Design and synthesis of novel uracil-linked Schiff bases as dual histone deacetylase type II/topoisomerase type I inhibitors with apoptotic potential.

Aim: The previously reported dual histone deacetylase type II (HDAC II) / topoisomerase type I (Topo I) inhibitors suffer pharmacokinetic limitations because of their huge molecular weights. Materials & methods: We report the design and synthesis of a smarter novel set of uracil-linked Schiff bases (19-30) as dual HDAC II/Topo I inhibitors keeping the essential pharmacophoric features. Cytotoxicity of all compounds was assessed against three cancer cell lines. Studies of their effects on the apoptotic BAX and antiapoptotic BCL2 genes, molecular docking studies, and absorption, distribution, metabolism and excretion studies were conducted. Results: Compounds 22, 25 and 30 exhibited significant activities. The bromophenyl derivative 22 displayed the best selectivity index, with IC50 values against HDAC II and Topo I of 1.12 and 13.44 µM, respectively. Conclusion: Compound 22 could be considered a lead HDAC II/Topo I inhibitor.

The emergence of an imported variant of dengue virus serotype 2 in the Jazan region, southwestern Saudi Arabia.

BACKGROUND: Dengue virus (DENV) infection is a global economic and public health concern, particularly in tropical and subtropical countries where it is endemic. Saudi Arabia has seen an increase in DENV infections, especially in the western and southwestern regions. This study aims to investigate the genetic variants of DENV-2 that were circulating during a serious outbreak in Jazan region in 2019. METHODS: A total of 482 serum samples collected during 2019 from Jazan region were tested with reverse transcription-polymerase chain reaction (RT-PCR) to detect and classify DENV; positive samples underwent sequencing and bioinformatics analyses. RESULTS: Out of 294 positive samples, type-specific RT-PCR identified 58.8% as DENV-2 but could not identify 41.2%. Based on sequencing and bioinformatics analyses, the samples tested PCR positive in the first round but PCR negative in the second round were found to be imported genetic variant of DENV-2. The identified DENV-2 imported variant showed similarities to DENV-2 sequences reported in Malaysia, Singapore, Korea and China. The results revealed the imported genetic variant of DENV-2 was circulating in Jazan region that was highly prevalent and it was likely a major factor in this outbreak. CONCLUSIONS: The emergence of imported DENV variants is a serious challenge for the dengue fever surveillance and control programmes in endemic areas. Therefore, further investigations and continuous surveillance of existing and new viral strains in the region are warranted.

Genetic Variation in DEAD-Box Helicase 20 as a Putative Marker of Recurrence in Propensity-Matched Colon Cancer Patients.

Variants of the DEAD-Box Helicase 20 (DDX20), one of the microRNAs (miRNAs) machinery genes, can modulate miRNA/target gene expressions and, hence, influence cancer susceptibility and prognosis. Here, we aimed to unravel the association of DDX20 rs197412 T/C variant with colon cancer risk and/or prognosis in paired samples of 122 colon cancer and non-cancer tissue specimens by TaqMan allelic discrimination analysis. Structural/functional bioinformatic analyses were carried out, followed by a meta-analysis. We found that the T allele was more frequent in cancer tissues compared to control tissues (60.2% vs. 35.7%, p < 0.001). Furthermore, the T variant was highly frequent in primary tumors with evidence of recurrence (73% vs. 47.5%, p < 0.001). Genetic association models, adjusted by age and sex, revealed that the T allele was associated with a higher risk of developing colon cancer under heterozygote (T/C vs. C/C: OR = 2.35, 95%CI = 1.25−4.44, p < 0.001), homozygote (T/T vs. C/C: OR = 7.6, 95%CI = 3.5−16.8, p < 0.001), dominant (T/C-T/T vs. C/C: OR = 3.4, 95%CI = 1.87−8.5, p < 0.001), and recessive (T/T vs. C/C-T/C: OR = 4.42, 95%CI = 2.29−8.54, p = 0.001) models. Kaplan−Meier survival curves showed the shift in the C > T allele to be associated with poor disease-free survival. After adjusting covariates using a multivariate cox regression model, patients harboring C > T somatic mutation were 3.5 times more likely to develop a recurrence (p < 0.001). A meta-analysis of nine studies (including ours) showed a higher risk of CRC (81%) in subjects harboring the T/T genotype than in T/C + C/C genotypes, supporting the potential clinical utility of the specified study variant as a biomarker for risk stratification in CRC cases. However, results were not significant in non-colorectal cancers. In conclusion, the DDX20 rs197412 variant is associated with increased colon cancer risk and a higher likelihood of recurrence in the study population.

DNA Barcoding of Potential Mosquito Disease Vectors (Diptera, Culicidae) in Jazan Region, Saudi Arabia.

The conventional morphological characterization of mosquito species remains heavily used for species identification in Jazan, Saudi Arabia. It requires substantial expertise and time, as well as having difficulty in confirming identity of morphologically similar species. Therefore, to establish a reliable and accurate identification system that can be applied to understanding spatial distribution of local mosquito species from the Jazan region, DNA barcoding was explored as an integrated tool for mosquito species identification. In this study, 44 adult mosquito specimens were analyzed, which contain 16 species belong to three genera of potential mosquito disease vectors (Aedes, Anopheles, and Culex). The specimens were collected from the Jazan region located in southwest Saudi Arabia. These included old and preserved mosquito voucher specimens. In addition, we assessed the genetic distance based on the generated mitochondrial partial COI DNA barcodes to detect cryptic diversity across these taxa. Nine mosquito species belonging to three genera were successfully barcoded and submitted to GenBank, namely: Aedes aegypti, Aedes caspius, Aedes vexans, Aedes vittatus, Anopheles arabiensis, Culex pipiens, Culex quinquefasciatus, Culex sitiens, and Culex tritaeniorhynchus. Of these nine species, Aedes vexans, Aedes vittatus, Culex sitiens, and Culex tritaeniorhynchus were registered in GenBank for the first time from Saudi Arabia. The DNA barcodes generated a 100% match to known barcodes of these mosquito species, that also matched with the morphological identification. Ae. vexans was found to be either a case of cryptic species (subspecies) or a new species from the region. However, more research has to be conducted to prove the latter. This study directly contributes to the development of a molecular reference library of mosquito species from the Jazan region and Saudi Arabia. The library is essential for confirmation of species in support of existing mosquito surveillance and control programmes.

Gastroprotective effect of low dose Eugenol in experimental rats against ethanol induced toxicity: Involvement of antiinflammatory and antioxidant mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: Syzygium aromaticum L. volatile oil (clove oil) has been traditionally used for various stomach disorders including inflammatory conditions. Eugenol is the major constituent present in the volatile oil, and it has been established as a gastroprotective agent through many published studies, but the exact and complete mechanism of ulcer protection is not delineated yet. Moreover, it plays precisely the opposite effect in higher dose in antiulcer properties with worsening the ulcer at a higher dose. AIM: This study aims to carry out the prophylactic cytoprotective effect of eugenol with single low doses and explore the probable interrelated underlying transcriptional and translational level mechanism of cytoprotection such as antioxidative, anti-inflammatory, mucous generation in rats using ethanol-induced ulcer model. METHODS: Rats were administered with different doses of eugenol before ethanol intragastrically. The effects of the eugenol on mucous production, Nitric oxide generation, PGE2 synthesis, lipid peroxidation were recorded together with cytokines measurement in the blood. TNF-α and IL-6, two key cytokines, were also studied in specific. In addition, studies on the immunohistochemical and gene expression of HSP70 and iNOS indicators have been conducted. RESULTS: According to our findings, Eugenol substantially reduced the ulcer index and completely protected the mucosa from lesions. By restoring the lowered GSH and NP-SH levels, the protective effect of the eugenol was found to be augmented at both doses. This finding has corresponded to an increase in MDA, which was lowered by ethanol administration. Pre-treatment with eugenol on the ethanol-induced ulcer reduced the plasma NO levels and increased PGE2 along with a decreased TNF-α and IL-6 concentration. Additionally, significant transcriptional and translational upregulation of HSP70 and downregulation of iNOS were detected in the eugenol-treated rat stomach tissue. CONCLUSION: Our findings demonstrated that eugenol had a considerable gastroprotective impact at low doses, which could be attributed to its ability to regulate inflammatory reactions and antioxidant capacity.

Cytotoxicity of Mahanimbine from Curry Leaves in Human Breast Cancer Cells (MCF-7) via Mitochondrial Apoptosis and Anti-Angiogenesis.

Mahanimbine (MN) is a carbazole alkaloid present in the leaves of Murraya koenigii, which is an integral part of medicinal and culinary practices in Asia. In the present study, the anticancer, apoptotic and anti-invasive potential of MN has been delineated in vitro. Apoptosis cells determination was carried out utilizing the acridine orange/propidium iodide double fluorescence test. During treatment, caspase-3/7,-8, and-9 enzymes and mitochondrial membrane potentials (Δψm) were evaluated. Anti-invasive properties were tested utilizing a wound-healing scratch test. Protein and gene expression studies were used to measure Bax, Bcl2, MMP-2, and -9 levels. The results show that MN could induce apoptosis in MCF-7 cells at 14 µM concentration IC50. MN-induced mitochondria-mediated apoptosis, with loss in Δψm, regulation of Bcl2/Bax, and accumulation of ROS (p ≤ 0.05). Caspase-3/7 and -9 enzyme activity were detected in MCF-7 cells after 24 and 48 h of treatment with MN. The anti-invasive property of MN was shown by inhibition of wound healing at the dose-dependent level and significantly suppressed mRNA and protein expression on MMP-2 and -9 in MCF-7 cells treated with a sub-cytotoxic dose of MN. The overall results indicate MN is a potential therapeutic compound against breast cancer as an apoptosis inducer and anti-invasive agent.

Association of B-cell lymphoma 2/microRNA-497 gene expression ratio score with metastasis in patients with colorectal cancer: A propensity-matched cohort analysis.

BACKGROUND: Deregulated microRNAs (miRs) significantly impact cancer development and progression. Our in silico analysis revealed that miR-497 and its target gene B-cell lymphoma-2 (BCL2) could be related to poor cancer outcomes. PURPOSE: To investigate the BCL2/miRNA-497 expression ratio in colorectal cancer (CRC) and explore its association with the clinicopathological characteristics and CRC prognosis. METHODS: Archived samples from 106 CRC patients were enrolled. MiR-497 and BCL2 gene expressions were detected by Taq-Man Real-Time quantitative polymerase chain reaction in propensity-matched metastatic and nonmetastatic cohorts after elimination of confounder bias. RESULTS: B-cell lymphoma-2 gene was upregulated in metastatic samples (median = 1.16, 95%CI = 1.09-1.60) compared to nonmetastatic (median = 1.02, 95%CI = 0.89-1.25, p < 0.001). In contrast, lower levels of miR-495 were detected in specimens with distant metastasis (median = 0.05, 95%CI = 0.04-0.20) than nonmetastatic samples (median = 0.54, 95%CI = 0.47-0.58, p < 0.001). Estimated BCL2/miR-497 ratio yielded a significant differential expression between the two cohort groups. Higher scores were observed in metastasis group (median = 1.39, 95%CI = 0.9-1.51) than nonmetastatic patients (median = 0.29, 95%CI = 0.19-0.39, p < 0.001). Receiver operating characteristic curve analysis showed BCL2/miR-497 ratio score to have the highest predictive accuracy for metastasis at presentation. The area under the curve was 0.90 (95%CI = 0.839-0.964, p < 0.001) at cut-off of >0.525, with high sensitivity 81.1% (95%CI = 68.6%-89.4%) and specificity 92.5% (95%CI = 82.1%-97.0%). Also, the ratio score was negatively correlated with disease-free survival (r = -0.676, p < 0.001) and overall survival times (r = -0.650, p < 0.001). Kaplan-Meier curves showed lower survival rates in cohorts with high-score compared to low-score patients. CONCLUSION: The BCL2/miR497 expression ratio is associated with poor CRC prognosis in terms of metastasis and short survival.

Focally amplified long non-coding RNA in epithelial cancer as a potential biomarker and therapeutic target.

Deregulation of long non-coding RNAs (lncRNAs) has been implicated in tumorigenesis. FALEC is a lncRNA upregulated in multiple cancer types. FALEC functions as an oncogene through various mechanisms, such as competitively binding miRNAs and regulation of PI3K/AKT, Tp53 and phosphatase and tensin homolog signaling pathways. Pertinent to clinical practice, the use of FALEC as a putative biomarker has been identified. These findings suggested that FALEC might play a pivotal role in human cancers. Further studies are warranted to examine the diagnostic and prognostic performance of FALEC as a noninvasive biomarker in liquid biopsy samples and promote its development to be a clinically utilizable prognostic cancer biomarker and molecular therapeutic target.

Applications of Adductomics in Chemically Induced Adverse Outcomes and Major Emphasis on DNA Adductomics: A Pathbreaking Tool in Biomedical Research.

Adductomics novel and emerging discipline in the toxicological research emphasizes on adducts formed by reactive chemical agents with biological molecules in living organisms. Development in analytical methods propelled the application and utility of adductomics in interdisciplinary sciences. This review endeavors to add a new dimension where comprehensive insights into diverse applications of adductomics in addressing some of society's pressing challenges are provided. Also focuses on diverse applications of adductomics include: forecasting risk of chronic diseases triggered by reactive agents and predicting carcinogenesis induced by tobacco smoking; assessing chemical agents' toxicity and supplementing genotoxicity studies; designing personalized medication and precision treatment in cancer chemotherapy; appraising environmental quality or extent of pollution using biological systems; crafting tools and techniques for diagnosis of diseases and detecting food contaminants; furnishing exposure profile of the individual to electrophiles; and assisting regulatory agencies in risk assessment of reactive chemical agents. Characterizing adducts that are present in extremely low concentrations is an exigent task and more over absence of dedicated database to identify adducts is further exacerbating the problem of adduct diagnosis. In addition, there is scope of improvement in sample preparation methods and data processing software and algorithms for accurate assessment of adducts.

Prevalence of ß-S Globin Haplotypes in Jazan Region of Saudi Arabia.

BACKGROUND: Sickle cell disease (SCD) is a common hematological genetic disorder in Saudi Arabia, Africa, the Mediterranean region, and India. The present study aimed to characterize ßS haplotypes found in the Jazan region, Saudi Arabia. METHODS: One hundred sickle cell trait (SCT) individuals, diagnosed during their visit to the premarital screening clinic at King Fahad Central Hospital, were included in the study. Molecular analysis was carried out by polymerase chain reaction (PCR) and six polymorphic sites of the ß-globin gene were analyzed using restriction endonucleases Hind II, Xmn-I, Hind III, and Ava II. RESULTS: The results of the current study revealed the presence of five typical haplotypes in which Benin, Bantu, and Senegal were found in homozygous state with 29%, 3% and 1% frequencies, respectively. Interestingly, 29% of the studied population showed atypical haplotypes in heterozygous state and 2% in homozygous state for the first time in Jazan region. CONCLUSIONS: In addition to the typical haplotypes, high frequency of atypical haplotypes in this study indicates a diverse genetic mechanism that might have a crucial effect on the severity of SCD in this region. Therefore, considering this study in a cohort population with SCD in Jazan region may provide more indepth details about the correlation between haplotypes and the clinical manifestation of the disease.

Association of cyclin-dependent kinase inhibitor 2B antisense RNA 1 gene expression and rs2383207 variant with breast cancer risk and survival.

BACKGROUND: The expression signature of deregulated long non-coding RNAs (lncRNAs) and related genetic variants is implicated in every stage of tumorigenesis, progression, and recurrence. This study aimed to explore the association of lncRNA cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) gene expression and the rs2383207A>G intronic variant with breast cancer (BC) risk and prognosis and to verify the molecular role and networks of this lncRNA in BC by bioinformatics gene analysis. METHODS: Serum CDKN2B-AS1 relative expression and rs2383207 genotypes were determined in 214 unrelated women (104 primary BC and 110 controls) using real-time PCR. Sixteen BC studies from The Cancer Genome Atlas (TCGA) including 8925 patients were also retrieved for validation of results. RESULTS: CDKN2B-AS1 serum levels were upregulated in the BC patients relative to controls. A/A genotype carriers were three times more likely to develop BC under homozygous (OR = 3.27, 95% CI 1.20-8.88, P = 0.044) and recessive (OR = 3.17, 95% CI 1.20-8.34, P = 0.013) models. G/G homozygous patients had a higher expression level [median and quartile values were 3.14 (1.52-4.25)] than A/G [1.42 (0.93-2.35)] and A/A [1.62 (1.33-2.51)] cohorts (P = 0.006). The Kaplan-Meier curve also revealed a higher mean survival duration of G/G cohorts (20.6 months) compared to their counterparts (A/A: 15.8 and A/G: 17.2 months) (P < 0.001). Consistently, BC data sets revealed better survival in cohorts with high expression levels (P = 0.003). Principal component analysis (PCA) showed a deviation of patients who had shorter survival towards A/A and A/G genotypes, multiple lesions, advanced stage, lymphovascular invasion, and HER2+ receptor staining. Ingenuity Pathway Analysis (IPA) showed key genes highly enriched in BC with CDKN2B-AS1. CONCLUSIONS: The findings support the putative role of CDKN2B-AS1 as an epigenetic marker in BC and open a new avenue for its potential use as a therapeutic molecular target in this type of cancer.

Frequency and genotyping of alpha thalassemia in individuals undergoing premarital screening.

OBJECTIVE: To evaluate the frequency of alpha thalassemia and detect mutations in the alpha genes in individuals undergoing premarital screening. METHODS: The cross-sectional study was conducted at King Fahad Central Hospital, Jazan, Saudi Arabia, from January 2018 to May 2019, and comprised blood samples of individuals visiting the premarital screening clinic. The samples were analyzed for complete blood counts and haemoglobin electrophoresis. Molecular analysis of samples suspected for alpha thalassemia was done using alpha-globin StripAssay kit. Data was anlaysed using SPSS 20. RESULTS: Of the 3,970 samples analysed, 1,859(46.83%) were from males and 2,111(53.17%) from females. The overall frequency of suspected alpha thalassemia was 4.43% based upon haematological parameters including complete blood count and haemoglobin electrophoresis. Overall, 80 suspected samples were selected for genetic analyses, and, of them, 76 (95%) were positive for deletional and non-deletional mutations of alpha-globin genes, while 4 (5%) were negative for any of the 21 mutations tested. CONCLUSIONS: Alpha thalassemia was found to be highly prevalent in the study area.

Kelch 13-propeller polymorphisms in Plasmodium falciparum from Jazan region, southwest Saudi Arabia.

BACKGROUND: Artemisinin-based combination therapy (ACT) is recommended at the initial phase for treatment of Plasmodium falciparum, to reduce morbidity and mortality in all countries where malaria is endemic. Polymorphism in portions of P. falciparum gene encoding kelch (K13)-propeller domains is associated with delayed parasite clearance after ACT. Of about 124 different non-synonymous mutations, 46 have been identified in Southeast Asia (SEA), 62 in sub-Saharan Africa (SSA) and 16 in both the regions. This is the first study designed to analyse the prevalence of polymorphism in the P. falciparum k13-propeller domain in the Jazan region of southwest Saudi Arabia, where malaria is endemic. METHODS: One-hundred and forty P. falciparum samples were collected from Jazan region of southwest Saudi Arabia at three different times: 20 samples in 2011, 40 samples in 2016 and 80 samples in 2020 after the implementation of ACT. Plasmodium falciparum kelch13 (k13) gene DNA was extracted, amplified, sequenced, and analysed using a basic local alignment search tool (BLAST). RESULTS: This study obtained 51 non-synonymous (NS) mutations in three time groups, divided as follows: 6 single nucleotide polymorphisms (SNPs) '11.8%' in samples collected in 2011 only, 3 (5.9%) in 2011and 2016, 5 (9.8%) in 2011 and 2020, 5 (9.8%) in 2016 only, 8 (15.7%) in 2016 and 2020, 14 (27.5%) in 2020 and 10 (19.6%) in all the groups. The BLAST revealed that the 2011 isolates were genetically closer to African isolates (53.3%) than Asian ones (46.7%). Interestingly, this proportion changed completely in 2020, to become closer to Asian isolates (81.6%) than to African ones (18.4%). CONCLUSIONS: Despite the diversity of the identified mutations in the k13-propeller gene, these data did not report widespread artemisinin-resistant polymorphisms in the Jazan region where these samples were collected. Such a process would be expected to increase frequencies of mutations associated with the resistance of ACT.

Tobacco Smoke Carcinogens Induce DNA Repair Machinery Function Loss: Protection by Carbon Nanotubes.

PURPOSE: DNA damage is a continuous process occurring within the cells caused by intrinsic and extrinsic factors, but it gets repaired regularly. If the DNA repair process is faulty, the incidences of damages/mutations can accumulate in cells resulting in cell transformation. It is hypothesized that the negative variations in DNA repair pathways in even at one point viz. genetic, translational or posttranslational stage may fairly be crucial for the beginning and development of carcinogenesis. Therefore, we investigated the potential of tobacco specific nitrosamines (TSNs) related carcinogens to interact with the enzymes involved in DNA repair mechanisms in the current study. METHODS: The derivatives of cigarettes' smoke like NNK and NNAL are very well known and recognized carcinogens. Therefore, almost 120 enzymes playing crucial role in the DNA repair process have been analysed for their reactivity with NNK and NNAL. RESULTS: The molecular docking study helped to screen out,  07 possible DNA repair enzyme targets for NNK, and 12for NNAL. Present study revealed the loss of activity of DNA repair enzymes in the presence of NNK and NNAL, and this accumulation may induce the tendency of DNA damage which can lead the transformation of exposed normal cells in to cancerous cells. This study also demonstrated the protective potential of nanoparticles like SWCNTs/MWCNTs against TSN's induced toxicity; here SWCNT against NNK (-17.16 Kcal/Mol) and MWCNT against NNK -17.01 Kcal/Mol were showing maximum binding affinities than the known biomolecular target of NNK 1UGH (Uracil-DNA glycosylase,-7.82Kcal/Mol). CONCLUSION: CNTs can be applied as chemo-preventive agents against environmental and tobacco induced carcinogens owing to their scavenging potential and warrants for in vivo and in vitro experimental validation of the results obtained from the present study.
.

Prognostic value of the miRNA-27a and PPAR/RXRα signaling axis in patients with thyroid carcinoma.

The authors aimed to evaluate the prognostic value of miRNA-27a (miR-27a), peroxisome proliferator-activated receptor alpha/gamma (PPARα/γ) and retinoid X receptor alpha (RXRα) tissue expression in patients with thyroid carcinoma. The expression levels were quantified in 174 archived thyroid specimens using real-time quantitative PCR. Downregulation of miR-27a was associated with lymph node stage and multifocality. PPARα expression was associated with histopathological type, tumor size and lymph node invasion. Moreover, RXRα expression was lower in patients who underwent total/subtotal thyroidectomy or received radioactive iodine treatment. Patients with upregulated miR-27a and downregulated RXRα showed a higher frequency of advanced lymph node stage and relapse by cluster analysis. Both miR-27a and PPARα/RXRα showed association with different poor prognostic indices in thyroid cancer patients.

Ameliorative effect of Boesenbergin A, a chalcone isolated from Boesenbergia rotunda (Fingerroot) on oxidative stress and inflammation in ethanol-induced gastric ulcer in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Boesenbergia rotunda (L.) Mansf. Kulturpfl., previously known as Boesenbergia pandurata (Family: Zingiberaceae) is a ginger species, locally known as fingerroot. It is an integral part of Southeast Asian traditional medicine in alleviating many gastrointestinal disorders such as flatulence, carminative, stomach ache, dyspepsia, and peptic ulcer. AIM OF THE STUDY: Earlier we have investigated the cytoprotective effect of Boesenbergia rotunda extract. In the present study, we investigated the gastroprotection activity of Boesenbergin A (BA), a chalcone isolated from Boesenbergia rotunda extract in ethanol-induced ulcer model in rats. Besides, the contribution of anti-inflammatory and anti-oxidant ability of BA as probable mechanisms involved in the anti-ulcer activity, also been studied. MATERIALS AND METHODS: BA was orally administered in rats before ulcer induction with ethanol. The lesions of the gastric mucosa were evaluated macroscopically and histopathologically. The efficiency of BA in mucus production, NO production, PGE2 synthesis, mucosal nonprotein sulphydryls, glutathione (GSH) level, and lipid peroxidation (MDA) level were studied. The involvement of the anti-inflammatory capacity of BA was analyzed by using the measurement of cytokines such as TNF-α and IL-6. Finally, the expression of biomarkers such as HSP 70 and iNOS was analyzed at the transcriptional and translational levels. RESULTS: We confirmed the protective capacity of BA via the reduction of ulcerated and haemorrhagic areas. It has induced the protection through lowering GSH, MDA and increased NP-SH level. The plasma NO levels were significantly less in BA treated rats. Both cytokines TNF-α and IL-6 were decreased together with elevated PGE2. Upregulation of HSP and downregulation of iNOS were determined in immunohistochemical and gene expression studies CONCLUSIONS: The current results suggest that the prophylactic effect found with BA is due to (i) boosting of gastric mucus production and suppression of inflammatory mediators, via pro-inflammatory cytokines and (ii) modulating the oxidative stress response. The usefulness of Boesenbergia rotunda in folk medicine in treating ulcers partially could be due to the presence of this chalcone.

Girinimbine from curry leaves promotes gastro protection against ethanol induced peptic ulcers and improves healing via regulation of anti-inflammatory and antioxidant mechanisms.

Curry leaves (Murraya koenigii) are a leafy spice used in Indian cookery for its fragrant aroma. Many bioactive functional compounds have been identified, and among them carbazole alkaloids have attracted wide attention due to their multi-dimensional medicinal value. Even though it has been established that the carbazole alkaloid is responsible for the anti-ulcer effect showed by this culinary herb, there is no further evidence to say which phytochemical is responsible for this. In the present study, we investigated the gastro-protective effects and mechanism of girinimbine, a major carbazole alkaloid present in curry leaves. Rats were administered with ethanol to produce gastric ulcers, and the prophylactic effect of girinimbine was evaluated. A macroscopic and histological examination was carried out to examine the lesions. Furthermore, the mucus production, NO production, PGE2 synthesis, mucosal nonprotein sulphydryls, glutathione (GSH) level, lipid peroxidation (MDA) level and COX inhibition were assessed. In addition, in particular, TNF-α and IL-6, two important cytokines, were evaluated. Immunohistochemical and gene expression studies were conducted to determine the HSP70 and iNOS biomarkers. Our results indicated that girinimbine significantly reduced the ulcer index and totally safeguarded the mucosa from lesions. The protective effect of girinimbine was complemented through the restoration of the reduced GSH and NP-SH level. This was associated with a reduction of MDA, which was elevated by the administration of ethanol. Pre-treatment of the ethanol induced ulcer with girinimbine reduced the NO concentration in the plasma and elevated PGE2 together with a decreased level of TNF-α and IL-6. Girinimbine had shown suppressing effects on COX-2 enzymes, but not on COX-1. In addition, significantly upregulated HSP70 and downregulated iNOS were observed in girinimbine treated rat tissue at both the transcriptional and translational level. Our results clearly indicated that girinimbine displayed a significant gastro-protection effect, via the capacity to inhibit inflammatory responses and antioxidant potential.

Influence of Interleukin-6 (IL-6) Promoter Gene Polymorphisms (-174G>C, -572G>C, and -597G>A) on IL-6 Plasma Levels and Their Impact in the Development of Acute Ischemic Stroke in Young Indians.

This study aimed to determine whether there is an influence of interleukin 6 (IL-6) gene promoter polymorphisms on IL-6 plasma levels and its role in the development of ischemic stroke in young Indians. One hundred young patients with ischemic stroke (age ≥ 45 years) and equal number of age- and sex-matched controls were genotyped for 174G>C, -572G>C, and -597G>A promoter polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. Plasma IL-6 levels were measured by enzyme-linked immunosorbent assay. Plasma IL-6 levels were significantly higher in patients as compared to controls (patients: 28.61 ± 8.61 pg/mL, controls: 7.60 ± 4.10 pg/mL, P = .001). Both -174G>C (allelic χ2/P value: 4.79/.028, genotypic χ2/P value: 5.3/.021) and -572G>C (allelic χ2/P value: 9.63/.00113 Genotypic χ2/P value: 74/.0002) polymorphisms exhibited genotypic as well as allelic significant association with the disease phenotype. Comparison was made between patients and controls for all 3 polymorphisms using a recessive model with respect to plasma IL-6 levels; no polymorphism showed any significant correlative association with the increased IL-6 levels (P = .31, .51, .32). Interleukin 6 is an inflammatory marker that is considerably influenced by nongenetic factors and is not a good candidate gene for studying genetic components associated with ischemic stroke. It seems that the variability in IL-6 levels is an integrated effect of nongenetic influences and the inflammatory events that follow ischemic stroke instead of being its cause. It is suggested that there is no direct association between -174G>C, -572G>C, and -597G>A polymorphisms and elevated IL-6 levels in the development of ischemic stroke.

Knockdown resistance mutations contributing to pyrethroid resistance in Aedes aegypti population, Saudi Arabia.

BACKGROUND: Dengue is endemic in Saudi Arabia especially in Jeddah, Makkah, Asir, and Jazan areas where pyrethroids are widely used to control the vector, Aedes aegypti. Resistance of Ae. aegypti to pyrethroid insecticides has been reported from most of these areas. AIMS: The present study was carried out in Jazan region in south-west Saudi Arabia to explore the resistance status of Ae. aegypti to pyrethroids and the consequent underlying mechanisms. METHODS: Three pyrethroids (permethrin, lambda-cyhalothrin, and cyfluthrin) were used to investigate the resistance status of Ae. aegypti adults following World Health Organization (WHO) standard methods: PCR and sequencing techniques were used to detect the S989P, V1016G and F1534C kdr mutations. RESULTS: Ae. aegypti populations were susceptible to cyfluthrin and having a possibility of resistance to permethrin while resistant to lambda-cyhalothrin. Three potential kdr mutations were detected for the first time in Ae. aegypti population, F1534C, V106G, and S989P. It was found that F1534C often co-exists with V1016G and this haplotype was strongly associated with permethrin and lambda-cyhalothrin resistance. On the other hand, S989P mutation was detected as RR in 18.8% with a low-frequency rate (R) of 18.8%, and in 55.5% as R with 58.3% frequency rate in permethrin and lambda-cyhalothrin- resistant female mosquitoes, respectively. CONCLUSIONS: Early detection of resistance alleles should be considered the essential tool for the successful implementation of insecticide resistance management strategies by providing early warning of insect resistance.

Niacin deficiency modulates genes involved in cancer: Are smokers at higher risk?

The role of niacin's metabolite, nicotinamide adenine dinucleotide (NAD), in DNA repair via base-excision repair pathway is well documented. We evaluated if niacin deficiency results in genetic instability in normal human fetal lung fibroblasts (MRC-5), and further, does it leads to enhanced accumulation of cigarette smoke-induced genetic damage? MRC-5 cells were grown discretely in niacin-proficient/deficient media, and exposed to nicotine-derived nitrosamine ketone (NNK, a cigarette smoke carcinogen). Niacin deficiency abated the NAD polymerization, augmented the spontaneous induction of micronuclei (MN) and chromosomal aberrations (CA) and raised the expression of 10 genes and suppressed 12 genes involved in different biological functions. NNK exposure resulted in genetic damage as measured by the induction of MN and CA in cells grown in niacin-proficient medium, but the damage became practically marked when niacin-deficient cells were exposed to NNK. NNK exposure raised the expression of 16 genes and suppressed the expression of 56 genes in cells grown in niacin-proficient medium. NNK exposure to niacin-deficient cells raised the expression of eight genes including genes crucial in promoting cancer such as FGFR3 and DUSP1 and suppressed the expression of 33 genes, including genes crucial in preventing the onset and progression of cancer like RASSF2, JUP, and IL24, in comparison with the cells grown in niacin-proficient medium. Overall, niacin deficiency interferes with the DNA damage repair process induced by chemical carcinogens like NNK, and niacin-deficient population are at the higher risk of genetic instability caused by cigarette smoke carcinogen NNK.