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Protective Effects of Rifampicin and Its Analog Rifampicin Quinone in a Mouse Model of Obesity-Induced Type 2 Diabetes
No full textAdvanced glycation end-products (AGEs) form when glucose reacts non-enzymatically with proteins, leading to abnormal protein function, oxidative stress, and inflammation. AGEs are associated with aging and age-related diseases; their formation is aggravated during diabetes. Therefore, drugs preventing AGE formation can potentially treat diabetic complications, positively affecting health. Earlier, we demonstrated that rifampicin and its analogs have potent anti-glycating activities and increase the life span of Caenorhabditis elegans. This study aimed to investigate the effects of rifampicin during hyperglycemia in C. elegans and in a mouse model of obesity-induced type 2 diabetes. The effects of rifampicin were assessed by determining the life span of C. elegans cultured in the presence of glucose and by measuring HbA1c, AGE levels, and glucose excursions in the diabetic mouse model. Our results show that rifampicin protects C. elegans from glucose-induced toxicity and increases life span. In mice, rifampicin reduces HbA1c and AGEs, improves insulin sensitivity, and reduces indications of diabetic nephropathy without inducing hepatotoxicity. Rifampicin quinone, an analog with lower anti-microbial activity, also reduces HbA1c levels, improves glucose homeostasis and insulin sensitivity, and lowers indications of diabetic nephropathy, without adversely affecting the liver of the diabetic mice. Altogether, our results indicate that rifampicin and its analog have protective roles during diabetes without inflicting hepatic damage and may potentially be considered for repositioning to treat hyperglycemia-related complications in patients
Case studies and numerical investigation of landslide triggering mechanisms in western ghats, Kerala, India.
No full textDue to significant rainfall during the monsoon, Kerala regularly sees landslides across the steep sloppy terrains of the Western Ghats. This causes significant harm to both man-made and natural ecosystems throughout several districts of the state. In order to find the root cause mechanisms of such failures, a finite-element-based stability analysis has been performed in this study. Additionally, fluctuations in several soil internal properties and deformation across time and space as a function of rainfall intensity have been discussed based on results of the recent literature. Further, Kerala is located inside a Stable Continental Region (SCR). Due to the presence of critically loaded faults dispersed across a wide region, the SCR seismicity includes destructive earthquakes and offers a significant overall danger. As many slopes in the area have already been undermined by prior landslides, even a small magnitude earthquake might cause slopes to fail or reactivate landslides. Therefore, in addition to static analysis, the performance of critically stable rainfall-affected slopes under earthquake conditions was described by explaining outcomes of the related literature. The methodology and results discussed in this article can be used to predict the performance of slopes situated in tropical regions under rainfall and earthquake conditions to prevent such calamities in the future
Biophysical investigations of antimicrobial peptide mimics for mechanistic studies
No full textWith a relentless rise in the growth of antimicrobial resistance, much attention is being focused on Antimicrobial peptides (AMP) and the development of AMP mimicking agents to combat this nefarious issue. However lesser reports come up with adequate reasoning behind the driving force of the membrane perturbing nature. Here, we shall be discussing the two branches of AMP mimics, peptoids and small molecules. Further, we explore the mode of action behind the antimicrobial properties displayed by the library of peptoids and small molecule mimics. To address this big challenge of understanding how the membrane active compound behaves, each of the compounds were introduced to the liposomes, mimicking the bacterial model membranes, and their interactions was recorded using solid state nuclear magnetic resonance spectroscopy. We observe that each of the mimics interact with the liposome as the global shape of the vesicles gets deformed. Also we observed a definite interaction with the fatty acyl chain as changes in order parameters were observed with respect to that of pure lipids. To develop a thorough understanding of the pore forming abilities of these compounds, a fluorescent dye release studies was executed using both bacterial and mammalian model membranes. The calcein dye release test revealed that the small molecule mimics undergo a cooperative effect. For the peptoids investigated, the extent of release could be correlated with their antimicrobial activity as well as the toxicity data
Mechanism of lipid bilayer perturbation by bactericidal membrane-active small molecules
No full textMembrane-active small molecules (MASMs) are small organic molecules designed to reproduce the fundamental physicochemical properties of natural antimicrobial peptides: their cationic charge and amphiphilic character. This class of compounds has a promising broad range of antimicrobial activity and, at the same time, solves some major limitations of the peptides, such as their high production costs and low in vivo stability. Most cationic antimicrobial peptides act by accumulating on the surface of bacterial membranes and causing the formation of defects when a threshold is reached. Due to the drastically different structures of the two classes of molecules, it is not obvious that small-molecule antimicrobials act in the same way as natural peptides, and very few data are available on this aspect. Here we combined spectroscopic studies and molecular dynamics simulations to characterize the mechanism of action of two different MASMs. Our results show that, notwithstanding their simple structure, these molecules act just like antimicrobial peptides. They bind to the membrane surface, below the head-groups, and insert their apolar moieties in the core of the bilayer. Like many natural peptides, they cause the formation of defects when they reach a high coverage of the membrane surface. In addition, they cause membrane aggregation, and this property could contribute to their antimicrobial activity
An interdisciplinary effort to understand chemical organizations at the origin of life
No full textThis backstory features the perspectives of three group leaders of a Franco-Indian collaboration on the origin of life, involving efforts to engineer evolvable chemical systems. The researchers explain how they overcame the difficulties to bring empiricist and theorist cultures together and the importance of such synergy for the future of origin of life research
Amino acid-based polymer-coated silver nanoparticles as insulin fibril inhibitors.
No full textTo explore the impact of polymer-coated silver nanoparticles (PC-AgNPs) on the extent of the insulin aggregation process, herein, we have synthesized three copolymers comprising poly(ethylene glycol) methyl ether methacrylate (PEGMA) and tert-butoxycarbonyl (Boc)-protected amino acid (alanine, leucine, and phenylalanine) containing methacrylate monomers, via reversible addition-fragmentation chain transfer (RAFT) polymerization. After deprotection of the Boc groups, the as-prepared water-soluble copolymers were coated on silver nanoparticles (Ag NPs), and the role of these NPs on insulin aggregation pathways was examined by multifarious spectroscopic and microscopic techniques. The extent of the inhibitory effect against the insulin fibrillation process was found to be related to the surface properties of the NPs, with the highest inhibitory effect detected for phenylalanine-based polymer-coated Ag NPs (PPhe-AgNPs). Using circular dichroism (CD) spectroscopy and Nile red (NR) fluorescence spectroscopy, we investigated the conformational changes and examined the role of hydrophobic interaction in inhibiting the aggregation properties of insulin upon treatment with PC-AgNPs. Furthermore, PC-AgNPs were also able to disintegrate the matured insulin fibrils and efficiently decreased the fibril-induced cytotoxicity, as confirmed by transmission electron microscopy (TEM) and the hemolysis study, respectively. Together, our findings established the novel amino acid-based PC-AgNPs as potent nanomaterials with 77–96% insulin fibril inhibition and marked disaggregation of matured insulin fibrils
Challenges and opportunities in providing palliative care services to children with a life-limiting illness: A systematic review
No full textBackground Palliative care for children is an innovative approach that helps improve the quality of life of children suffering from life-limiting illnesses, and their family members. The WHO recognized palliative care as a part of universal health coverage. However, there is inadequate availability and inequitable distribution of palliative care services for children in most parts of the world. We reviewed the existing literature to assess (i) the challenges in providing palliative care services for children suffering from life-limiting illnesses and (ii) the strategies or opportunities to overcome these challenges. Methods We conducted systematic searches in the PubMed and Scopus databases to find articles published in the past 10 years (January 2011 to December 2020). The population, concept and context (PCC) framework was used to devise a search strategy in an electronic database. Results A total of 1562 articles were found by searching the database and other sources. Title and abstracts of articles were screened, and 206 articles were selected for full-text review. After scrutiny 28 articles met the inclusion criteria. Barriers to and opportunities in the provision of palliative care services for children were identified at policy, organizational, healthcare provider, and patient/family levels. Conclusion We found that the majority of barriers to provision of palliative care services for children with life-limiting illnesses can be addressed by adopting research-driven strategies. Adequate and equitable distribution of palliative care services is required for improving children and their family members' quality of life
Translation and psychometric evaluation of the hindi language version of the pediatric nausea assessment tool (penat) in the indian population
No full textObjectives
To translate the Pediatric Nausea Assessment Tool (PeNAT) into Hindi and validate it in Indian pediatric cancer patients and survivors.
Methods
The PeNAT-Hindi was finalized by forward and backward translations, and pilot testing. The PeNAT-Hindi was administered to 200 Hindi-speaking pediatric (4–18 y) cancer patients/survivors, in three groups. These included pediatric cancer patients who had recently received chemotherapy (n = 150); who received no chemotherapy within 5 d (n = 25) and survivors (n = 25). Construct validity was tested by comparing scores among the three groups. Test–retest reliability and criterion validity were estimated by the correlation of the first PeNAT score with the second (taken 1 h later) PeNAT score and the number of vomiting/retching episodes, respectively. Convergent validity and discriminant validity were estimated by correlating PeNAT scores with parent-assessed nausea severity, and pain, respectively. The responsiveness was tested by comparing second PeNAT scores with subsequent divergent PeNAT scores among patients reporting subjective change (improvement and worsening, respectively) in nausea severity.
Results
Test–retest reliability of PeNAT-Hindi was good (intraclass correlation = 0.791). The initial PeNAT score had moderate correlation with the number of vomiting/retching episodes (Spearman ρ = 0.401). Median PeNAT scores in group 1 versus groups 2 and 3 were significantly different (p < 0.001). Initial PeNAT scores showed a moderate correlation with parent-assessed nausea (Spearman ρ = 0.657) and a weak correlation with parent-assessed pain (Spearman ρ = 0.319). The responsiveness (standardized response mean) of PeNAT-Hindi to the change in nausea severity was −1.79 (improvement) and 2.19 (worsening), respectively.
Conclusion
PeNAT-Hindi showed good reliability and acceptable validity. It may be used among Hindi-speaking children for measuring nausea. The responsiveness of PeNAT-Hindi needs further evaluation
Aml-459 genetic landscape in primary acute myeloid leukemia (aml) and relation with wilms tumor 1 (wt-1) gene expression
No full textContext
Acute myeloid leukemia (AML) involves abnormal differentiation and clonal proliferation of myeloid progenitor cells in the bone marrow. The Wilms tumor 1 (WT-1) gene regulates cell growth, apoptosis, and differentiation, but its biological role in AML is poorly understood.
Objectives
Evaluation of RNA expression and molecular functions of WT-1 gene in the context of other genetic alterations in AML.
Design
Prospective clinical research
Setting
Tertiary cancer care referral center
Patients or Other Participants
A total of 112 diagnosed cases of AML, having blast percentage of ≥20% blasts in peripheral blood or bone marrow on Day-0 and treated with induction therapy for 28 days were enrolled.
Materials and Methods
WT-1 gene expression was assessed using RNA extracted from blood/bone marrow samples. The molecular functions of WT-1 were analyzed by performing gene set enrichment analysis (GSEA), and the relationship of WT-1 expression with immune checkpoints was analyzed using the Sangerbox 3.0 database. Kaplan–Meier survival analysis was performed to estimate the prognostic significance of the WT-1 gene in AML.
Results
Out of 112 patients, 73 were males, and 39 were females. A total of 97 (86.60%) cases showed increased expression of the WT-1 gene at Day-0 as compared to cases in complete remission (P=<0.001). WT-1 expression was inversely correlated with normal hematopoiesis and positively correlated with age, high marrow blast counts, M4 subtype, and inferior outcomes compared to patients with low WT-1 expression levels. In GSEA, the WT-1 gene displayed an important role in misregulating DNA-binding transcription factor activity, RNA and protein binding, as well as negative regulation of cell growth and cell population proliferation. In immune checkpoint analysis, WT-1 gene expression was positively correlated with CD28, CD40, CD44, CD48, CD80, CD70, CD27, CD86. In survival analysis, poorer overall survival was seen in patients having higher WT-1 gene expression.
Conclusions
Increased expression of the WT-1 gene positively correlates with the leukemic burden in most cases of AML. The gene can be considered a promising molecular marker for early diagnosis, MRD detection, and a target for developing novel therapeutic approaches against AML
Photo-responsive signatures in a porous organic polymer enable visible light-driven CO<sub>2</sub> photofixation
No full textPorous organic polymers (POPs) continue to garner immense attention for CO2 capture and sequestration (CCS) as well as CO2 fixation to generate useful chemicals for alleviating global warming. Functionally engineered, visible light responsive organic photopolymers with extended π-conjugation and abundant heteroatoms enable photogenerated charge carriers, enhancement in visible light absorption, higher charge separation, and reduction in charge recombination during photocatalysis. In this work, we have explored the construction of a chemically stable, pyridine-equipped, and imine-linked porous organic polymer (Py-POP) by template-free Schiff base condensation of 1,3,5-tris(4-aminophenyl) benzene (APB) and 2,6-pyridinedicarboxaldehyde (PDC). This donor–acceptor Py-POP with extensive π-conjugations enables photocatalytic fixation of CO2 with styrene epoxide (STE) under visible light illumination. We have achieved an impressive conversion of STE to styrene carbonate (STC) (∼99%) under optimized reaction conditions using tert-butyl ammonium bromide (TBAB) as a promoter. Both the efficient CO2 adsorption and activation for photocatalytic fixation reaction are enabled by the existence of both imine and pyridine moieties in Py-POP. The interaction between Py-POP and CO2 is further illustrated by density functional theory (DFT) calculations that show that all the POP-CO2 interactions are favorable and exergonic. Using in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) characterization techniques, we elucidate the mechanistic pathways of active key surface species in CO2 photofixation with Py-POP. Our results provide mechanistic insight into the effectiveness of efficient, sustainable porous organic photocatalysts in visible light-driven CO2 conversion for various energy applications