behavioral model for modeling the hyperelastic behavior of trachea and scaffold. In total, the results of this research showed that the scaffolds obtained from decellularization by preserving the main compositions of the desired tissue can be a suitable platform for investigating cell behaviors.

Coordinated modification in expression levels of HSPA1A/B, DGKH, and NOTCH2 in Parkinson's patients' blood and substantia nigra as a diagnostic sign: the transcriptomes' relationship.

BACKGROUND: Diagnosis of Parkinson's disease (PD) is associated with a vast number of challenges. This study aimed to assess the overlap of PD patients' transcriptomes in the substantia nigra (SN) with peripheral blood mononuclear cells (PBMCs) to discover potential biomarkers for diagnosis. METHODS: GEO data were used to select genes with significant changes in expression level in the SN region and eligible studies. Also, transcriptome data related to blood of PD patients with other neurodegenerative diseases (ND) was considered. Differential expression genes between PD and control were evaluated in the SN and blood, and RT-qPCR was applied to validate the findings. RESULTS: At the expression level, no significant similarity in long non-coding RNA was found between the patients' SN and blood. While in silico results revealed 16 common mRNAs in SN and blood with significant expression levels. Among all overexpressed mRNAs, HSPA1A/B expression level had the highest expression difference between control and PD samples. Moreover, DGKH had the highest score of down-regulated genes in both blood and SN. The NOTCH pathway had the highest score pathway among up-regulated pathways, and the expression levels of NOTCH2, H4C8, and H2BC21 associated with this pathway had the most ability to separate the control and PD populations. Furthermore, RT-qPCR results revealed that HSPA1A/B, NOTCH2, and H4C8 were overexpressed in PD PBMCs, while DGKH expression levels were lower compared to controls. CONCLUSION: Our findings indicate that expression levels of HSPA1A/B, DGKH, and NOTCH2 could be applied as candidate biomarkers to diagnose PD patients in the SN region and PBMCs.

Identification of genes with high heterogeneity of expression as a predictor of different prognosis and therapeutic responses in colorectal cancer: a challenge and a strategy.

BACKGROUND: Molecular heterogeneity is one of the most important concerns in colorectal cancer (CRC), which results in a wide range of therapy responses and patient prognosis. We aimed to identify the genes with high heterogeneity of expression (HHE) and their relation with prognosis and drug resistance. METHODS: Two cohort studies, the cancer genome atlas (TCGA) and the GSE39582, were used to discover oncogenes genes with HHE. The relationship between identified genes with clinical and genomic characteristics was evaluated based on TCGA data. Also, the GDSC and CCLE data were used for drug resistance and sensitivity. Sixty CRC samples were used to validate the obtained data by RT-qPCR. RESULTS: Findings revealed that 132 genes with HHE were found to be up-regulated in both cohorts and were enriched in pathways such as hypoxia, angiogenesis, and metastasis. Forty-nine of selected genes related to clinical and genomic variables, including stage, common mutations, the tumor site, and microsatellite state that were ignored. The expression level of CXCL1, SFTA2, SELE, and SACS as genes with HHE were predicted survival patients, and RT-qPCR results demonstrated that levels of SELE and SACS had HHE in CRC samples. The expression of many identified genes like BGN, MMP7, COL11A1, FAP, KLK10, and TNFRSE11B was associated with resistance to chemotherapy drugs. CONCLUSIONS: Some genes expression, including SELE, SACS, BGN, KLK10, COL11A1, and TNFRSE11B have an oncogenic function with HHE, and their expression can be used as indicators for differing treatment responses and survival rates in CRC.

Antiapoptotic and anti-inflammatory effects of Pparγ agonist, pioglitazone, reversed Dox-induced cardiotoxicity through mediating of miR-130a downregulation in C57BL/6 mice.

Doxorubicin (Dox) is an antitumor agent widely used in cancer therapy, with notable side effects of cardiac toxicity. Peroxisome proliferator-activated receptor γ (PPARγ), is a transcriptional factor with antiapoptotic and anti-inflammatory properties. Recently we indicated that cardiac toxicity of Dox was due to upregulation of miR-130a and further suppressive effect on cardiac Pparγ in vitro. In this study, we extended our proposed hypothesis in vivo. To achieve this, pioglitazone (Pio) and GW9662 were used as the specific agonist and antagonist of Pparγ to treat Dox-injected mice. Heart function, apoptosis, and inflammation in heart tissue were studied. Pretreatment of Dox-injected mice with Pio resulted in elevated expression of Pparγ and suppression of miR-130a. However, GW9662 pretreatment was unable to increase miR-130a expression. Pio pretreatment led to partially cardiac toxicity limitation of Dox whereas GW9662 caused heart damage. Finally, our observation determined that activation of Pparγ was not adequate to reverse the Dox-induced toxicity completely.

MiR-193b deregulation is associated with Parkinson's disease.

PGC-1α/FNDC5/BDNF has found to be a critical pathway in neurodegeneration. MicroRNAs (miR(NA)s) are non-coding regulatory RNAs whose dysregulation has been observed in multiple neurological disorders, and miRNA-mediated gene deregulation plays a decisive role in PD. Here, candidate miRNA was chosen based on the literature survey and in silico studies. Chronic and acute models of PD were created using MPP+-treated SH-SY5Y cells. Twenty PD patients and 20 healthy volunteers were recruited. RT-qPCR was performed to assess the expression of miRNA and genes. Severe mitochondrial dysfunction induced by acute MPP+ treatment instigated compensatory mechanisms through enhancing expression of PGC-1α/FNDC5/BDNF pathway genes, while chronic MPP+ toxicity led to down-regulated levels of the genes in SH-SY5Y cells. PD peripheral blood mononuclear cells (PBMCs) also showed decreased expression of target genes. There were significant changes in the level of miR-193b in both models, as well as PD PBMCs. Moreover, miR-193b overexpression significantly affected PGC-1α, FNDC5 and TFAM levels. Interestingly, down-regulations of PGC-1α, FNDC5, BDNF and TFAM were inversely correlated with miR-193b up-regulation in PD PBMCs. This study showed the deregulation of PGC-1α/FNDC5/BDNF pathway in PD models and PBMCs, verifying its importance in neurodegeneration. Our findings also revealed that miR-193b functions in PD development, possibly through regulating PGC-1α/FNDC5/BDNF pathway, suggesting miR-193b as a potential biomarker for PD diagnosis.

The role of cell surface proteins gene expression in diagnosis, prognosis, and drug resistance of colorectal cancer: In silico analysis and validation.

Cell surface proteins (CSPs) are an important type of protein in different essential cell functions. This study aimed to distinguish overexpressed CSPs in colorectal cancer to investigate their biomarker, prognosis, and drug resistance potential. Raw data of three datasets including 1187 samples was downloaded then normalization and differential expression were performed. By the combination of the cancer genome atlas (TCGA) clinical data, survival analysis was carried out. Information of all CSPs was collected from cell surface protein atlas. The role of each candidate gene expression was investigated in drug resistance by CCEL and GDSC data from PharmacoGX. CRC samples including 30 tumor samples and adjacent normal were used to confirm data by RT-qPCR. Outcomes showed that 66 CSPs overexpressed in three datasets, and 146 CSPs expression associated with poor prognosis features in TCGA data that TIMP1 and QSOX2 can associate with poor patient survival independently. High-risk patients illustrated more fatality than low-risk patients based on the risk score calculated by the expression level of these genes. Receiver operating characteristic curve analysis showed that 39 CSPs as perfect biomarkers for diagnosis in CRC. Furthermore, QSOX2 and TIMP1 expression levels increased in tumor samples compared to adjacent normal samples. The Drug resistance analysis demonstrated ADAM12 and COL1A2 up-regulation among 66 overexpressed CSPs caused resistance to Venetoclax and Cyclophosphamide with a high estimate, respectively. Many CSPs are deregulated in CRC, and can be valuable candidates as biomarkers for diagnosis, prognosis, and drug resistance.

LAMTOR5 expression level is a biomarker for colorectal cancer and lncRNA LAMTOR5-AS1 predicting miRNA sponging effect.

BACKGROUND: Strong evidence indicated that high expression of HBXIP (also known as LAMTOR5) promotes cancer cells proliferation and helps cancer progression. Long non-coding RNAs (lncRNA) have also a crucial role in developing cancer. In this study, we aimed to determine the expression of LAMTOR5 and its nearby lncRNA, LAMTOR5-AS1 and investigate their potential as a biomarker in colorectal cancer (CRC) patients. METHODS: 75 tissues of colorectal tumors and non-tumor adjacent normal sampled in this study. After RNA procedure then RT-qPCR was applied for expression analysis. Moreover, in silico investigation also enrolled for predicting sponging effect of lncRNA with miRNAs. RESULTS: LAMTOR5 transcription level significantly overexpressed (p value < 0.001) and has shown a diagnostic potential (AUC = 0.8) in CRC. LAMTOR5-AS1 did not indicate any remarkable expression change overall, but showed a significant overexpressed in elderly patients (> 60) with CRC (p value < 0.0097). Moreover, the correlation analysis between LAMTOR5 and LAMTOR5-AS1 revealed a significant association in CRC (p value = 0.0074) which can be partly explained by its predicting act as a mediator with sponging effect on hsa-miR-let-7b-3p and hsa-miR-20a-5p. CONCLUSION: LAMTOR5 gene can be considered as prognostic biomarker for CRC. LAMTOR5-AS5 which is a nearby lncRNA of this gene could play a regulatory impact through its sponging effect on hsa-miR-let-7b-3p and hsa-miR-20a-5p which both have shown a significant impact on overall survival rate in CRC patients in high expression levels.

Modified level of miR-376a is associated with Parkinson's disease.

Parkinson's disease (PD) is a frequent progressive neurodegenerative disorder. Impaired mitochondrial function is a major feature of sporadic PD. Some susceptibility or causative genes detected in PD are strongly associated with mitochondrial dysfunction including PGC1α, TFAM and GSK3ß. microRNAs (miRNAs) are non-coding RNAs whose altered levels are proven in disparate PD models and human brains. Therefore, the aim of this study was to detect modulations of miRs upstream of PGC1α, TFAM and GSK3ß in association with PD onset and progress. In this study, a total of 33 PD subjects and 25 healthy volunteers were recruited. Candidate miRNA (miR-376a) was selected through target prediction tools and literature survey. Chronic and acute in vitro PD models were created by MPP+ -intoxicated SHSY5Y cells. The levels of miR-376a and aforementioned genes were assessed by RT-qPCR. The expression of target genes was decreased in chronic model while there were dramatically up-regulated levels of those genes in acute model of PD. miR-376a was strongly altered in both acute and chronic PD models as well as PBMCs of PD patients. Our results also showed overexpression of PGC1α, and TFAM in PBMCs is inversely correlated with down-regulation of miR-376a, suggesting that miR-376a possibly has an impact on PD pathogenesis through regulation of these genes which are involved in mitochondrial function. miR-376a expression in PD-derived PBMCs was also correlated with disease severity and may serve as a potential biomarker for PD diagnosis. This is the first study showing altered levels of miR-376a in PD models and PBMCs, suggesting the probable role of this miRNA in PD pathogenesis. The present study also proposed TFAM and PGC1α as target genes of miR-376a for the first time, through which it possibly can exert its impact on PD pathogenesis.

Integrative in silico and in vitro transcriptomics analysis revealed new lncRNAs related to intrinsic apoptotic genes in colorectal cancer.

BACKGROUND: Pathogenesis of colorectal cancer (CRC) is connected to deregulation of apoptosis while the effect of lncRNAs, as critical regulatory molecules, on this pathway is not clear well. The present study aimed to identify differential expression of genes and their related lncRNAs which are significantly associated with intrinsic apoptotic pathway in CRC. METHODS: The connection between CRC and apoptosis was investigated by literature reviews and the genes were enriched by using Enrichr. At the next step, differential expression of enriched genes were evaluated between normal and tumor populations in data sets and were downloaded from GEO. Then, meta-analysis and probe re-annotation were performed. For lncRNAs selection through the highest expression correlation with each of candidate genes, mRNA-lncRNA interaction of screened genes and all of lncRNAs were visualized using Cytoscape. Identified differential expression genes and lncRNAs were validated using TCGA-COAD and the obtained data were confirmed by in vitro studies in the presence of Ag@Glu-TSC nanoparticle as an apoptotic inducer. Cytotoxicity and apoptosis induction effect of Ag@Glu-TSC on Caco-2 cells was determined via MTT and Annexin V/PI, respectively. The expression of genes and lncRNAs were assayed in presence of mentioned nanoparticle. Finally, the expression level of desired genes and lncRNAs were proven in CRC tissues compared to adjacent normal tissues. RESULTS: After detection of 48 genes associated with intrinsic apoptosis in CRC according to literature, Enrichr screened 12 common genes involved in this pathway. Among them, 6 genes including BCL2, BCL2L11, BAD, CASP7, CASP9, and CYCS expression reduced in tumor tissue compared to normal according to meta-analysis studies and RNA-seq TCGA data. Afterwards, association of 8 lncRNAs comprising CDKN2B-AS1, LOC102724156, HAGLR, ABCC13, LOC101929340, LINC00675, FAM120AOS, PDCD4-AS1 with more than 5 candidate genes were identified. In vitro studies revealed that four selected lncRNAs including, CDKN2B-AS1, LOC102724156, HAGLR and FAM120AOS were significantly increased in the presence of in optimum concentration of Ag@Glu/TSC and decreased in tumor tissues versus adjacent normal tissues. CONCLUSION: This study developed a new data mining method to screen differentially expressed lncRNAs which are involved in regulation of intrinsic apoptosis pathway in CRC quickly using published gene expression profiling microarrays. Moreover, we could validate a number of these regulators in the cellular and laboratory disease models.

A genetic variant of pri-miR-182 may impact the risk for the onset of multiple sclerosis in the Iranian population.

BACKGROUND: Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system affecting young adults. SNPs can be used as genetic biomarkers to identify disease-related genes such as MS. Moreover, SNPs can be considered as important determinants for an increased risk of autoimmune diseases such as MS. Studies have shown that miR-182 is of importance in Treg cell development and function as critical regulators in autoimmune disease. So far, no study has been conducted to investigate the association between rs4541843 polymorphism in pri-miR-182 and MS. In the present study, we assessed the frequency of rs4541843 different alleles and genotypes and their association with MS risk in Iranian population. METHODS: The rs4541843 was genotyped in 81 patients with MS and 89 healthy subjects, using the PCR-RFLP method. The frequency of alleles and genotypes and the association of this polymorphism with MS risk and the gender of the patients was then statistically analyzed. RESULTS: Statistical analysis showed the protective role of AA genotype against MS risk (P = .031, OR = 0.348) while there was no significance correlation between the frequency of rs4541843 different alleles and the other genotypes. CONCLUSION: Our findings illustrated that the pri-miR-182 rs4541843 G>A polymorphism is associated with the risk of MS in Isfahan population. However, additional large-scale association studies in various ethnicities and more molecular studies are necessary to elaborate our findings.

Embryos derived from couples with consanguineous marriages with globozoospermia should be screened for gender or DPY19L2 deletion.

Globozoospermia or round-headed spermatozoa are a rare type of infertility which accounts for <0.1% of male infertility. Several genes are associated with this disease, including DPY19L2, SPATA16, PICK1 and CCIN that DPY19L2 accounts for 75% of globozoospermia. Isfahan Fertility and Infertility Center (IFIC) is a referral centre for globozoospermia, and individuals with globozoospermia are routinely screened for DPY19L2 deletion. In the present study, we have screened six couples with globozoospermia and consanguineous marriages. Genomic DNA both female and male partners were screened for DPY19L2 deletion for exons 1, 11 and 22 as exons most prone to non-homologous recombination. In addition, qPCR was carried out on genomic samples of their partners to determine whether they are heterozygous for DPY19L2 deletion. The results revealed that one female was heterozygous for DPY19L2 deletion. Therefore, this couple decided to undergo intracytoplasmic sperm injection and gender selection and two XX embryos were transferred for this couple and two healthy girls were born. In conclusion, we advise for the couples with DPY19L2-globozoospermia and consanguineous marriages to be screened for DPY19L2 deletion in the hope of reducing occurrence of globozoospermia in future progeny.

Ameliorating the Effect of Pioglitazone on LPS-Induced Inflammation of Human Oligodendrocyte Progenitor Cells.

Oligodendrocyte progenitor cells (OPCs) are appropriate model cells for studying the progress of neurodegenerative disorders and evaluation of pharmacological efficacies of small molecules for treatment of these disorders. Here, we focused on the therapeutic role of Pioglitazone, which is a selective agonist of peroxisome proliferator-activated receptor gamma (PPARγ), a respective nuclear receptor in inflammatory responses. Human embryonic stem cell-derived OPCs were pretreated by Pioglitazone at differing concentrations. Pretreated OPCs were further examined after induction of inflammation by LPS. Interestingly, Pioglitazone reversed the inflammatory conditions and enhanced OPC viability. Data showed that Pioglitazone reduced Nitric Oxide (NO) production. Moreover, Pioglitazone enhanced cell viability through distinct mechanisms including reduction of apoptosis and regulation of cell cycle markers. This study demonstrated that NO induces apoptosis through FOXO1 and degradation of ß-catenin, while the presence of Pioglitazone inhibited these effects in rescuing human OPCs from apoptosis. Also, Pioglitazone did not show a significant influence on mRNA levels of TLR2, TRL4, and TNFα. Furthermore, simultaneous treatment of Pioglitazone with CHIR, a GSKß inhibitor, facilitated anti-apoptotic responses of OPCs. Taken together, therapy with Pioglitazone represents a novel potential drug in alleviating the loss of OPCs in neurodegenerative conditions.

Ameliorating Effect of Osteopontin on H2O2-Induced Apoptosis of Human Oligodendrocyte Progenitor Cells.

Recently our group used oligodendrocyte progenitor cells (OPCs) as appropriate model cells to pinpoint the mechanism of the progress of neurodegenerative disorders. In the present study, we focused on the therapeutic role of osteopontin (OPN), a secreted glycosylated phosphoprotein, involved in a number of physiological events including bone formation and remodeling, immune responses, and tumor progression. Protective role of OPN, as a negative regulator of tumorigenesis, has already been clarified. Human embryonic stem cell-derived OPCs were pretreated with OPN before induction of apoptosis by H2O2. Data indicated that OPN prohibited cell death and enhanced OPC viability. This effect is achieved through reduction of apoptosis and induction of anti-apoptosis markers. In addition OPN induces expression of several integrin subunits, responsible for OPN interaction. Notably, our findings showed that expression of αV ß1/ß3/ß5 and ß8 integrins increased in response to OPN, while treatment with H2O2 down-regulated αV ß1/ß5 and ß8 integrins expression significantly. In conclusion, OPN may act via αV integrin signaling and trigger suppression of P53-dependent apoptotic cascades. Therefore OPN therapy may be considered as a feasible process to prevent progress of neurodegenerative diseases in human.

The Synergistic Enhancement of Cloning Efficiency in Individualized Human Pluripotent Stem Cells by Peroxisome Proliferative-activated Receptor-γ (PPARγ) Activation and Rho-associated Kinase (ROCK) Inhibition.

Although human pluripotent stem cells (hPSCs) provide valuable sources for regenerative medicine, their applicability is dependent on obtaining both suitable up-scaled and cost effective cultures. The Rho-associated kinase (ROCK) inhibitor Y-27632 permits hPSC survival upon dissociation; however, cloning efficiency is often still low. Here we have shown that pioglitazone, a selective peroxisome proliferative-activated receptor-γ agonist, along with Y-27632 synergistically diminished dissociation-induced apoptosis and increased cloning efficiency (2-3-fold versus Y-27632) without affecting pluripotency of hPSCs. Pioglitazone exerted its positive effect by inhibition of glycogen synthase kinase (GSK3) activity and enhancement of membranous ß-catenin and E-cadherin proteins. These effects were reversed by GW-9662, an irreversible peroxisome proliferative-activated receptor-γ antagonist. This novel setting provided a step toward hPSC manipulation and its biomedical applications.

Nurr1 and PPARγ protect PC12 cells against MPP(+) toxicity: involvement of selective genes, anti-inflammatory, ROS generation, and antimitochondrial impairment.

Parkinson's disease (PD) can degenerate dopaminergic (DA) neurons in midbrain, substantia-nigra pars compacta. Alleviation of its symptoms and protection of normal neurons against degeneration are the main aspects of researches to establish novel therapeutic strategies. PPARγ as a member of PPARs have shown neuroprotection in a number of neurodegenerative disorders such as Alzheimer's disease and PD. Nuclear receptor related 1 protein (Nurr1) is, respectively, member of NR4A family and has received great attentions as potential target for development, maintenance, and survival of DA neurons. Based on neuroprotective effects of PPARγ and dual role of Nurr1 in anti-inflammatory pathways and development of DA neurons, we hypothesize that PPARγ and Nurr1 agonists alone and in combined form can be targets for neuroprotective therapeutic development for PD in vitro model. 1-Methyl-4-phenylpyridinium (MPP(+)) induced neurotoxicity in PC12 cells as an in vitro model for PD studies. Treatment/cotreatment with PPARγ and Nurr1 agonists 24 h prior to MPP(+) induction enhanced the viability of PC12 cell. The viability of PC12 cells was determined by MTS test. Mitochondrial membrane potential (MMP) and intracellular reactive oxygen species (ROS) were detected by flow cytometry. In addition, the relative expression of four genes including TH (the marker of DA neurons), Ephrin A1, Nurr1, and Ferritin light chain were assessed by RT-qPCR. In the MPP(+)-pretreated PC12 cells, PPARγ and Nurr1 agonists and their combined form resulted in a decrease in the cell death rate. Moreover, production of intracellular ROS and MMP modulated by MPP(+) was decreased by PPARγ and Nurr1 agonists' treatment alone and in the combined form.

Identification, cloning, and functional analysis of the TATA-less mouse FNDC5 promoter during neural differentiation.

FNDC5 (also termed PEP) gene encodes a type I membrane protein which is cleaved and secreted as Irisin hormone. We have identified mouse putative core promoter of FNDC5 and characterized its activity. FNDC5 is located within mouse chromosome 4, spans about 7,534 bp, and consists of 6 exons. The mouse FNDC5 promoter is TATA-less and lacks a consensus initiator sequence. In silico analyses revealed that the core promoter (-561/+101 with respect to translation start site) is located in a GC-rich domain (approximately 70.01 %) with one CpG island as a promoter index and several GC box factors including GC/SP1 which is necessary for transcription of TATA-less promoters. The core promoter showed a lower activity than CMV promoter in CHO and P19 cell lines when located upstream of EGFP CDS in an appropriate expression vector. Data implicated that both exon 1 and intron 1 of the gene are included in the core promoter. Upon treating with retinoic acid, FNDC5 expression was upregulated during embryoid body formation and decreased slowly at final stage of neural differentiation when neurospheres emerged. However, Noggin induction induced up regulation of FNDC5 expression at final stage of neural differentiation. In conclusion, stage dependent expression of FNDC5 is affected by neural induction method used for neural differentiation.

Genetic insights and therapeutic potential for colorectal cancer: mutation analysis of KRAS gene and efficacy of Oleuropein-conjugated iron oxide nanoparticles.

This study aimed to address the challenges of treating advanced stages of colon cancer (CRC) by exploring potential therapeutic options. The research focused on the genetic aspects of CRC, specifically the mutation rate of the KRAS gene, along with other genes like TTN, APC, MUC16, and TP53, using the TCGA dataset. Additionally, the study investigated the efficacy of Oleuropein, a polyphenolic compound found in olives, in combating CRC by using iron oxide nanoparticles coated with glucose and conjugated with Oleuropein. The study characterized the physicochemical properties of the nanoparticles, and the cytotoxic effects of the nanoparticles were evaluated on CRC and normal fibroblast cell lines, demonstrating significantly higher cytotoxicity against CRC cells compared to normal cells. Furthermore, the study analyzed gene expression changes using the GSE124627 dataset to understand the influence of KRAS alterations. It identified numerous upregulated and downregulated genes in KRAS-overexpressing samples, suggesting their involvement in critical cancer-related pathways. These findings suggest that KRAS-influenced genes could serve as potential therapeutic targets for CRC treatment. The study also examined the expression levels of identified genes in CRC samples compared to normal samples. Among the upregulated genes, 22 showed significant increases in cancer samples, while 14 downregulated genes exhibited decreased expression in both KRAS-influenced and cancer samples. Cox regression analysis identified specific upregulated genes, including ANKZF1, SNAI1, PPFIA4, SIX4, and NOTUM, associated with poor prognosis. Kaplan-Meier analysis further confirmed the correlation between increased expression of these genes and higher patient mortality rates. In conclusion, this study provided valuable insights into the genetic aspects of CRC and potential therapeutic strategies. The use of Oleuropein-conjugated iron oxide nanoparticles showed promising cytotoxic effects on colon cancer cells. These findings contribute to advancing our understanding of CRC and offer potential targets for further investigation and the development of novel therapeutic approaches.

Association of fatty acid binding protein-4 (FABP-4) T87C and rs8192688 gene polymorphisms and FABP-4 level with cardiovascular disease susceptibility in type 2 diabetic patients.

Type 2 Diabetes Mellitus (T2DM) is known to cause dyslipidemia and increase the risk of cardiovascular disease (CVD). Fatty acid binding protein (FABP)-4 plays a significant role in various stages of T2DM and CVD. Although it has been demonstrated that genetic variations of the FABP-4 gene can affect insulin sensitivity, the results obtained so far are controversial. The aim of this study was to investigate the possible association between T87C and rs8192688 polymorphisms and serum levels of FABP-4 with CVD susceptibility in T2DM patients. The study included 70 healthy controls, 70 individuals with T2DM, and 70 T2DM patients with CVD. Genomic DNA was extracted, and FABP-4 T87C and rs8192688 gene polymorphic sites were amplified using the ARMS-PCR method. Lipid profile and FABP-4 serum levels were significantly higher in T2DM patients with CVD compared to those with only T2DM (p < 0.05). Additionally, FABP-4 T87C gene polymorphism (TC genotypes) and dominant model (TT vs. TC + CC) were significantly associated with a decreased risk of both T2DM and T2DM with CVD patients (p < 0.05). Patients carrying TC + CC genotypes had significantly lower levels of triglyceride and FABP-4 compared to those carrying the TT genotype (p < 0.05). There was no significant association between FABP-4 rs8192688 polymorphism and either T2DM or CVD disease. It appears that FABP-4 T87C polymorphism decreases FABP-4 levels leading to decreased serum TG levels. Since both T2DM and CVD have inflammatory backgrounds, reducing inflammation can improve insulin sensitivity and lower TG levels in these patients.