Biology subjects

Parajuli, N.

Publications and source records attributed to Parajuli, N..

4 recordsLinked to original sources

bioRxiv2025

Elucidating the perception, awareness and biosecurity practices among the live poultry/poultry-meat sellers to mitigate the risk of zoonotic salmonellosis

Zoonotic salmonellosis remains a major public health concern, especially in low-resource settings where poultry handling practices are often informal. Biosecurity measure of live poultry/poultry-meat vending shop is necessary to address this zoonoses. This study investigated the knowledge, attitudes, and biosecurity practices of poultry/poultry-meat sellers toward the risk of zoonotic salmonellosis in Bangladesh. A quantitative, descriptive, cross-sectional study was conducted among the 432 poultry/poultry-meat sellers through a structured questionnaire in multistage sampling approach. Majority of the poultry/poultry-meat sellers (n=432) were male (75.5%), age between 26-34 years (31.9%), had primary education (28.9%), experience of [≤]5 years (40.3%), and monthly income was <20000 BDT (43.3%). Additionally, minimal had training on live poultry marketing (33.1%), and poultry-meat processing and marketing (28.5%). The 33.34% and 62.03% of poultry/poultry-meat sellers had the good knowledge and positive attitudes respectively. While 41.43% were involved in correct biosecurity practice. Moreover, the mean KAP score was 53.12{+/-}0.89, 68.59{+/-}0.79 and 54.58{+/-}0.73 respectively. From the multivariate analyses, higher education was a strong predictor of good knowledge (Bachelors degree: OR=6.64, 95%CI:2.59-17.04, p<0.01), positive attitude (Bachelors degree: OR=13.48, 95%CI:3.72-48.87, p<0.01), and correct biosecurity practices (HS: OR=5.52, 95%CI:2.62-11.63, p<0.01; Bachelors degree: OR=4.81, 95%CI:2.03-11.39, p<0.01). The sellers with good knowledge, positive attitudes, and correct biosecurity practices perceived higher zoonotic risk (median=7, p<0.05), with perception co-relation that significantly influenced by education (r=0.131, p<0.01) and training (r=0.084, p<0.05). Despite moderate awareness, sellers showed notable gaps in safe practices, highlighting the need for practical training that enhances risk perception, promotes behaviour change, and builds hands-on biosecurity skills.

scientific communication and education↗

bioRxiv2023

Ser14-RPN6 Phosphorylation Mediates the Activation of 26S Proteasomes by cAMP and Protects against Cardiac Proteotoxic Stress in Mice

BackgroundA better understanding of the regulation of proteasome activities can facilitate the search for new therapeutic strategies. A cell culture study shows that cAMP-dependent protein kinase (PKA) activates the 26S proteasome by phosphorylating Ser14 of RPN6 (pS14-RPN6), but this discovery and its physiological significance remain to be established in vivo. MethodsMale and female mice with Ser14 of Rpn6 mutated to Ala (S14A) or Asp (S14D) to respectively block or mimic pS14-Rpn6 were created and used along with cells derived from them. cAMP/PKA were manipulated pharmacologically. Ubiquitin-proteasome system (UPS) functioning was evaluated with the GFPdgn reporter mouse and proteasomal activity assays. Impact of S14A and S14D on proteotoxicity was tested in mice and cardiomyocytes overexpressing the misfolded protein R120G-CryAB (R120G). ResultsPKA activation increased pS14-Rpn6 and 26S proteasome activities in wild-type (WT) but not S14A embryonic fibroblasts (MEFs), adult cardiomyocytes (AMCMs), and mouse hearts. Basal 26S proteasome activities were significantly greater in S14D myocardium and AMCMs than in WT counterparts. S14D::GFPdgn mice displayed significantly lower myocardial GFPdgn protein but not mRNA levels than GFPdgn mice. In R120G mice, a classic model of cardiac proteotoxicity, basal myocardial pS14-Rpn6 was significantly lower compared with non- transgenic littermates, which was not always associated with reduction of other phosphorylated PKA substrates. Cultured S14D neonatal cardiomyocytes displayed significantly faster proteasomal degradation of R120G than WT neonatal cardiomyocytes. Compared with R120G mice, S14D/S14D::R120G mice showed significantly greater myocardial proteasome activities, lower levels of total and K48-linked ubiquitin conjugates and of aberrant CryAB protein aggregates, less reactivation of fetal genes and cardiac hypertrophy, and delays in cardiac malfunction. ConclusionsThis study establishes in animals that pS14-Rpn6 mediates the activation of 26S proteasomes by PKA and that the reduced pS14-Rpn6 is a key pathogenic factor in cardiac proteinopathy, thereby identifies a new therapeutic target to reduce cardiac proteotoxicity.

cell biology↗

bioRxiv2020

In Silico Analysis of Secondary Metabolites that Modulates Enzymes of Cholesterol Target

Hypercholesterolemia has posed a serious threat of heart diseases and stroke worldwide. Xanthine oxidase (XO), the rate-limiting enzyme in uric acid biosynthesis, is regarded as the root of reactive oxygen species (ROS) that generates atherosclerosis and cholesterol crystals. {beta}-Hydroxy {beta}-methylglutaryl-coenzyme A reductase (HMGR) is a rate-limiting enzyme in cholesterol biosynthesis. Although some commercially available enzyme inhibiting drugs have effectively reduced the cholesterol level, most of them have failed to meet the requirements of being apt drug candidates. Here, we have carried out an in-silico analysis of secondary metabolites that have already shown good inhibitory activity against XO and HMGR. Out of 118 secondary metabolites reviewed, sixteen molecules inhibiting XO and HMGR were taken based on IC50 values reported in vitro assays. Further, receptor-based virtual screening was carried out against secondary metabolites using GOLD Protein-Ligand Docking Software, combined with subsequent post-docking, to study the binding affinities of ligands to the enzymes. In-Silico ADMET analysis was carried out to study their pharmacokinetic properties, followed by toxicity prediction through ProTox-II. The molecular docking of amentoflavone (1) (GOLD score 70.54), and ganomycin I (9) (GOLD score 59.61) evinced that the drug has effectively bind at the competitive site of XO and HMGR, respectively. Besides, 6-paradol (3) and selgin (4) could be potential drug candidates to inhibit XO. Likewise, n-octadecanyl-O--D-glucopyranosyl(6[->]1")-O--D-glucopyranoside (10) could be potential drug candidates to maintain serum cholesterol. In-silico ADMET analysis showed that the sixteen metabolites were optimal within the categorical range in comparison to commercially available XO and HMGR inhibitors, respectively. Toxicity analysis through Protox-II revealed that 6-gingerol (2), ganoleucoin K (11), and ganoleucoin Z (12) are toxic for human use. This computational analysis supports earlier experimental evidence towards the inhibition of XO and HMGR by natural products. Further study is necessary to explore the clinical efficacy of these secondary molecules, which might be alternatives for the treatment of hypercholesterolemia. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=163 HEIGHT=200 SRC="FIGDIR/small/219998v2_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@48d66borg.highwire.dtl.DTLVardef@1f51741org.highwire.dtl.DTLVardef@1c9d87dorg.highwire.dtl.DTLVardef@a41e70_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2019

The Calcineurin-TFEB-p62 Pathway Mediates the Activation of Cardiac Macroautophagy by Proteasomal Malfunction

RationaleThe ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) are pivotal to proteostasis. Targeting these pathways is emerging as an attractive strategy for treating cancer. However, a significant proportion of patients who receive a proteasome inhibitor-containing regime for example, show cardiotoxicity. Moreover, UPS and ALP defects are implicated in the pathogenesis of a large subset of heart disease. Hence, a better understanding of the cross-talk between the two catabolic pathways should help advance cardiac pathophysiology and medicine. ObjectiveSystemic pharmacological proteasome inhibition (PSMI) was shown to increase p62/SQSTM1 expression and induce myocardial macroautophagy. The present study investigates whether cardiomyocyte-restricted PSMI activates myocardial ALP and, more importantly, how proteasome malfunction activates the ALP in the heart. Methods and ResultsMyocardial macroautophagy, transcription factor EB (TFEB) expression and activity, and p62 expression were markedly increased in mice with either cardiomyocyte-restricted ablation of Psmc1 (a 19S proteasome subunit gene) or pharmacological PSMI. In cultured cardiomyocytes, PSMI-induced increases in TFEB activation and p62 expression were blunted markedly by calcineurin inhibition (cyclosporine A) and by siRNA-mediated Molcn1 silence. PSMI induced remarkable increases in myocardial autophagic flux in wild type mice but not p62 null mice. In cultured wild type, but not p62-null, mouse cardiomyocytes, PSMI induced increases in LC3-II flux and in the lysosomal removal of ubiquitinated proteins. Myocardial TFEB activation by PSMI as reflected by TFEB nuclear localization and target gene expression was strikingly less in p62 null mice compared with wild type mice. Conclusions(1) The activation of cardiac macroautophagy by proteasomal malfunction is mediated by the Mocln1-calcineurin-TFEB-p62 pathway; (2) both Mocln1 and p62 form a feed-forward loop with TFEB during TFEB activation by proteasome malfunction; and (3) targeting the Mcoln1-calcineurin-TFEB-p62 pathway may provide new means to intervene cardiac ALP activation in a proteasome malfunction setting.

cell biology↗