Neuroprotective effects of Daphnetin on hippocampal neurons and blood-brain barrier integrity in a mouse model of cerebral ischemia.

The purpose of this research was to assess the impact of different doses of Daphnetin (DAP, a natural compound derived from coumarin) on hippocampus neuronal injury, neurobehavioral function, blood-brain barrier (BBB) integrity, expression of claudin-5, brain-derived neurotrophic factor (BDNF), superoxide dismutase (SOD), and inflammatory markers in a mouse model of cerebral ischemia. Cerebral ischemia was induced in mice through 30 minutes of bilateral common carotid occlusion (BCCAO), followed by 48 hours of reperfusion. The viability of hippocampal neurons was assessed using Cresyl violet staining and BBB function was determined by measuring Evans blue (E.B) dye leakage. Spatial memory was tested using the Radial Arm Water Maze (RAWM) task. Claudin-5 and BDNF were measured by immunofluorescence, while SOD, interleukin-1 beta (IL-1ß), and nuclear factor-κB (NF-κB) expression were determined through western blotting. Administering DAP significantly increased neuron survival in the hippocampus CA1, CA3, and dentate gyrus (DG) regions and improved spatial memory dose-dependently (P<0.0001). Treatment with DAP (40 mg/kg IP) significantly reduced E.B leakage and brain water content (P<0.001). Furthermore, it increased the claudin-5, BDNF, and SOD levels and diminished NF-κB and IL-1ß expression (P<0.0001). The research found that DAP protected neurons in the CA1, CA3, and DG areas of the hippocampus, enhanced behavioral functions, and preserved BBB integrity in a cerebral ischemia model. This positive impact is achieved by increasing the expression of claudin-5, BDNF, and SOD and diminishing neuroinflammation. Further research is required to clarify the mechanisms and possible clinical uses.

Risk factors and population attributable fractions for displaced abomasum in Iranian dairy cattle: a retrospective analysis of field data.

Displaced abomasum (DA) usually occurs in the early postpartum period and can negatively affect production and welfare of dairy cows. The objective of this research was to identify predictors for the occurrence of DA in Iranian Holsteins. Therefore, we analyzed data collected from six commercial dairy farms in Iran (calving between January 2011 and October 2020). We used generalized linear mixed-effects model to identify predictors based on estimates of odds ratios (ORs). Population attributable fractions (PAFs) were then calculated, as these are expected to more accurately prioritize risk factors on population level by considering the association between the risk factor and the its prevalence in the population. Over the 6 herds, the average percentage of DA was 2.5% (range 1.1-3.4% across herds). The results showed that calving during winter increased the odds of DA 1.4 times. Cows with high milk fat-to-protein ratio before the occurrence of disease, abnormal calving (including dystocia, stillbirth, and twinning) and long pregnancy length (≥ 280 d) showed increased odds of DA with ORs of 1.52, 1.31 and 1.30, respectively. Milk yield was also positively associated with DA in next lactation. Among the modifiable predictors of DA, the highest PAF was for the ratio of milk fat-to-protein (11.0%); other PAFs were retained placenta (4.1%), metritis (3.1%), abnormal calving (2.7%), and ketosis (2.7%). The results of the present study can provide managers with the a helpful strategy to reduce the occurrence of DA.

Non-destructive diagnosis of Inflammatory Bowel Disease by near-infrared spectroscopy and aquaphotomics.

Inflammatory Bowel Disease includes Crohn's Disease and Ulcerative Colitis. Currently, diagnosing involves a series of current diagnostic methods that are invasive, time-consuming, and expensive. Near-infrared spectroscopy and aquaphotomics can detect changes in biofluids and thus have the potential to diagnose disease. This study aimed to investigate the diagnostic ability of near infrared spectroscopy and aquaphotomics for Inflammatory Bowel Disease and its types. This method used blood plasma and saliva samples absorbance spectrum and multivariate analysis with the Principal Component Analysis and, Linear Discriminant Analysis, Quadratic Discriminant Analysis, and Support Vector Machine in the range 1300-1600 nm and 12 water absorbance bands in this range, separately. In the near-infrared range, total accuracy of 100% led to the separation of the healthy group and Inflammatory Bowel Disease and then the separation of the healthy group and patients with Ulcerative Colitis and Crohn's Disease. The aquaphotomics approach was used to investigate the changes in the 12 water absorbance bands and their impact on the accuracy of the diagnostic method. Aquaphotomics also detected 100% of the mentioned samples. We achieved a fast, accurate, non-invasive method based on near-infrared spectroscopy and aquaphotomics to diagnose Inflammatory Bowel Disease and its types using blood plasma or saliva samples. The current study found that monitoring blood plasma or saliva using near-infrared spectra offers an opportunity to thoroughly investigate biofluids and changes in their water spectral patterns caused by complex physiological changes due to Inflammatory Bowel Disease and its types, and to visualize these changes using aquagram.

Impact of reproductive traits on productive life in Iranian Holstein dairy cows.

Enhancing reproductive performance is a key strategy to mitigate involuntary culling rates, thereby extending productive life (PL) and ultimately improving profitability in dairy cattle herds. A piecewise Weibull proportional hazards model was used to investigate the effect of several important reproductive traits on PL in Holstein dairy cows. Data comprised 200,747 lactation records from 82,505 cows sired by 1952 bulls across 36 dairy herds. PL was defined as the number of days from the first calving to the last milk record or censoring. The statistical model accounted for the time-dependent fixed effects of changes in herd size, year-season, milk production, fat and protein contents, and the time-independent fixed effect of age at first calving. Herd-year and sire effects were also included as random effects. Reproductive traits include calving traits such as calving ease (CE), calf size (CZ), and calf survival (CS), as well as female fertility traits such as number of inseminations per conception (NI), days from calving to first service (CFS), days from first service to conception (FSC), and days open (DO). All reproductive traits had a significant effect on PL (p < 0.001). Each reproductive trait was analysed separately. The relative risk (RR) of being culled increased as the severity of calving difficulties increased in both primiparous and multiparous cows. Cows that calved small or large calves showed a higher risk of being culled compared with those that calved medium size calves. The increased RR of culling was observed only for primiparous cows that gave birth to dead calves. In addition, cows that required more NI, a longer CFS, FSC, and DO had shorter longevity. These insights can deepen our comprehension of the factors affecting PL and provide information for refining management and breeding strategies, which could lead to increased profitability and sustainability in Iranian dairy farming.

A novel diagnostic approach to Paratuberculosis in dairy cattle using near-infrared spectroscopy and aquaphotomics.

Introduction: As a contagious and chronic disease in the livestock industry, Paratuberculosis is a significant threat to dairy herds' genetic and economic resources. Due to intensive breeding and high production of dairy cattle, the incidence and prevalence are higher. Developing non-destructive diagnostic methods for the early detection and identification of healthy animals is paramount for breeding programs. Conventional methods are almost entirely destructive, have low accuracy, lack precision, and are time-consuming. Near-infrared spectroscopy (NIRS) and aquaphotomics can detect changes in biofluids and thus have the potential to diagnose disease. This study aimed to investigate the diagnostic ability of NIRS and aquaphotomics for Paratuberculosis in dairy cattle. Methods: Blood plasma from dairy cattle was collected in the NIR range (1,300 nm to 1,600 nm) 60 days before and 100 days to 200 days after calving in two groups, positive and negative, using the same consecutive enzyme-linked immunosorbent assay test results three times as a reference test. Results: NIRS and aquaphotomics methods invite 100% accuracy, sensitivity, and specificity to detect Paratuberculosis using data mining by unsupervised method, Principal Component Analysis, and supervised methods: Soft Independent Modeling of Class Analogiest, Linear Discriminant Analysis, Quadratic Discriminant Analysis, Partial Least Square-Discriminant Analysis, and Support Vector Machine models. Discussion: The current study found that monitoring blood plasma with NIR spectra provides an opportunity to analyze antibody levels indirectly via changes in water spectral patterns caused by complex physiological changes, such as the amount of antibodies related to Paratuberculosis by aquagram.

Coadministration of doxorubicin with vitamin D3, Lactobacillus acidophilus, and Lactobacillus casei in the 4T1 mouse model of breast cancer: anticancer and enteroprotective effects.

The use of doxorubicin (Dox) in the treatment of breast cancer negatively affects the intestines and other tissues. Many studies have proven that probiotics and vitamin D3 have antitumor and intestinal tissue-protecting properties. To achieve effectiveness and minimize side effects, the current study aims to administer Dox together with probiotics (Lactobacillus acidophilus and Lactobacillus casei) and vitamin D3. Forty-two female BALB/c inbred mice were divided into six groups: Group 1 (Control), Group 2 (Dox), Group 3 (Dox and probiotics), Group 4 (Dox and vitamin D3), Group 5 (Dox, probiotics, and vitamin D3), and Group 6 (probiotics and vitamin D3). The 4T1 mouse carcinoma cell line was injected into the mammary fat pad of each mouse. Gene expression was examined using quantitative real-time PCR. The treated groups (except group 6) showed significantly reduced tumor volume and weight compared to the control group (P < 0.05, P < 0.01). Probiotics/vitamin D3 with Dox reduced chemotherapy toxicity and a combination of supplements had a significant protective effect against Dox (P < 0.05, 0.01, 0.001). The treated groups (except 6) had significantly higher expression of Bax/Caspase 3 genes and lower expression of Bcl-2 genes than the control group (P < 0.05, 0.01). Coadministration of Dox with probiotics and vitamin D3 showed promising results in reducing tumor size, protecting intestinal tissue and influencing gene expression, suggesting a strategy to enhance the effectiveness of breast cancer treatment while reducing side effects.

Farm management and economic factors associated with bulk tank total bacterial count in Holstein dairy herds in Iran.

The objectives of this research were (1) to study different factors affecting milk total bacterial count (TBC) and (2) to estimate the economic value associated with TBC in Holstein dairy herds in Iran. The relationships between bulk tank TBC and farm management and economic factors were examined on 56 randomly selected intensive dairy farms. Herd management factors associated with bulk tank TBC were determined using mixed linear models. The median bulk tank TBC for the sample herds was 299 (range 81-1185) × 103 cfu/ml. The average economic premium opportunity from bulk tank TBC was US$ 1.32 per ton of milk ranging from US$ 0.02 per ton of milk for herds applying wet tissue procedures as teat cleaning material and washing the water troughs three times per day to US$ 5.20 per ton of milk for herds with dirty barns. Results showed that the following management factors were associated with low TBC and high economic value: frequency of cleaning water troughs, teat cleaning material, the frequency of milk delivery to the processor, bedding material, herd size, education level of workers, udder washing material, material of milking parlor wall, frequency of disinfection of the calving area, presence of veterinarian, water quality control, having a hospital pen and barn hygiene. In conclusion, our findings highlight the need to pay more attention to farm management issues, particularly farm hygiene practices to reduce milk TBC and so reduce the economic burden of TBC in dairy herds in Iran.

Integrated co-expression analysis of regulatory elements (miRNA, lncRNA, and TFs) in bovine monocytes induced by Str. uberis.

Non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), together with transcription factors, are critical pre-, co-, and post-transcriptional regulators. In addition to their criteria as ideal biomarkers, they have great potential in disease prognosis, diagnosis, and treatment of complex diseases. Investigation of regulatory mechanisms in the context of bovine mastitis, as most common and economic disease in the dairy industry, to identify elements influencing the expression of candidate genes as key regulators of the mammary immune response is not yet fully understood. Transcriptome profiles (50 RNA-Seq and 50 miRNA-Seq samples) of bovine monocytes induced by Str. uberis were used for co-expression module detection and preservation analysis using the weighted gene co-expression network analysis (WGCNA) approach. Assigned mi-, lnc-, and m-modules used to construct the integrated regulatory networks and miRNA-lncRNA-mRNA regulatory sub-networks. Remarkably, we have identified 18 miRNAs, five lncRNAs, and seven TFs as key regulators of str. uberis-induced mastitis. Most of the genes introduced here, mainly involved in immune response, inflammation, and apoptosis, were new to mastitis. These findings may help to further elucidate the underlying mechanisms of bovine mastitis, and the discovered genes may serve as signatures for early diagnosis and treatment of the disease.

Genome-wide post-transcriptional regulation of bovine mammary gland response to Streptococcus uberis.

MicroRNAs (miRNAs) as post-transcriptionally regulators of gene expression have been shown to be critical regulators to fine-tuning immune responses, besides their criteria for being an ideal biomarker. The regulatory role of miRNAs in responses to most mastitis-causing pathogens is not well understood. Gram-positive Streptococcus uberis (Str. uberis), the leading pathogen in dairy herds, cause both clinical and subclinical infections. In this study, a system biology approach was used to better understand the main post-transcriptional regulatory functions and elements of bovine mammary gland response to Str. uberis infection. Publicly available miRNA-Seq data containing 50 milk samples of the ten dairy cows (five controls and five infected) were retrieved for this current research. Functional enrichment analysis of predicted targets revealed that highly confident responsive miRNAs (4 up- and 19 downregulated) mainly regulate genes involved in the regulation of transcription, apoptotic process, regulation of cell adhesion, and pro-inflammatory signaling pathways. Time series analysis showed that six gene clusters significantly differed in comparisons between Str. uberis-induced samples with controls. Additionally, other bioinformatic analysis, including upstream network analysis, showed essential genes, including TP53 and TGFB1 and some small molecules, including glucose, curcumin, and LPS, commonly regulate most of the downregulated miRNAs. Upregulated miRNAs are commonly controlled by the most important genes, including IL1B, NEAT1, DICER1 enzyme and small molecules including estradiol, tamoxifen, estrogen, LPS, and epigallocatechin. Our study used results of next-generation sequencing to reveal key miRNAs as the main regulator of gene expression responses to a Gram-positive bacterial infection. Furthermore, by gene regulatory network (GRN) analysis, we can introduce the common upregulator transcription factor of these miRNAs. Such milk-based miRNA signature(s) would facilitate risk stratification for large-scale prevention programs and provide an opportunity for early diagnosis and therapeutic intervention.

A framework for non-preserved consensus gene module detection in Johne's disease.

Johne's disease caused by Mycobacterium avium subsp. paratuberculosis (MAP) is a major concern in dairy industry. Since, the pathogenesis of the disease is not clearly known, it is necessary to develop an approach to discover molecular mechanisms behind this disease with high confidence. Biological studies often suffer from issues with reproducibility. Lack of a method to find stable modules in co-expression networks from different datasets related to Johne's disease motivated us to present a computational pipeline to identify non-preserved consensus modules. Two RNA-Seq datasets related to MAP infection were analyzed, and consensus modules were detected and were subjected to the preservation analysis. The non-preserved consensus modules in both datasets were determined as they are modules whose connectivity and density are affected by the disease. Long non-coding RNAs (lncRNAs) and TF genes in the non-preserved consensus modules were identified to construct integrated networks of lncRNA-mRNA-TF. These networks were confirmed by protein-protein interactions (PPIs) networks. Also, the overlapped hub genes between two datasets were considered hub genes of the consensus modules. Out of 66 consensus modules, 21 modules were non-preserved consensus modules, which were common in both datasets and 619 hub genes were members of these modules. Moreover, 34 lncRNA and 152 TF genes were identified in 12 and 19 non-preserved consensus modules, respectively. The predicted PPIs in 17 non-preserved consensus modules were significant, and 283 hub genes were commonly identified in both co-expression and PPIs networks. Functional enrichment analysis revealed that eight out of 21 modules were significantly enriched for biological processes associated with Johne's disease including "inflammatory response," "interleukin-1-mediated signaling pathway", "type I interferon signaling pathway," "cytokine-mediated signaling pathway," "regulation of interferon-beta production," and "response to interferon-gamma." Moreover, some genes (hub mRNA, TF, and lncRNA) were introduced as potential candidates for Johne's disease pathogenesis such as TLR2, NFKB1, IRF1, ATF3, TREM1, CDH26, HMGB1, STAT1, ISG15, CASP3. This study expanded our knowledge of molecular mechanisms involved in Johne's disease, and the presented pipeline enabled us to achieve more valid results.

Anti-inflammatory function of apolipoprotein B-depleted plasma is impaired in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular events. HDL exerts various protective functions on the cardiovascular system including anti-inflammatory activity by suppressing adhesion molecules expression in inflammation-induced endothelial cells. This study was designed to search if the anti-inflammatory capacity of apolipoprotein B-depleted plasma (apoB-depleted plasma) is altered in NAFLD patients. METHODS: A total of 83 subjects including 42 NAFLD and 41 control subjects were included in this cross-sectional study. Anti-inflammatory function of HDL was determined as the ability of apoB-depleted plasma to inhibit tumor necrosis factor-α (TNF-α)-induced expression of adhesion molecules in human umbilical vein endothelial cells (HUVECs). RESULTS: Incubation of inflammation-stimulated HUVECs with the NAFLD patients' apo-B depleted plasma led to higher levels of expression of adhesion molecules compared to the control subjects' plasma samples, reflecting an impaired anti-inflammatory capacity of apoB-depleted plasma in the NAFLD patients. Impaired anti-inflammatory capacity of apoB-depleted plasma was correlated with fatty liver and obesity indices. After adjustment with obesity indices, the association of anti-inflammatory capacity of apoB-depleted plasma with NAFLD remained significant. CONCLUSION: Impaired anti-inflammatory activity of apoB-depleted plasma was independently associated with NAFLD.

Chrysin-Enhanced Cytotoxicity of 5-Fluorouracil-Based Chemotherapy for Colorectal Cancer in Mice: Investigating its Effects on Cyclooxygenase-2 Expression

Abstract 5-fluorouracil (5-FU) has been recognized as an effective medication used to treat colorectal cancer (CRC); however, its administration is facing limitations due to some complications reported. It is also generally accepted that combination therapy is among strategies to improve chemotherapy efficiency. Therefore, chrysin, with its anticancer effects, in combination with 5-FU was investigated in the present study. Azoxymethane (AOM) as a carcinogenic substance along with dextran sodium sulfate (DSS) was additionally utilized to induce CRC in mice. The anticancer effects of chrysin were then evaluated using aberrant crypt foci (ACF) counting and percentage of pathologic lesions in epithelial tissues from distal colon. In this study, cyclooxygenase (COX-2) protein expression was correspondingly explored through immunohistochemistry (IHC). The results revealed that chrysin alone or in combination with 5-FU could decrease ACF counting and percentage of pathologic lesions in comparison with AOM (p<0.05). Moreover, the combination of chrysin (at a dose of 50 mg/kg) with 5-FU reduced COX-2 expression compared with 5-FU alone (p<0.001) or 5-FU in combination with chrysin at a dose of 100 mg/kg (p<0.05). Furthermore, the combined chrysin boosted 5-FU efficiency, so it was suggested as an auxiliary therapy for CRC.

Association of anti-oxidative capacity of HDL with subclinical atherosclerosis in subjects with and without non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) patients are at a substantial risk for developing cardiovascular disease (CVD). High-density lipoprotein (HDL) is well known to have protective effects against the development of atherosclerotic CVD. One of the major antiatherogenic effects of HDL is its anti-oxidative function. OBJECTIVES: This study investigated the association of anti-oxidative capacity of HDL with subclinical atherosclerosis in NAFLD and non-NAFLD subjects. METHODS: A total of 143 subjects including 51 NAFLD and 92 control subjects were included in this case-control study. HDL oxidative index (HOI) was determined spectrophotometrically using a cell-free method in the presence of a fluorescent substrate dichlorofluorescein diacetate (DCFDA). Paraoxonase 1 (PON1) activity, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) plasma levels were assessed in both groups. RESULTS: The NAFLD patients with impaired HDL anti-oxidative function (HOI ≥ 1) had higher MDA levels, aspartate amino transferase (AST), liver stiffness (LS), and carotid intima-media thickness (cIMT) values compared to the controls. HDL oxidative index (HOI) was positively correlated with MDA levels and cIMT and negatively correlated with SOD activity. CONCLUSIONS: Higher circulating levels of MDA were associated with the impaired anti-oxidative function of HDL in NAFLD. The impaired anti-oxidative capacity of HDL might be related to NAFLD severity and subclinical atherosclerosis in NAFLD patients.

H. pylori effects on ghrelin axis: Preliminary change in gastric pathogenesis.

Ghrelin and its receptors are present in the stomach, suggesting that the ghrelin axis plays an essential role in gastrointestinal complications. This investigation aimed to explore the effects of H. pylori infection and gastritis on serum ghrelin and ghrelin axis gene expression. In this study, we enrolled 68 adult ambulatory people referred for upper gastrointestinal endoscopy. The individuals were classified into three groups based on H. pylori infection and gastritis. Total serum ghrelin and tissue gene expression were tested with ELISA and quantitative RT-PCR, respectively. Serum ghrelin and mRNA expression were significantly lower in H. pylori-positive with gastritis subjects compared with both H. pylori-negative with and without gastritis. Growth hormone secretagogue receptor1a mRNA expression was not different between groups while GHSR1b expression was significantly higher in patients with H. pylori infection and gastritis. We propose the ghrelin axis intermediaries, such as GHSR1b, as a potential clinical target for gastric disorders.

Integrated Analysis of lncRNAs, mRNAs, and TFs to Identify Regulatory Networks Underlying MAP Infection in Cattle.

Johne's disease is a chronic infection of ruminants that burdens dairy herds with a significant economic loss. The pathogenesis of the disease has not been revealed clearly due to its complex nature. In order to achieve deeper biological insights into molecular mechanisms involved in MAP infection resulting in Johne's disease, a system biology approach was used. As far as is known, this is the first study that considers lncRNAs, TFs, and mRNAs, simultaneously, to construct an integrated gene regulatory network involved in MAP infection. Weighted gene coexpression network analysis (WGCNA) and functional enrichment analysis were conducted to explore coexpression modules from which nonpreserved modules had altered connectivity patterns. After identification of hub and hub-hub genes as well as TFs and lncRNAs in the nonpreserved modules, integrated networks of lncRNA-mRNA-TF were constructed, and cis and trans targets of lncRNAs were identified. Both cis and trans targets of lncRNAs were found in eight nonpreserved modules. Twenty-one of 47 nonpreserved modules showed significant biological processes related to the immune system and MAP infection. Some of the MAP infection's related pathways in the most important nonpreserved modules comprise "positive regulation of cytokine-mediated signaling pathway," "negative regulation of leukocyte migration," "T-cell differentiation," "neutrophil activation," and "defense response." Furthermore, several genes were identified in these modules, including SLC11A1, MAPK8IP1, HMGCR, IFNGR1, CMPK2, CORO1A, IRF1, LDLR, BOLA-DMB, and BOLA-DMA, which are potentially associated with MAP pathogenesis. This study not only enhanced our knowledge of molecular mechanisms behind MAP infection but also highlighted several promising hub and hub-hub genes involved in macrophage-pathogen interaction.

Co-administration of 5FU and propolis on AOM/DSS induced colorectal cancer in BALB-c mice.

AIMS: Currently, the main problems with chemotherapy are its side effects, toxicity, and drug resistance. Propolis has biological activities, such as anti-inflammatory and anti-cancer properties. This study aims to examine the combined effects of 5-fluorouracil (5FU) and propolis on colorectal cancer (CRC) in mouse models. MATERIALS AND METHODS: The chemical composition of ethanolic extract of propolis was determined by gas chromatography-mass spectrometry (GC-MS). In this study, 49 male Balb/c mice (16-20 g) were divided in seven groups as a control group and experimental groups (treated and untreated CRC model [azoxymethane + dextran sodium sulfate]). This study was conducted in 8 weeks. To examine the anti-cancer effects of propolis, the number of aberrant crypt foci (ACF) was counted and the pathological lesions in the distal colonic epithelial tissue were diagnosed. In this study, the expression of beta-catenin (ß-catenin), induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (Cox-2) proteins, which play a major role in the incidence and progression of cancer, were determined. KEY FINDINGS: GC-MS analysis of propolis showed the presence of hydrocarbons, alcohols, ketones, terpenes, phenols, and flavonoids. Administering propolis in combination with 5FU reduced the number of ACFs and pathological lesions in comparison with cancer control groups (p < 0.0001) and 5FU-alone treatment (p < 0.05). The propolis combined with 5FU reduced the expression of Cox-2, iNOS, and ß-catenin proteins. SIGNIFICANCE: The results showed that propolis increased the efficiency of 5FU and could be taken into account as the adjunct therapy for colorectal cancer.

Systems Biology-Derived Genetic Signatures of Mastitis in Dairy Cattle: A New Avenue for Drug Repurposing.

Mastitis, a disease with high incidence worldwide, is the most prevalent and costly disease in the dairy industry. Gram-negative bacteria such as Escherichia coli (E. coli) are assumed to be among the leading agents causing acute severe infection with clinical signs. E. Coli, environmental mastitis pathogens, are the primary etiological agents of bovine mastitis in well-managed dairy farms. Response to E. Coli infection has a complex pattern affected by genetic and environmental parameters. On the other hand, the efficacy of antibiotics and/or anti-inflammatory treatment in E. coli mastitis is still a topic of scientific debate, and studies on the treatment of clinical cases show conflicting results. Unraveling the bio-signature of mastitis in dairy cattle can open new avenues for drug repurposing. In the current research, a novel, semi-supervised heterogeneous label propagation algorithm named Heter-LP, which applies both local and global network features for data integration, was used to potentially identify novel therapeutic avenues for the treatment of E. coli mastitis. Online data repositories relevant to known diseases, drugs, and gene targets, along with other specialized biological information for E. coli mastitis, including critical genes with robust bio-signatures, drugs, and related disorders, were used as input data for analysis with the Heter-LP algorithm. Our research identified novel drugs such as Glibenclamide, Ipratropium, Salbutamol, and Carbidopa as possible therapeutics that could be used against E. coli mastitis. Predicted relationships can be used by pharmaceutical scientists or veterinarians to find commercially efficacious medicines or a combination of two or more active compounds to treat this infectious disease.

Effects of CD133 Silencing on Survival and Migration of HT-29 Colorectal Cancer Cells.

BACKGROUND: Colorectal cancer (CRC) is attributed as one of the most common malignancies worldwide. CD133 molecule, as a pentaspan transmembrane glycoprotein, confers stem cell-related characteristics, including self-renewal and multi-directional differentiation capability. CD133 plays important roles in the progression of CRC by conferring apoptotic resistance and migration ability. OBJECTIVE: To investigate the anti-apoptotic and anti-angiogenic effect of CD-133 targeted siRNA in a colorectal cancer cell line. METHODS: In this study, CD133-targeted siRNA transfection was conducted into HT-29 cells. MTT assay was employed to evaluate the cytotoxic effects of transfection on the cells. Flow cytometry was used to evaluate the apoptosis rate. The mRNA expression of apoptosis and metastasis related genes were assessed by quantitative Real-Time PCR (qRT-PCR). Wound healing assay was used to assess the migration potency of the infected cells. RESULTS: Expression of CD133 was significantly downregulated after transfection of CD133-specific siRNA. Moreover, the rate of apoptosis was significantly increased after transfection. The migration potential of cells was diminished after transfection. siRNA delivery resulted in the modulation of expression of apoptosis and metastasis-related genes. CONCLUSION: siRNA mediated targeting of CD133 could be considered as a promising approach to treat CRC through suppressing the cancerous behavior of tumor cells.