Elucidating the role of EPPK1 in lung adenocarcinoma development.

BACKGROUND: We recently found that epiplakin 1 (EPPK1) alterations were present in 12% of lung adenocarcinoma (LUAD) cases and were associated with a poor prognosis in early-stage LUAD when combined with other molecular alterations. This study aimed to identify a probable crucial role for EPPK1 in cancer development. METHODS: EPPK1 mRNA and protein expression was analyzed with clinical variables. Normal bronchial epithelial cell lines were exposed to cigarette smoke for 16 weeks to determine whether EPPK1 protein expression was altered after exposure. Further, we used CRISPR-Cas9 to knock out (KO) EPPK1 in LUAD cell lines and observed how the cancer cells were altered functionally and genetically. RESULTS: EPPK1 protein expression was associated with smoking and poor prognosis in early-stage LUAD. Moreover, a consequential mesenchymal-to-epithelial transition was observed, subsequently resulting in diminished cell proliferation and invasion after EPPK1 KO. RNA sequencing revealed that EPPK1 KO induced downregulation of 11 oncogenes, 75 anti-apoptosis, and 22 angiogenesis genes while upregulating 8 tumor suppressors and 12 anti-cell growth genes. We also observed the downregulation of MYC and upregulation of p53 expression at both protein and RNA levels following EPPK1 KO. Gene ontology enrichment analysis of molecular functions highlighted the correlation of EPPK1 with the regulation of mesenchymal cell proliferation, mesenchymal differentiation, angiogenesis, and cell growth after EPPK1 KO. CONCLUSIONS: Our data suggest that EPPK1 is linked to smoking, epithelial to mesenchymal transition, and the regulation of cancer progression, indicating its potential as a therapeutic target for LUAD.

PLAAT1 deficiency alleviates high-fat diet-induced hepatic lipid accumulation in mice.

The phospholipase A and acyltransferase (PLAAT) family is composed of three isoforms in mice (PLAAT1, 3, and 5), all of which function as phospholipid-metabolizing enzymes exhibiting phospholipase A1 /A2 and acyltransferase activities. Plaat3-deficient (Plaat3-/- ) mice were previously reported to show lean phenotype and remarkable hepatic fat accumulation under high-fat diet (HFD) feeding, while Plaat1-/- mice have not been analyzed. In the present study, we generated Plaat1-/- mice and investigated the effects of PLAAT1 deficiency on HFD-induced obesity, hepatic lipid accumulation, and insulin resistance. After HFD treatment, PLAAT1 deficiency caused a lower body weight gain compared to wild-type mice. Plaat1-/- mice also showed reduced liver weight with negligible hepatic lipid accumulation. In accordance with these findings, PLAAT1 deficiency improved HFD-induced hepatic dysfunction and lipid metabolism disorders. Lipidomics analysis in the liver revealed that in Plaat1-/- mice, the levels of various glycerophospholipids tended to increase, while all classes of lysophospholipids examined tended to decrease, suggesting that PLAAT1 functions as phospholipase A1 /A2 in the liver. Interestingly, the HFD treatment of wild-type mice significantly increased the mRNA level of PLAAT1 in the liver. Furthermore, the deficiency did not appear to elevate the risk of insulin resistance in contrast to PLAAT3 deficiency. These results suggested that the suppression of PLAAT1 improves HFD-induced overweight and concomitant hepatic lipid accumulation.

Pharmacokinetic-Pharmacodynamic Determinants of Clinical Outcomes for Rifampin-Resistant Tuberculosis: A Multisite Prospective Cohort Study.

BACKGROUND: Rifampin-resistant and/or multidrug-resistant tuberculosis (RR/MDR-TB) treatment requires multiple drugs, and outcomes remain suboptimal. Some drugs are associated with improved outcome. It is unknown whether particular pharmacokinetic-pharmacodynamic relationships predict outcome. METHODS: Adults with pulmonary RR/MDR-TB in Tanzania, Bangladesh, and the Russian Federation receiving local regimens were enrolled from June 2016 to July 2018. Serum was collected after 2, 4, and 8 weeks for each drug's area under the concentration-time curve over 24 hours (AUC0-24). Quantitative susceptibility of the M. tuberculosis isolate was measured by minimum inhibitory concentrations (MICs). Individual drug AUC0-24/MIC targets were assessed by adjusted odds ratios (ORs) for favorable treatment outcome, and hazard ratios (HRs) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into 4 clusters by AUC0-24/MIC exposures. RESULTS: Among 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC0-24/MIC target of 58 was associated with favorable treatment outcome (OR, 3.75; 95% confidence interval, 1.21-11.56; P = .022); levofloxacin AUC0-24/MIC of 118.3, clofazimine AUC0-24/MIC of 50.5, and pyrazinamide AUC0-24 of 379 mg × h/L were associated with faster culture conversion (HR >1.0, P < .05). Other individual drug exposures were not predictive. Clustering by AUC0-24/MIC revealed that those with the lowest multidrug exposures had the slowest culture conversion. CONCLUSIONS: Amidst multidrug regimens for RR/MDR-TB, serum pharmacokinetics and M. tuberculosis MICs were variable, yet defined parameters to certain drugs-fluoroquinolones, pyrazinamide, clofazimine-were predictive and should be optimized to improve clinical outcome. CLINICAL TRIALS REGISTRATION: NCT03559582.

Phyllanthus emblica (Amla) methanolic extract regulates multiple checkpoints in 15-lipoxygenase mediated inflammopathies: Computational simulation and in vitro evidence.

Amla (Phyllanthus emblica) has long been used in traditional folk medicine to prevent and cure a variety of inflammatory diseases. In this study, the antioxidant activity (DPPH scavenging and reducing power), anti-inflammatory activity (RBC Membrane Stabilization and 15-LOX inhibition), and anticoagulation activity (Serin protease inhibition and Prothrombin Time assays) of the methanolic extract of amla were conducted. Amla exhibited a substantial amount of phenolic content (TPC: 663.53 mg GAE/g) and flavonoid content (TFC: 418.89 mg GAE/g). A strong DPPH scavenging effect was observed with an IC50 of 311.31 µg/ml as compared to standard ascorbic acid with an IC50 of 130.53 µg/ml. In reducing power assay, the EC50 value of the extract was found to be 196.20 µg/ml compared to standard ascorbic acid (EC50 = 33.83 µg/ml). The IC50 value of the RBC membrane stabilization and 15-LOX assays was observed as 101.08 µg/ml (IC50 of 58.62 µg/ml for standard aspirin) and 195.98 µg/ml (IC50 of 19.62 µg/ml for standard quercetin), respectively. The extract also strongly inhibited serine protease (trypsin) activity with an IC50 of 505.81 µg/ml (IC50 of 295.44 µg/ml for standard quercetin). The blood coagulation time (PTT) was found to be 11.91 min for amla extract and 24.11 min for standard Warfarin. Thus, the findings of an in vitro study revealed that the methanolic extract of amla contains significant antioxidant, anti-inflammatory, and anticoagulation activity. Furthermore, in silico docking and simulation of reported phytochemicals of amla with human 15-LOXA and 15-LOXB were carried out to validate the anti-inflammatory activity of amla. In this analysis, epicatechin and catechin showed greater molecular interaction and were considerably stable throughout the 100 ns simulation with 15-lipoxygenase A (15-LOXA) and 15-lipoxygenase B (15-LOXB) respectively.

Roles of Endocannabinoids and Endocannabinoid-Like Molecules in Energy Homeostasis and Metabolic Regulation: A Nutritional Perspective.

The endocannabinoid system is involved in signal transduction in mammals. It comprises principally G protein-coupled cannabinoid receptors and their endogenous agonists, called endocannabinoids, as well as the enzymes and transporters responsible for the metabolism of endocannabinoids. Two arachidonic acid-containing lipid molecules, arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol, function as endocannabinoids. N-acylethanolamines and monoacylglycerols, in which the arachidonic acid chain is replaced with a saturated or monounsaturated fatty acid, are not directly involved in the endocannabinoid system but exhibit agonistic activities for other receptors. These endocannabinoid-like moleculesinclude palmitoylethanolamide, oleoylethanolamide (OEA), and 2-oleoylglycerol. Endocannabinoids stimulate feeding behavior and the anabolism of lipids and glucose, while OEA suppresses appetite. Both central and peripheral systems are included in these nutritional and metabolic contexts. Therefore, they have potential in the treatment and prevention of obesity. We outline the structure, metabolism, and biological activities of endocannabinoids and related molecules, and focus on their involvement in energy homeostasis and metabolic regulation.

Disability-friendly healthcare at public health facilities in Bangladesh: a mixed-method study to explore the existing situation.

BACKGROUND: Several strategies and policies are being implemented in Bangladesh to address the healthcare needs of people with disabilities, who comprise about 10% of the country's total population. However, these measures are not adequate to provide accessible or friendly healthcare to the people with disabilities. This study aimed to explore the disability-friendliness of healthcare facilities, and the challenges of people with disabilities in terms of access to 1) information and communication, 2) access to infrastructure, and 3) providers' capacity in Bangladesh. METHODS: An explanatory sequential mixed-method study was conducted, including a cross-sectional survey of healthcare facilities, followed by structured-interview with people with disabilities and healthcare managers, and qualitative interviews among people with disabilities or their caregivers, healthcare providers (HCPs), policymakers, and community leaders. Data were collected from 150 public healthcare (primary-to-tertiary) facilities and from 300 people with disabilities in 16 districts across Bangladesh between January-December 2019. An observational checklist and structured questionnaires were used to assess the situation of healthcare facilities, and literature-guided guidelines were used for qualitative interviews. During analysis, the disability-friendliness of healthcare facilities were quantified through a scoring system, and thematic analysis of qualitative data was performed to identify the challenges of implementing disability-friendly healthcare (DFHC). RESULTS: The score for providing DFHC was low across all the four objectives in the healthcare facilities. The highest score (mean percentage) was observed in the infrastructure domain: 29.3 ± 20.5, followed by communication: 18.2 ± 4.8, and information: 14.6 ± 6.22, and the lowest (0.93 ± 7.1) score was for capacity of the HCPs to provide DFHC. Mean percentage scores for access to 13 infrastructure points were low, and extremely low scores were found in areas such as access to elevators (5.6 ± 5.0), ticket counters (7.3 ± 17.7) and toilets (10.6 ± 9.3). Furthermore, about 59.1% of people with disabilities expressed dissatisfaction regarding access to information and communication. The majority (98.2%) recommended that training of HCPs can improve the situation. CONCLUSION: This study revealed that most of the public health facilities in Bangladesh were not disability-friendly. Findings can inform development of a national disability-friendly policy with implementation guidelines.

Prevalence of and factors associated with insufficient physical activity among adolescents: evidence from a nationwide survey in Bangladesh.

The World Health Organization set a target of a 15% relative reduction in the prevalence of insufficient physical activity (IPA) by 2025 among adolescents and adults globally. In Bangladesh, there are no national estimates of the prevalence of IPA among adolescents. The aim of this study was to estimate the prevalence of and risk factors associated with IPA among adolescent girls and boys. Data for 4865 adolescent girls and 4907 adolescent boys, collected as a part of a National Nutrition Surveillance in 2018-19, were analysed for this study. A modified version of the Global Physical Activity Questionnaire (GPAQ) was used to collect physical activity data. The World Health Organization recommended cut-off points were used to estimate the prevalence of IPA. Bivariate and multivariable logistic regression was performed to identify factors associated with IPA. Prevalences of IPA among adolescent girls and boys were 50.3% and 29.0%, respectively, and the prevalence was significantly higher among early adolescents (10-14 years) than late adolescents (15-19 years) among both boys and girls. The IPA prevalence was highest among adolescents living in non-slum urban areas (girls: 77.7%; boys: 64.1%). For both boys and girls, younger age, non-slum urban residence, higher paternal education and increased television viewing time were significantly associated with IPA. Additionally, residing in slums was significantly associated with IPA only among the boys. Higher maternal education was associated with IPA only among the girls. This study identified several modifiable risk factors associated with IPA among adolescent boys and girls in Bangladesh. These factors should be addressed through comprehensive public health interventions to promote physical activity among adolescent girls and boys.

Synthesis of Sugar and Nucleoside Analogs and Evaluation of Their Anticancer and Analgesic Potentials.

Chemical modification of sugars and nucleosides has a long history of producing compounds with improved selectivity and efficacy. In this study, several modified sugars (2-3) and ribonucleoside analogs (4-8) have been synthesized from α-d-glucose in a total of 21 steps. The compounds were tested for peripheral anti-nociceptive characteristics in the acetic acid-induced writhing assay in mice, where compounds 2, 7, and 8 showed a significant reduction in the number of writhes by 56%, 62%, and 63%, respectively. The compounds were also tested for their cytotoxic potential against human HeLa cell line via trypan blue dye exclusion test followed by cell counting kit-8 (CCK-8) assay. Compound 6 demonstrated significant cytotoxic activity with an IC50 value of 54 µg/mL. Molecular docking simulations revealed that compounds 2, 7, and 8 had a comparable binding affinity to cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. Additionally, the bridged nucleoside analogs 7 and 8 potently inhibited adenosine kinase enzyme as well, which indicates an alternate mechanistic pathway behind their anti-nociceptive action. Cytotoxic compound 6 demonstrated strong docking with cancer drug targets human cytidine deaminase, proto-oncogene tyrosine-protein kinase Src, human thymidine kinase 1, human thymidylate synthase, and human adenosine deaminase 2. This is the first ever reporting of the synthesis and analgesic property of compound 8 and the cytotoxic potential of compound 6.

Nutrition and Food Security in Bangladesh: Achievements, Challenges, and Impact of the COVID-19 Pandemic.

BACKGROUND: Bangladesh has experienced remarkable transformation in demographic, health, and nutritional status of the population. The changes have exposed the population to a number of challenges, the detrimental effect of which on health and nutrition is likely to be increased by the coronavirus disease 2019 (COVID-19) pandemic. We provide an overview of health and nutritional challenges in Bangladesh in relation to demographic transition and the COVID-19 pandemic. METHODS: We identified and reviewed recent reports, published articles, and pertinent gray literature on nutrition and food security in Bangladesh to provide historical and contextual information. RESULTS: The review identifies the progress as well as existing burden regarding nutrition and food security in Bangladesh and highlights the challenges in the coming days in regard to population growth and the COVID-19 pandemic. The country is on track to reduce all forms of childhood undernutrition, while the proportion of nutrition-related noncommunicable diseases is rising owing to changes in dietary intake, low physical activity, and sedentary lifestyle. CONCLUSIONS: Despite remarkable progress, health and nutritional status of the population in Bangladesh faces challenges, particularly in relation to demographic transition and compounded by the COVID-19 pandemic, which require concerted attention from policymakers as well as stakeholders.

Xpert Ultra Assay on Stool to Diagnose Pulmonary Tuberculosis in Children.

BACKGROUND: The World Health Organization recommends the Xpert MTB/RIF Ultra assay for diagnosing pulmonary tuberculosis (PTB) in children. Though stool is a potential alternative to respiratory specimens among children, the diagnostic performance of Xpert Ultra on stool is unknown. Thus, we assessed the diagnostic performance of Xpert Ultra on stool to diagnose PTB in children. METHODS: We conducted a cross-sectional study among consecutively recruited children (< 15 years of age) with presumptive PTB admitted in 4 tertiary care hospitals in Dhaka, Bangladesh, between January 2018 and April 2019. Single induced sputum and stool specimens were subjected to culture, Xpert, and Xpert Ultra. We considered children as bacteriologically confirmed on induced sputum if any test performed on induced sputum was positive for Mycobacterium tuberculosis and bacteriologically confirmed if M. tuberculosis was detected on either induced sputum or stool. RESULTS: Of 447 children, 29 (6.5%) were bacteriologically confirmed on induced sputum and 72 (16.1%) were bacteriologically confirmed. With "bacteriologically confirmed on induced sputum" as a reference, the sensitivity and specificity of Xpert Ultra on stool were 58.6% and 88.1%, respectively. Xpert on stool had sensitivity and specificity of 37.9% and 100.0%, respectively. Among bacteriologically confirmed children, Xpert Ultra on stool was positive in 60 (83.3%), of whom 48 (80.0%) had "trace call." CONCLUSIONS: In children, Xpert Ultra on stool has better sensitivity but lesser specificity than Xpert. A high proportion of Xpert Ultra assays positive on stool had trace call. Future longitudinal studies on clinical evolution are required to provide insight on the management of children with trace call.

Source, distribution and emerging threat of micro- and nanoplastics to marine organism and human health: Socio-economic impact and management strategies.

The nature of micro- and nanoplastics and their harmful consequences has drawn significant attention in recent years in the context of environmental protection. Therefore, this paper aims to provide an overview of the existing literature related to this evolving subject, focusing on the documented human health and marine environment impacts of micro- and nanoplastics and including a discussion of the economic challenges and strategies to mitigate this waste problem. The study highlights the micro- and nanoplastics distribution across various trophic levels of the food web, and in different organs in infected animals which is possible due to their reduced size and their lightweight, multi-coloured and abundant features. Consequently, micro- and nanoplastics pose significant risks to marine organisms and human health in the form of cytotoxicity, acute reactions, and undesirable immune responses. They affect several sectors including aquaculture, agriculture, fisheries, transportation, industrial sectors, power generation, tourism, and local authorities causing considerable economic losses. This can be minimised by identifying key sources of environmental plastic contamination and educating the public, thus reducing the transfer of micro- and nanoplastics into the environment. Furthermore, the exploitation of the potential of microorganisms, particularly those from marine origins that can degrade plastics, could offer an enhanced and environmentally sound approach to mitigate micro- and nanoplastics pollution.

A palladium-catalyzed Barluenga cross-coupling - reductive cyclization sequence to substituted indoles.

A short and flexible synthesis of substituted indoles employing two palladium-catalyzed reactions, a Barluenga cross-coupling of p-tosylhydrazones with 2-nitroarylhalides followed by a palladium-catalyzed, carbon monoxide-mediated reductive cyclization has been developed. A one-pot, two-step methodology was further developed, eliminating isolation and purification of the cross-coupling product. This was accomplished by utilizing the initially added 0.025 equivalents of bis(triphenylphosphine)palladium dichloride, thus serving a dual role in the cross-coupling and the reductive cyclization. It was found that addition of 1,3-bis(diphenylphosphino)propane and carbon monoxide after completion of the Barluenga reaction afforded, in most cases, significantly better overall yields.

Genomic Underpinnings of Tumor Behavior in In Situ and Early Lung Adenocarcinoma.

Rationale: We have a limited understanding of the molecular underpinnings of early adenocarcinoma (ADC) progression. We hypothesized that the behavior of early ADC can be predicted based on genomic determinants.Objectives: To identify genomic alterations associated with resected indolent and aggressive early lung ADCs.Methods: DNA was extracted from 21 ADCs in situ (AISs), 27 minimally invasive ADCs (MIAs), and 54 fully invasive ADCs. This DNA was subjected to deep next-generation sequencing and tested against a custom panel of 347 cancer genes.Measurements and Main Results: Sequencing data was analyzed for associations among tumor mutation burden, frequency of mutations or copy number alterations, mutation signatures, intratumor heterogeneity, pathway alterations, histology, and overall survival. We found that deleterious mutation burden was significantly greater in invasive ADC, whereas more copy number loss was observed in AIS and MIA. Intratumor heterogeneity establishes early, as in AIS. Twenty-one significantly mutated genes were shared among the groups. Mutation signature profiling did not vary significantly, although the APOBEC signature was associated with ADC and poor survival. Subclonal KRAS mutations and a gene signature consisting of PIK3CG, ATM, EPPK1, EP300, or KMT2C mutations were also associated with poor survival. Mutations of KRAS, TP53, and NF1 were found to increase in frequency from AIS and MIA to ADC. A cancer progression model revealed selective early and late drivers.Conclusions: Our results reveal several genetic driver events, clonality, and mutational signatures associated with poor outcome in early lung ADC, with potential future implications for the detection and management of ADC.

Involvement of the γ Isoform of cPLA2 in the Biosynthesis of Bioactive N-Acylethanolamines.

Arachidonylethanolamide (anandamide) acts as an endogenous ligand of cannabinoid receptors, while other N-acylethanolamines (NAEs), such as palmitylethanolamide and oleylethanolamide, show analgesic, anti-inflammatory, and appetite-suppressing effects through other receptors. In mammalian tissues, NAEs, including anandamide, are produced from glycerophospholipid via N-acyl-phosphatidylethanolamine (NAPE). The ɛ isoform of cytosolic phospholipase A2 (cPLA2) functions as an N-acyltransferase to form NAPE. Since the cPLA2 family consists of six isoforms (α, ß, γ, δ, ɛ, and ζ), the present study investigated a possible involvement of isoforms other than ɛ in the NAE biosynthesis. Firstly, when the cells overexpressing one of the cPLA2 isoforms were labeled with [14C]ethanolamine, the increase in the production of [14C]NAPE was observed only with the ɛ-expressing cells. Secondly, when the cells co-expressing ɛ and one of the other isoforms were analyzed, the increase in [14C]N-acyl-lysophosphatidylethanolamine (lysoNAPE) and [14C]NAE was seen with the combination of ɛ and γ isoforms. Furthermore, the purified cPLA2γ hydrolyzed not only NAPE to lysoNAPE, but also lysoNAPE to glycerophospho-N-acylethanolamine (GP-NAE). Thus, the produced GP-NAE was further hydrolyzed to NAE by glycerophosphodiesterase 1. These results suggested that cPLA2γ is involved in the biosynthesis of NAE by its phospholipase A1/A2 and lysophospholipase activities.

Cryopreservation Studies on Silver Carp (Hypophthalmichthys molitrix) Embryos.

BACKGROUND: Cryopreservation is an effective tool for the preservation of live biological materials. OBJECTIVE: This study examined the suitability of cryopreservation protocols and the effectiveness of ultrasound for silver carp embryos. MATERIALS AND METHODS: Embryos at three developmental stages were exposed to 10, 15, 20, and 25% of five cryoprotectants (CPAs), namely propylene glycol (PG), dimethylformamide (DFA), DMSO, MeOH, and ethylene glycol (EG) for 20 min. Embryos were exposed to twelve vitrification solutions (VSs) for 10 (five steps of 2 min), 15 (five steps of 3 min), 20 (five steps of 4 min) min. Embryos were also exposed to ultrasound in VSs prior to cooling for cryopreservation. RESULTS: Hatching rates decreased with increasing CPA concentrations while toxicity varied in the order of PG < DMSO < EG < MeOH < DFA. Tail elongation stage was more tolerant to CPA than 6-somites and morula stages. The survival of embryos exposed to ultrasound in VS was remarkably lower than in water. Embryos exposed to ultrasound in VSs under the best conditions did not response well after attempted vitrification. CONCLUSION: Ultrasound-mediated CPA impregnation could be effective but other innovative methods may be needed to attain successful cryopreservation.

Disruption in Circularity? Impact analysis of COVID-19 on ship recycling using Weibull tonnage estimation and scenario analysis method.

The sustainability of the ship recycling industry strongly linked with the global shipping market and international commodity flows. More than 80% of the End of Life (EoL) ships are dismantled in South Asian countries, namely Bangladesh, India, and Pakistan. Due to measures taken to minimize the propagation of the Coronavirus disease (COVID-19), an international supply chain is broken to a historic low, except for certain medical-related urgencies. Due to the disruption of global supply chains, the industry may submerge into uncertainty due to, perhaps, lack of adequate labor force to dismantle increased EoL ships and due to disturbances of vessel transportation to the recycling nations amid strong precautionary measures. Our estimate suggests that about 300 million Gross Tonnage (GT) available for demolition in the next five years and the inability to get them recycled would cost about 20 billion dollars. More importantly, South Asian recycling nations would suffer from economic losses and employment opportunities. In this study, we also apply a scenario analysis technique to understand the impact range of COVID-19 in the short term and in the long term. The disruption is viewed through a circular economy framework, identifying a critical lack of 'global scale' acknowledgment in the circular economy framework. This article suggests that a formalized global scale, paralleled with favorable policies, may reduce supply chain disruption and improve sustainable development in the receiving nations.

Synthesis, in vivo and in silico analgesic and anti-inflammatory studies of α-D-ribofuranose derivatives.

Five α-D-ribofuranose analogues (2, 3, 4, 5 and 6) were synthesized in good yields from 3-O-benzyl-4-C-(hydroxymethyl)-1, 2-O-isopropylidene-α-D-ribofuranose (1). The synthesized compounds were then subjected to analgesic, anti-inflammatory, antimicrobial and antioxidant assays. Compound 3 demonstrated 79.74% (P < 0.001) writhing inhibition and highest reaction time of 2.55 ± 0.13 min (P < 0.001) after 30 min of oral administration in peripheral and central analgesic assay, respectively, at 50 mg/kg dose. Compound 2 and 6 exhibited significant anti-inflammatory activity at 100 mg/kg dose with paw edema inhibition of 91.15% (P < 0.001) and 95.13% (P < 0.001), respectively, in 4th hour. The synthesized analogues did not show notable antioxidant and antibacterial properties. Molecular docking study revealed higher binding affinity of -8.1 kcal/mol and -8.9 kcal/mol of compound 3 towards cyclooxygenase-1 and phospholipase A2, respectively, compared to -7.7 and -7.6 kcal/mol respectively for corresponding native ligands. Compound 2 demonstrated binding affinity of -9.1 kcal/mol towards interleukin-1 receptor-associated kinase-4 compared to -8.7 kcal/mol of the native ligand. The molecular properties related to drug likeness of compounds were found to be within acceptable range. Synthesized D-ribofuranose analogues demonstrated promising analgesic and anti-inflammatory activities and further development may lead to new potent analgesic and anti-inflammatory agents.

Addition of olive (olea europaea) leaf extract as a source of natural antioxidant in mutton meatball stored at refrigeration temperature.

This study was aimed to evaluate the effects of using different levels of olive (Olea europaea) leaf extract on fresh and preserved mutton meatballs. Meatballs were divided into four different groups and treated as T0 (0), T1 (0.1), T2 (0.2) and T3 (0.3%), respectively based on olive leaf extract supplementation. Days of intervals of experiment were 0, 5, 10 days. Samples were preserved at 4˚C for up to 10 days. Different types of analysis such as, sensory (color, flavor, juiciness and overall acceptability), proximate composition (CP %), physicochemical (pH), biochemical (POV, FFA and TBARS) and microbiological (TVC, TCC and TYMC) were determined. Color, flavor and acceptability reduced significantly (p < 0.05) with the increase of the storage periods. Values of the studied quality parameters in all the treatment groups differed significantly (p < 0.05). Based on our findings 0.3% olive leaf extract is found suitable to add in mutton meatballs as a source of natural antioxidant.

Tobacco smoking induces cardiovascular mitochondrial oxidative stress, promotes endothelial dysfunction, and enhances hypertension.

Tobacco smoking is a major risk factor for cardiovascular disease and hypertension. It is associated with the oxidative stress and induces metabolic reprogramming, altering mitochondrial function. We hypothesized that cigarette smoke induces cardiovascular mitochondrial oxidative stress, which contributes to endothelial dysfunction and hypertension. To test this hypothesis, we studied whether the scavenging of mitochondrial H2O2 in transgenic mice expressing mitochondria-targeted catalase (mCAT) attenuates the development of cigarette smoke/angiotensin II-induced mitochondrial oxidative stress and hypertension compared with wild-type mice. Two weeks of exposure of wild-type mice with cigarette smoke increased systolic blood pressure by 17 mmHg, which was similar to the effect of a subpresssor dose of angiotensin II (0.2 mg·kg-1·day-1), leading to a moderate increase to the prehypertensive level. Cigarette smoke exposure and a low dose of angiotensin II cooperatively induced severe hypertension in wild-type mice, but the scavenging of mitochondrial H2O2 in mCAT mice completely prevented the development of hypertension. Cigarette smoke and angiotensin II cooperatively induced oxidation of cardiolipin (a specific biomarker of mitochondrial oxidative stress) in wild-type mice, which was abolished in mCAT mice. Cigarette smoke and angiotensin II impaired endothelium-dependent relaxation and induced superoxide overproduction, which was diminished in mCAT mice. To mimic the tobacco smoke exposure, we used cigarette smoke condensate, which induced mitochondrial superoxide overproduction and reduced endothelial nitric oxide (a hallmark of endothelial dysfunction in hypertension). Western blot experiments indicated that tobacco smoke and angiotensin II reduce the mitochondrial deacetylase sirtuin-3 level and cause hyperacetylation of a key mitochondrial antioxidant, SOD2, which promotes mitochondrial oxidative stress. NEW & NOTEWORTHY This work demonstrates tobacco smoking-induced mitochondrial oxidative stress, which contributes to endothelial dysfunction and development of hypertension. We suggest that the targeting of mitochondrial oxidative stress can be beneficial for treatment of pathological conditions associated with tobacco smoking, such as endothelial dysfunction, hypertension, and cardiovascular diseases.

Effective syntheses of 2',4'-BNANC monomers bearing adenine, guanine, thymine, and 5-methylcytosine, and the properties of oligonucleotides fully modified with 2',4'-BNANC.

We efficiently synthesized 2'-O,4'-C-aminomethylene-bridged nucleic acid (2',4'-BNANC) monomers bearing the four nucleobases, guanine, adenine, thymine, and 5-methylcytosine and incorporated these monomers into oligonucleotides. Initially, we carried out the transglycosylation reaction on several 2'-O-substituted 5-methyluridines to evaluate the effects of 2'-substitutions on this reaction. Under the optimized conditions, purine nucleobases were successfully introduced, and 2',4'-BNANC monomers bearing adenine or guanine were obtained over several steps. In addition, the improved synthesis of the 2',4'-BNANC monomers bearing thymine or 5-methylcytosine was also achieved. The obtained 2',4'-BNANC monomers were subsequently incorporated into oligonucleotides and the duplex-forming abilities of the modified oligonucleotides were investigated. Duplexes containing 2',4'-BNANC monomers in both or either strands were found to possess excellent thermal stabilities.