Genetic variants rs2910164, rs4636297 and rs895819 may contribute to the onset of acute myocardial infarction in Pakistani population.

The most serious type of coronary artery disease (CAD), acute myocardial infarction (AMI), is a major global cause of death. The development of AMI is accompanied by several risk factors. AMI may be caused by variations in the microRNA (miRNA) genes, which have a negative impact on miRNA-mediated regulation of gene expression. The target mRNAs are dysregulated because of these genetic changes in the miRNA genes, which interfere with the vital biological processes that result in AMI. Using allele-specific PCR, the aim of the study is to examine the association of the variants (rs2910164, rs4636297, and rs895819) in MIR146A, MIR126, and MIR27A with AMI susceptibility. A difference in genotype distribution among the patients and control for variation rs2910164 was identified by co-dominant [χ2 = 68.34,2; P value<0.0001], dominant (G/G vs G/C + C/C) [OR = 4.167 (2.860-6.049); P value<0.0001], recessive (C/C vs G/C + G/G) [OR = 0.2584 (0.1798-0.3731); P value<0.0001], and additive models [OR = 3.847 (2.985-4.959); P value<0.0001]. Whereas the association of rs4636297 was investigated by co-dominant [χ2 = 6.882,2; P value = 0.0320], dominant (G/G vs G/A + A/A) [OR = 0.6914 (0.4849-0.9948); P value = 0.0489], recessive (A/A vs A/G + G/G) [OR = 2.434 (0.9849-5.616830); P value = 0.0595], and additive models [OR = 0.7716 (0.6000-0.9918); P value = 0.0433]. Similarly, association of rs895819 was determined by co-dominant [χ2 = 5.277, 2; P value = 0.0715], dominant (G/G vs G/A + A/A) [OR = 1.654(0.9819-2.801); P value = 0.06440], recessive (A/A vs A/G + G/G) [OR = 0.7227 (0.5132-1.022); P value = 0.0748], and additive models [OR = 1.3337 (1.041-1.719); P value = 0.0233]. The results of this study found a significant association of rs2910164 and rs4636297 with AMI and are considered as the risk factor for AMI in the Pakistani population. We observed no significant association of the variant MIR27A (rs895819) with AMI incidence.

The miRNA variants MIR196A2 (rs11614913) and MIR423 (rs6505162) contribute to an increase in the risk of myocardial infarction.

INTRODUCTION: MicroRNAs (miRNAs) are small, single-stranded RNA molecules that negatively regulate gene expression and play a key role in the pathogenesis of human diseases. Recent studies have suggested that miRNAs contribute to cardiovascular diseases (CVDs). However, the association between single-nucleotide polymorphisms (SNPs) in miRNAs and myocardial infarction (MI) remains in infancy. AIM: The current study was designed to find out the association of SNPs in MIR196A2 and MIR423 (rs11614913 and rs6505162, respectively). METHODS: Using Tetra-Primer Amplification Refractory Mutation System-Polymerase Chain Reaction (T-ARMS PCR) in 400 cases (MI patients) and 336 healthy controls. Using different inheritance models (co-dominant, homozygous dominant, homozygous recessive, and additive models), the association of these SNPs was genotyped with MI risk. RESULTS: For variant rs11614913, significant distribution of the genotypes among the cases and controls was determined by co-dominant [χ2 = 29.19, 2; p value < 0.0001], dominant (C/C vs. C/T + T/T) [OR = 0.45 (0.34 to 0.61); p < 0.0001], recessive (T/T vs. C/T + C/C) [OR = 1.009 (0.63 to 1.63); p-value p value > 0.999], and additive models [OR = 0.65 (0.52 to 0.80); p value = 0.0001]. Similarly, a significant association of rs6505162 was determined by co-dominant [χ2 = 24.29, 2; p value < 0.0001], dominant (C/C vs. A/C+ A/A) [OR = 0.44 (0.32 to 0.61); p value < 0.0001], recessive (A/A vs. A/C + C/C) [OR = 1.29 (0.85 to 1.98); p value = 0.28], and additive models [OR = 0.65 (0.52 to 0.81); p value = 0.0001]. CONCLUSION: Therefore, the current study showed that both variants rs11614913 and rs6505162 are significantly associated with MI in the Pakistani population.

Genome sequencing of Pakistani families with male infertility identifies deleterious genotypes in SPAG6, CCDC9, TKTL1, TUBA3C, and M1AP.

BACKGROUND: There are likely to be hundreds of monogenic forms of human male infertility. Whole genome sequencing (WGS) is the most efficient way to make progress in mapping the causative genetic variants, and ultimately improve clinical management of the disease in each patient. Recruitment of consanguineous families is an effective approach to ascertain the genetic forms of many diseases. OBJECTIVES: To apply WGS to large consanguineous families with likely hereditary male infertility and identify potential genetic cases. MATERIALS AND METHODS: We recruited seven large families with clinically diagnosed male infertility from rural Pakistan, including five with a history of consanguinity. We generated WGS data on 26 individuals (3-5 per family) and analyzed the resulting data with a computational pipeline to identify potentially causal single nucleotide variants, indels, and copy number variants. RESULTS: We identified plausible genetic causes in five of the seven families, including a homozygous 10 kb deletion of exon 2 in a well-established male infertility gene (M1AP), and biallelic missense substitutions (SPAG6, CCDC9, TUBA3C) and an in-frame hemizygous deletion (TKTL1) in genes with emerging relevance. DISCUSSION AND CONCLUSION: The rate of genetic findings using the current approach (71%) was much higher than what we recently achieved using whole-exome sequencing (WES) of unrelated singleton cases (20%). Furthermore, we identified a pathogenic single-exon deletion in M1AP that would be undetectable by WES. Screening more families with WGS, especially in underrepresented populations, will further reveal the types of variants underlying male infertility and accelerate the use of genetics in the patient management.

Synthesis of fructose bound Fe(iii) integrated carbon dots as a robust turn-off detection sensor for chlortoluron.

A simple, sensitive, and robust fluorescent sensor for chlortoluron detection has been developed. Fluorescent carbon dots were synthesized using ethylene diamine and fructose via a hydrothermal protocol. The molecular interaction between fructose carbon dots and Fe(iii) resulted in a fluorescent metastable state exhibiting remarkable fluorescence quenching at λem of 454 nm and interestingly, further quenching occurred upon the addition of chlortoluron. The quenching in the fluorescence intensity of CDF-Fe(iii) towards chlortoluron occurred in the concentration range of 0.2-5.0 µg mL-1 where the limit of detection was found to be 0.0467 µg mL-1, the limit of quantification was 0.14 µg mL-1, and the relative standard deviation was 0.568%. The selective and specific recognitive nature of the Fe(iii) integrated fructose bound carbon dots towards the chlortoluron make it a suitable sensor for real sample applications. The proposed strategy was applied for the determination of chlortoluron in soil, water, and wheat samples with recoveries in the range of 95% to 104.3%.

Exploring the Associations and Molecular Impacts of miR-146a/rs2910164 and miR-196a2/rs185070757 with Rheumatoid Arthritis in a Pakistani Population.

INTRODUCTION: MicroRNAs (miRNAs) are a new class of molecules that participate in post-transcriptional regulation of gene expression and hence have been reported to have a crucial role in the pathogenesis of rheumatoid arthritis (RA). We aimed to investigate the association of miR-146a rs2910164 (G/C) and miR-196a2 rs185070757 (T/G) with RA susceptibility in Pakistani patients and to bioinformatically predict the molecular function of these miRNAs. METHODS: A case-control study on 600 individuals was conducted, including 300 RA patients and 300 matching healthy controls. Genotyping was performed by tetra-primer amplification of refractory mutation system-polymerase chain reaction, and the association between variants and RA was statistically determined using different models. RESULTS: For the variant rs2910164 (G/C) in miR-146a, no difference in genotype distribution was observed between RA cases and controls, as determined using co-dominant (χ2 = 4.33; p = 0.114), homozygous dominant (C/C vs. G/G + C/G) (OR = 0.740 [0.531-1.032]; p = 0.091), homozygous recessive (G/G vs. C/C + G/C) (odds ratio [OR] = 01.432 [0.930-2.206]; p = 0.126), heterozygous (G/C vs. C/C + G/G) (OR = 1.084 [0.786-1.494]; p = 0.682), and additive (OR 0.778 [0.617-0.981]; p = 0.039) models. Similarly, the GT genotype in the rs185070757 (T/G) miR-196a2 variant did not differ between cases and controls with any models (p > 0.05). For the first time, we report no association of miR-146a rs2910164 (G/C) and miR-196a2 rs185070757 (T/G) with RA in a Pakistani population. A subsequent bioinformatic analysis revealed that the CC genotype of miR-146a rs2910164 might have a protective role against RA pathogenesis, with no effect observed with the miR-196a2 rs185070757. CONCLUSION: Our findings suggest that these miRNAs might have little-to-no impact on the RA pathogenesis in the Pakistani population.

MIR149 rs2292832 and MIR499 rs3746444 Genetic Variants Associated with the Risk of Rheumatoid Arthritis.

INTRODUCTION: MicroRNAs (miRNAs) are small non-coding RNAs that play a key role in post-transcriptional modulation of individual genes' expression. Several miRNA variants from different populations are known to be associated with an increased risk of rheumatoid arthritis (RA). AIM: This study was undertaken with the aim to investigate the association of single nucleotide variants; namely, rs2292832, rs3746444, rs11614913, rs1044165, and rs767649 of MIR149, MIR499, MIR196, MIR223, and MIR155, respectively, with RA in the Pakistani population. METHODS: A case-control study was performed by recruiting and genotyping a total of 600 individuals (300 cases and 300 controls) for these five variants using a TaqMan single-nucleotide polymorphism (SNP) genotyping assay. The resultant genotypic data was statistically analyzed through a chi-squared test for its association with RA under different inheritance models. RESULTS: We found a significant association of rs2292832 with RA at genotypic (co-dominant (p < 0.0001), dominant (CC vs. TT + CT: OR 2.063 (1.437-2.962); p = 0.0001), recessive (TT vs. CT + CC: OR 0.376 (0.259-0.548); p < 0.0001)), and allelic (allele C) levels ((OR 0.506 (0.402-0637); p < 0.0001)). Similarly, the rs3746444 showed a significant association with RA under co-dominant (p = 0.0001), dominant (GG vs. AA + AG: OR 5.246 (3.414-8.061); p < 0.0001), recessive (AA vs. GG + AG: OR 0.653 (0.466-0.916); p = 0.014), and additive models (G vs. A; OR 0.779 (0.620-0.978); p = 0.03). However, we did not observe any significant association of rs11614913, rs1044165, or rs767649 with RA in our subjects. CONCLUSION: To our knowledge, this was the first study that investigated and found an association between functional polymorphisms in miRNAs and RA in the Pakistani population.

Genetic Variants of MIR27A, MIR196A2 May Impact the Risk for the Onset of Coronary Artery Disease in the Pakistani Population.

Genetic variants in microRNA genes have a detrimental effect on miRNA-mediated regulation of gene expression and may contribute to coronary artery disease (CAD). CAD is the primary cause of mortality worldwide. Several environmental, genetic, and epigenetic factors are responsible for CAD susceptibility. The contribution of protein-coding genes is extensively studied. However, the role of microRNA genes in CAD is at infancy. The study is aimed to investigate the impact of rs895819, rs11614913, and rs2168518 variants in MIR27A, MIR196A2, and MIR4513, respectively, in CAD using allele-specific PCR. Results: For variant rs11614913, significant distribution of the genotypes among the cases and controls was determined by co-dominant [χ2 = 54.4; p value ≤ 0.0001], dominant (C/C vs. C/T + T/T) [OR = 0.257 (0.133-0.496); p value ≤ 0.0001], recessive (T/T vs. C/T + C/C) [OR = 1.56 (0.677-0.632); p value = 0.398], and additive models [OR = 0.421 (0.262-0.675); p value = 0.0004]. Similarly, a significant association of rs895819 was determined by co-dominant [χ2 = 9.669; p value ≤ 0.008], dominant (A/A vs. A/G + G/G) [OR = 0.285 (0.1242-0.6575); p value ≤ 0.0034], recessive (G/G vs. A/G + A/A) [OR = 0.900 (0.3202-3.519); p value = 1.000], and additive models [OR = 0.604 (0.3640-1.002); p value = 0.05] while no significant association of rs2168518 with CAD was found. Conclusion: The variants rs895819 and rs11614913 are the susceptibility factors for CAD.

Association of AFF3 Gene Polymorphism rs10865035 with Rheumatoid Arthritis: A Population-Based Case-Control Study on a Pakistani Cohort.

Rheumatoid arthritis (RA) is one of the complex diseases with the involvement of the genetic as well as environmental factors in its onset and severity. Different genome-wide association and candidate gene studies have shown the role of several genetic variants in multiple loci/genes with ethnical and geographical variations. This study was designed to detect the association of a single-nucleotide polymorphism (SNP) rs10865035 in the AFF3 gene with the genetic background of rheumatoid arthritis (RA) in the Pakistani cohort. A total of 703 individuals, including 409 RA patients and 294 healthy controls, were genotyped using TaqMan assay and Tri primer ARMS-PCR (amplification-refractory mutation system-polymerase chain reaction) methods. The association of rs10865035 with the RA was statistically determined using different models. Interestingly, besides the homozygous recessive model (G/G vs. A/G + A/A) (OR = 1.693(1.06-2.648); P = 0.025), all other models, which included the codominant (χ 2 = 5.169; P = 0.075), homozygous dominant (A/A vs. G/G + A/G) (OR = 0.867 (0.636-1.187); P = 0.41), heterozygous (A/G vs. A/A + GG) (OR = 0.491 (0.667-1.215); P = 0.49), and additive model (OR = 0.826 (0.665-1.027); P = 0.08) showed insignificant distribution of the genotypes among the cases and controls. These findings suggest that the AFF3 gene (rs10865035) has no significant role in the onset of RA in the Pakistani population.

Deciphering the Variants Located in the MIR196A2, MIR146A, and MIR423 with Type-2 Diabetes Mellitus in Pakistani Population.

MicroRNAs (miRNAs) are small non-coding RNA molecules that control the post-transcriptional gene expression. They play a pivotal role in the regulation of important physiological processes. Variations in miRNA genes coding for mature miRNA sequences have been implicated in several diseases. However, the association of variants in miRNAs genes with Type 2 Diabetes Mellitus (T2DM) in the Pakistani population is rarely reported. Therefore, the current study was designed to investigate the association of rs11614913 T/C (MIR196A2), rs2910164 G/C (MIR146A), and rs6505162 C/A (MIR423) in clinicopathological proven T2DM patients and gender-matched healthy controls. The tetra-primer amplification refractory mutation system-polymerase chain (ARMS-PCR) reaction method was used to determine the genotypes and to establish the association of each variant with T2DM through inherited models. In conclusion, the present study showed that variants rs11614913 T/C and rs2910164 G/C were linked with the risk of T2DM. The data suggested that rs11614913 T/C and rs2910164 G/C could be considered as novel risk factors in the pathogenesis of T2DM in the Pakistani population.

Antioxidant Potential of Physicochemically Characterized Gracilaria blodgettii Sulfated Polysaccharides.

Marine rhodophyte polysaccharides have a wide range of described biological properties with nontoxic characteristics, and show great potential in prebiotics and the functional foods industries. However, there is a virtual lack of Gracilaria blodgettii polysaccharides (GBP) profiling and their bioactivities. This study was designed while keeping in view the lack of physical and chemical characterization of GBP. This polysaccharide was also not previously tested for any bioactivities. A linear random coil conformation was observed for GBP, which was found to be a polysaccharide. A significant sulfate (w/w, 9.16%) and 3,6-anhydrogalactose (AHG, w/w, 17.97%) content was found in GBP. The significant difference in its setting (27.33 °C) and melting (64.33 °C) points makes it resistant to increasing heat. This, in turn, points to its utility in industrial scale processing and in enhancing the shelf-life of products under high temperatures. A radical scavenging activity of 19.80%, 25.42% and 8.80% was noted for GBP (3 mg/mL) in 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (ABTS) and hydroxyl radical (HO) scavenging assays, respectively. Therefore, the findings suggest that Gracilaria blodgettii polysaccharides display a good antioxidant potential and may have potential applications in the functional food industry.

Predictive role of single nucleotide polymorphism (rs11614913) in the development of breast cancer in Pakistani population.

Aim: miRNAs play an important role in breast cancer (BC). Variations in miRNAs influence their maturation, expression and consequently regulation of their target genes. Materials & methods: In this study, single nucleotide polymorphism rs11614913 was genotyped in BC patients (n = 300) and 230 controls by employing tetra primer amplification refractory mutation system PCR and Sanger sequencing (Macrogen Korea). Results: A significant difference was observed in the genotypes through co-dominant (χ2.#x00A0;= 42.03; p < 0.0001), additive (odds ratio [OR] = 0.6441 [0.4887-0.8490, 95% confidence interval]; p < 0.0019), dominant (OR = 0.3996 [0.2809-0.5686], p < 0.0001) and recessive (OR = 0.2993 [0.1220-0.7347], p < 0.009) statistical models showed decreased risk association of C allele with BC. Conclusion: Females having CT genotype are at higher risk of BC as compared with those having CC genotype.

An in silico approach to characterize nonsynonymous SNPs and regulatory SNPs in human TOX3 gene.

Cancer is one of the deadliest complex diseases having multigene nature where the role of single-nucleotide polymorphism (SNP) has been well explored in multiple genes. TOX high mobility group box family member 3 (TOX3) is one such gene, in which SNPs have been found to be associated with breast cancer. In this study, we have examined the potentially damaging nonsynonymous SNPs(nsSNPs) in TOX3 gene using in silico tools, namely PolyPhen2, SNP&GO, PhD-SNP and PROVEAN, which were further confirmed by I-Mutant, MutPred1.2 and ConSurf for their stability, functional and structural effects. nsSNPs rs368713418 (A266D), rs751141352 (P273S, P273T), rs200878352 (A275T) have been found to be the most deleterious that may have a vital role in breast cancer. Premature stop codon producing SNPs (Q527STOP), rs1259790811 (G495STOP), rs1294465822 (S395STOP) and rs1335372738 (G8STOP) were also found having prime importance in truncated and malfunctional protein formation. We also characterized regulatory SNPs for its potential effect on TOX3 gene regulation and found nine SNPs that may affect the gene regulation. Further, we have also designed 3D models using I-TASSER for the wild type and four mutant TOX3 proteins. Our study concludes that these SNPs can be of prime importance while studying breast cancer and other associated diseases as well. They are required to be studied in model organisms and cell cultures, and may have potential importance in personalized medicines and gene therapy.

Association of MIR146A rs2910164 variation with a predisposition to sporadic breast cancer in a Pakistani cohort.

Single-nucleotide polymorphisms (SNPs) in genes coding for microRNAs (miRNAs) play a pivotal role in the progression of breast cancer (BC). We investigated the association of miR-146a rs2910164 GC polymorphism with the risk of BC in the Pakistani population. The miR-146a rs2910164 polymorphism was genotyped in 300 BC cases and 300 age- and gender-matched healthy controls using T-ARMS-PCR. Genotype and allele frequencies were calculated and the association between genotypes and the risk of BC was calculated by odds ratio (OR) and confidence interval (95%). A significant difference in genotypic frequencies (χ2  = 63.10; P = <0.0001) and allelic frequencies (OR = 0.3955 (0.3132-0.4993); P = < 0.0001) was observed between cases and controls. Furthermore, we also found that miR-146 rs2910164 CC homozygote increased the risk of BC in the dominant (OR = 0.2397 (0.1629-0.3526); P = 0.0001; GG vs. GC + CC) and recessive (OR = 2.803 (1.865-4.213); P = <0.0001; CC vs. GC + GG) inheritance models. In summary, miR-146a rs2910164 GC is significantly associated with BC in the Pakistani population. To our knowledge, this is the first study that assessed MIR146a rs2910164 G > C SNP in Pakistani population. By analyzing the secondary structure of MIR146A variant, a significant structural modification was noted. Study with a larger sample size is needed to further confirm of these findings.

Frequency of mitochondrial m.1555A > G mutation in Syrian patients with non-syndromic hearing impairment.

BACKGROUND: Mitochondrial maternally inherited hearing impairment (HI) appears to be increasing in frequency. The incidence of mitochondrial defects causing HI is estimated to be between 6 and 33% of all hearing deficiencies. Mitochondrial m.1555A > G mutation is the first mtDNA mutation associated with non-syndromic sensorineural deafness and also with aminoglycoside induced HI. Its prevalence varied geographically between different populations. METHODS: We carried out PCR, restriction enzyme based screening, and sequencing of 337 subjects (including 132 patients diagnosed clinically with hereditary deafness) from 54 families from Syria for m.1555A > G mitochondrial mutation. RESULTS: Mitochondrial m.1555A > G mutation was detected in one of fifty-four families (1.85%), six out of the 132 (4.5%) of all patients with NSHI and one propositus of the 205 individuals with normal hearing (0.48%). CONCLUSION: This is the first study to report prelingual deafness causative gene mutations identified by sequencing technology in Syrian families. It is obvious from the results that the testing for the m.1555A > G mutation is useful for diagnosis of hearing loss in Syrian patients and should also be considered prior to treatment with aminoglycosides in predisposed individuals.

Frequency of c.35delG Mutation in GJB2 Gene (Connexin 26) in Syrian Patients with Nonsyndromic Hearing Impairment.

BACKGROUND: Hearing impairments (HI) are the most common birth defect worldwide. Very large numbers of genes have been identified but the most profound is GJB2. The clinical interest regarding this gene is very pronounced due to its high carrier frequency (0.5-5.4%) across different ethnic groups. This study aimed to determine the prevalence of common GJB2 mutations in Syrian patients with profound sensorineural HI. METHODS: We carried out PCR, restriction enzyme based screening, and sequencing of 132 Syrian patients diagnosed clinically with hereditary deafness for different GJB2 mutations. RESULTS: The result revealed that, in GJB2 gene, c.35delG is the most prevalent among affected studied subjects (13.64%), followed by c.457G>A (2.4%). CONCLUSION: The benefit of this study on the one hand is its first report of prelingual deafness causative gene mutations identified by sequencing technology in the Syrian families. It is obvious from the results that the deployment in biomedical research is highly effective and has a great impact on the ability to uncover the cause of genetic variation in different genetic diseases.

A TMC1 (transmembrane channel-like 1) mutation (p.S320R) in a Polish family with hearing impairment.

After excluding frequent mutations in common genes like GJB2, SLC26A4 and MT-RNR1 by straightforward Sanger sequencing in about 20 Polish families with hearing impairment, new and possibly pathogenic mutations were searched for by next-generation sequencing (NGS) screening using a specialised panel including more than 80 genes connected with hearing disorders. Due to high rates of false-positive pathogen predictions for newly discovered single-nucleotide polymorphisms (SNPs), different prediction models were combined to enhance the prediction power. In one family with a record of over four generations, II,3 and II,4 were suspected of hearing impairment without medical records. A male person (III,2) displayed hearing loss of 40 dB hearing level (HL) and his two sons, IV,1 and IV,2, were both affected; one with 90 dB HL and the other with 40 dB HL. Here, one heterozygous, non-synonymous variant was detected, with the SNP causing an amino acid substitution in TMC1 (transmembrane channel-like 1), a gene reported with many mutations in DFNA36 and DFNB7/11 (OMIM #606705 and #600974, respectively). Until now, the substitution p.S320R has not been described in any database. Instead of the significance of this mutation by bioinformatics tools, we confirmed the genotype-phenotype co-segregation in family members. The involvement of TMC1 in hereditary hearing impairment has not been observed in the Polish population so far.

Trefoil factor family member 2 (Tff2) KO mice are protected from high-fat diet-induced obesity.

INTRODUCTION: Trefoil factor family member 2 (Tff2) is a small gut peptide, mainly known for its protective and healing functions. As previously demonstrated, high-fat (HF) feeding can rapidly and specifically modulate Tff2 transcription in key tissues of mice, including the duodenum and mesenteric adipose tissue, therefore suggesting a novel role for this gene in energy balance. DESIGN AND METHODS: To explore whether and how Tff2 can influence feeding behavior and energy metabolism, Tff2 knock-out (KO) mice were challenged with HF diet for 12 weeks, hence food and energy intakes, body composition, as well as energy excretion and serum lipid and hormonal levels were analyzed. Finally, energy efficiency was estimated. RESULTS: Tff2 KO mice showed a greater appetite and higher energy intake compared to wild-type (WT). Consistently, they presented lower levels of serum leptin, and increased transcription of agouti-related protein (Agrp) in the hypothalamus. Though energy and triglyceride fecal excretion were augmented in Tff2 KO mice, digestible energy intake was superior. However, KO mice were finally protected from HF diet-induced obesity, and accumulated less weight and fat depots than WT animals, while keeping a normal lean mass. Energy efficiency was lower in HF-KO mice, while energy expenditure and locomotor activity were globally increased. CONCLUSIONS: The present work demonstrates previously unsuspected roles for Tff2 and suggests it to be a mastermind in the control of energy balance and a promising therapeutic target for obesity.

A set of specific miRNAs is connected with murine and human gastric cancer.

MircoRNAs as a new class of regulatory molecules have been investigated in many specific cells and organs in healthy and diseased conditions. Although miRNA signatures can be directly assessed in patients' affected tissues such as tumor sections, recent studies revealed that miRNA profiles can also be obtained indirectly, that is, from the patients' peripheral blood. For better understanding of miRNA's contribution to gastric carcinoma (one of the leading causes of cancer-related mortality worldwide), we screened for deregulated miRNAs in blood collected from human cancer patients and compared the expression patterns with a gastric carcinoma mouse model (Tff1 knock-out). The profiles were assessed using species-specific miRNA microarrays. Among many dozens of deregulated miRNAs (219 in H. sapiens; 75 in M. musculus), a subset of eight miRNAs comparable in sequence from both species was noted. By in silico analysis, their involvement in targeting neoplastic and MAPkinase pathways was demonstrated. We found a high probability of linkage of all noted miRNAs to pathways in cancer with P-values of 0.013 and 0.018 in mice and humans, respectively. Linkage to the MAPK-signaling pathway in mice was observed with a P-value of 0.01. Moreover, when comparing the 219 deregulated miRNAs obtained from blood with deregulated miRNAs derived from gastric cancer (GC) tissues, as published previously, 24 miRNAs were identical. If confirmed in a larger patient pool, these miRNAs could constitute appropriate blood-born biomarkers for GC.

Altered miRNA expression patterns in Tff2 knock-out mice correlate with cellular pathways of neoplastic development and caloric metabolism.

The trefoil peptide family, consisting in mammals of three members namely TFF1, 2 and 3, plays a cytoprotective role in epithelial cells of various tissues, mainly in the digestive tract. Tff1, Tff2 or Tff3 knock-out mouse models developed various kinds of gastrointestinal impairment. microRNAs are known to be novel gene regulators. We aimed to investigate the physiological role of such miRNAs in Tff2 knock-out mice. Whole miRNome profiling and in silico analysis were performed for Tff2-KO and WT mice. Our latest data explored the role of miRNAs in the regulatory cascades and molecular processes of Tff2-/- mice. As much as 6% of the Tff2-KO mice miRNome was significantly dys-regulated. Further in silico analysis suggests that the respective dys-regulated part of the miRNome is involved in human pathological processes, including pancreatic, colorectal and basal cell cancer. Additionally, the dys-regulated miRNome targets pathways involved in carbohydrate metabolism and adipocytokine signaling. The latter links deficient caloric maintenance in Tff2 and previous observation in Tff3-KO mice with miRNAs. In summary, our proof-of-concept study indicates that miRNAs may play an important role in the regulatory processes of the trefoil peptide family, especially in the regulation of cancer-related cascades.