Revealing the Role of Solvent in anti-Oxypalladation-Triggered Regiocontrolled Domino Reactions for the Synthesis of Benzazepine- and Tetrahydroquinoline-Containing Scaffolds: A Combined Computational and Experimental Study.

Palladium-catalyzed regiocontrolled intramolecular oxypalladation-initiated cascades of multifunctional internal alkyne bearing an N-tosyl tether deliver functionalized benzazepine as an exclusive product via 6-endo-dig pathway in 1,4-dioxane solvent and tetrahydroquinoline scaffold as a major product via the 5-exo-dig pathway in the DMSO solvent. The role of the solvent in controlling the regioselectivity is still unknown which can be a major hurdle for further reaction development. Moreover, the reaction in DMSO suffered from having a mixture of products, and no exclusive formation of tetrahydroquinoline was achieved. Herein, we report a concerted computational and experimental study, revealing the role of the solvent in controlling the reaction outcome. DFT study revealed that the formation of the σ-vinylpalladium intermediate is reversible for the 5-exo-dig pathway while it is irreversible for the 6-endo-dig mechanism in 1,4-dioxane and consequently, the 5-exo-dig pathway is difficult to proceed. In contrast, both the 5-exo-dig and 6-endo-dig pathways are irreversible in DMSO. We predicted an exclusive formation of isobenzofuranone-fused chromane via the 5-exo-dig pathway when the N-tosyl tether is replaced by the O-tether in the internal alkyne in DMSO. The experimental study confirms the theoretical hypothesis and provides a highly chemo-divergent approach for the synthesis of biologically significant chromane with a large substrate scope and up to 95% yield at room temperature.

Highly stereoselective synthesis of α-glycosylated carboxylic acids by phenanthroline catalysis.

Carbohydrate molecules with an α-glycosylated carboxylic acid motif provide access to biologically relevant chemical space but are difficult to synthesize with high selectivity. To address this challenge, we report a mild and operationally simple protocol to synthesize a wide range of functionally and structurally diverse α-glycosylated carboxylic acids in good yields with high diastereoselectivity. Although there is no apparent correlation between reaction conversion and pK a of carboxylic acids, we found that carboxylic acids with a pK a of 4-5 provide high selectivity while those of a pK a of 2.5 or lower do not. Our strategy utilizes readily available 2,9-dibutyl-1,10-phenanthroline as an effective nucleophilic catalyst to displace a bromide leaving group from an activated sugar electrophile in a nucleophilic substitution reaction, forming phenanthrolinium intermediates. The attack of the carboxylic acid takes place from the α-face of the more reactive intermediate, resulting in the formation of α-glycosylated carboxylic acid. Previous calculations suggested that the hydroxyl group participates in the hydrogen bond interaction with the basic C2-oxygen of a sugar moiety and serves as a nucleophile to attack the C1-anomeric center. In contrast, our computational studies reveal that the carbonyl oxygen of the carboxylic acid serves as a nucleophile, with the carboxylic acid-OH forming a hydrogen bond with the basic C2-oxygen of the sugar moiety. This strong hydrogen bond (1.65 Å) interaction increases the nucleophilicity of the carbonyl oxygen of carboxylic acid and plays a critical role in the selectivity-determining step. In contrast, when alcohol acts as a nucleophile, this scenario is not possible since the -OH group of the alcohol interacts with the C2-oxygen and attacks the C1-anomeric carbon of the sugar moiety. This is also reflected in alcohol-OH's weak hydrogen bond (1.95 Å) interaction with the C2-oxygen. The O(C2)-HO (carboxylic acid) angle was measured to be 171° while the O(C2)-HO (alcohol) angle at 122° deviates from linearity, resulting in weak hydrogen bonding.

Evaluating Diastolic Dysfunction as an Indicator of Cirrhotic Cardiomyopathy in Decompensated Chronic Liver Disease.

BACKGROUND: The clinical syndrome of cirrhotic cardiomyopathy (CCM) occurs quite frequently in decompensated chronic liver disease (DCLD) patients without any prior incidence. The compromised life expectancy under such conditions was the key that prompted us to conduct this study. PURPOSE: This study was planned to study the prevalence of diastolic dysfunction in chronic liver disease patients, to understand the diagnostic criteria of left ventricular diastolic dysfunction (LVDD) in cirrhotic patients, and to evaluate its occurrence as an early indicator of CCM. METHODS: A hospital-based, cross-sectional study was conducted on 158 patients, admitted to the Department of Medicine, Rajendra Institute of Medical Sciences, Ranchi, India, who conformed to our criteria for inclusion and exclusion. The study period was for 18 months. The subjects were clinically and radiologically diagnosed with chronic liver disease. Regression analysis for variables was performed to score the effects of potential variables with outcomes for diastolic dysfunction (DD) prediction. RESULTS: Out of 158 patients, 116 belonged to the age group of 31-60 years, pronouncing age to be a significant factor for LVDD. Fifty-three subjects had serum bilirubin levels >2mg/dL and we found serum bilirubin levels to bear a significant correlation with LVDD by exhibiting a p-value <0.0001. Both the Child-Turcotte-Pugh score class (p-value=0.0180) and QTc (p-value <0.0001) bear significant correlation with the development of LVDD, which is also evident from their area under the curve (AUC) values of 0.64 in the receiver operating characteristic (ROC) curve. CONCLUSION: Our study concludes that LVDD is an early indicator for assessing the severity of liver cirrhosis in DCLD. The correlation of DCLD with prolonged QTc could predispose patients with DCLD to ventricular arrhythmias. Hence, such patients should undergo serum bilirubin tests, and electrocardiographic checks at regular intervals for early detection, to increase their overall survival rates.

Capitalizing on strengths and minimizing weaknesses of veterans in civilian employment interviews: Perceptions of interviewers and veteran interviewees.

Like all job applicants, veterans have to face the ubiquitous employment interview and pass this potential hurdle to civilian sector employment. So, because of the uniqueness of transitioning from the military to civilian employment, the present paper sought to identify perceived interviewing strengths and weaknesses of veteran interviewees from (a) the perspective of civilian sector human resource professionals (i.e. hiring personnel) with experience interviewing veterans (Study 1, five focus groups, N = 14), and (b) veterans (Study 2, N = 93). Qualitative analysis of the focus group transcripts resulted in the emergence of two theme categories: (1) veteran interviewee strengths and (2) veteran interviewee weaknesses. This information guided the development of a 10-item survey that was completed by 93 veterans (Study 2). In its totality, the results (from both Study 1 and Study 2) indicated that communication of soft skills, confidence, and professionalism were perceived to be strengths that veterans displayed during civilian employment interviews, and conversely, the ineffective translation and communication of relevant technical skills acquired in the military, use of military jargon, and nervousness were considered to be weaknesses. Recommendations to capitalize on the strengths and mitigate the weaknesses are presented.

Estimating the Effect of Genital vs Extragenital Warts on Immunocompetent Indian Adult Patients; Quality of Life: A Comparative Cross-Sectional Study.

Introduction: Extragenital warts, often known as EGWs, affect between 7% and 10% of the population. Despite the plethora of research on the impact of genital warts (GWs) on "Quality Of Life", EGWs have received little attention. The purpose of this study was to conduct a cross-sectional investigation with the objective of contrasting the effects of GWs and EGWs on the health-related quality of life and other characteristics. Participants and Procedures: A cross-sectional clinical study was piloted at a tertiary care center. Participants in the study included two groups of healthy adults, each group consisting of 100 adult subjects. Those diagnosed with EGWs were included in group A, while patients diagnosed with GWs made up group B. The "Dermatology Life Quality Index" questionnaire was used to evaluate various parameters. Observations were compared for significance. Results: The majority of the subjects in both the groups were observed to have less than 10 warts. The Dermatology Life Quality Index score for the EGWs had an average of 8.66 ± 2.31 score; GWs had an average of 5.12 ± 3.25. This mean variance was statistically significant. The level of the dissatisfaction was highly significantly different among the groups and the subjects being more in the EGW group dissatisfied. Conclusion: The findings of this investigation indicate that EGWs have a significant and detrimental effect on the Quality Of Life. Medical experts must teach people how to prevent the disease's spread and recurrence due to its persistence. They must also consider the psychological and societal repercussions of the disease while discussing therapy choices.

Assessment of Right Ventricular Function by Strain Imaging in Patients Presenting with Acute Myocardial Infarction: An Original Research.

Objective: This study sought to determine the relationship between right ventricular (RV) function and clinical variables and prognosis in individuals with acute myocardial infarction (AMI) utilizing strain imaging. Materials and Methods: A prospective observational research involving 150 patients who had been admitted with AMI was carried out. Utilizing two-dimensional speckle-tracking strain imaging, RV function was assessed. Age, sex, risk factors, and comorbidities were recorded as clinical parameters. A 12-month follow-up was conducted to assess major adverse cardiovascular events (MACE). Results: 65% of the study's participants were men, with a mean age of 58.2 years. When compared to a healthy control group, individuals with AMI had significantly lower RV longitudinal strain (RVLS) (P 0.001). RVLS and left ventricular ejection fraction had a statistically significant connection (r = 0.642, P 0.001). Patients with compromised RVLS had a greater rate of MACE over the follow-up period compared to those with maintained RV function (P = 0.014). Conclusion: In conclusion, strain imaging offers useful information for evaluating RV function in patients with AMI. Reduced left ventricular performance and a higher likelihood of unfavorable clinical outcomes are linked to impaired RVLS. Utilizing strain imaging to detect RV dysfunction early can help direct treatment plans and enhance patient outcomes.

ZBTB12 is a molecular barrier to dedifferentiation in human pluripotent stem cells.

Development is generally viewed as one-way traffic of cell state transition from primitive to developmentally advanced states. However, molecular mechanisms that ensure the unidirectional transition of cell fates remain largely unknown. Through exact transcription start site mapping, we report an evolutionarily conserved BTB domain-containing zinc finger protein, ZBTB12, as a molecular barrier for dedifferentiation of human pluripotent stem cells (hPSCs). Single-cell RNA sequencing reveals that ZBTB12 is essential for three germ layer differentiation by blocking hPSC dedifferentiation. Mechanistically, ZBTB12 fine-tunes the expression of human endogenous retrovirus H (HERVH), a primate-specific retrotransposon, and targets specific transcripts that utilize HERVH as a regulatory element. In particular, the downregulation of HERVH-overlapping long non-coding RNAs (lncRNAs) by ZBTB12 is necessary for a successful exit from a pluripotent state and lineage derivation. Overall, we identify ZBTB12 as a molecular barrier that safeguards the unidirectional transition of metastable stem cell fates toward developmentally advanced states.

Pattern of Adverse Drug Reactions among Pregnant Women and Pediatric Patients in a Tertiary Care Hospital.

BACKGROUND: Adverse drug reactions (ADRs) among pregnant women and pediatric patients are a significant public health concern. ADRs monitoring and documentation are considered essential practices to decrease the chances of ADRs and ensure the safe use of drugs. OBJECTIVE: Therefore, the study was designed to evaluate the pattern of adverse drug reactions among pregnant women and pediatric patients in a tertiary care hospital. METHODS: The study was conducted at Kalpana Chawla Government Medical College and Hospital, Karnal, Haryana, for a period of 2 years. During this period, ADRs reported by the healthcare professionals of gynecology and pediatric department to the ADRs monitoring centre of our institute were included in the study. RESULTS: Out of 54 total ADRs, 40 ADRs occurred among pregnant women, and 14 ADRs were reported in pediatric patients. The majority of the ADRs were observed in the age group of 21-30 years (pregnant women) and 3-5 years (pediatric patients). Antibiotics were most commonly implicated in ADRs among pregnant women (60%) and pediatric patients (79%). In our study, the dermatological system was mostly affected among pregnant women and pediatric patients. Urticaria, contact dermatitis, and erythematous rash were the most commonly reported ADRs among pregnant women and pediatric patients. CONCLUSION: Over-prescribing and irrational use of antibiotics make these vulnerable populations more susceptible to ADRs and antibiotic resistance. Therefore, there is a need to create awareness among health care professionals regarding the spontaneous reporting of ADRs for ensuring drug safety and reducing morbidity and mortality among pregnant women and pediatric patients.

Assessment of cardiac function in children by strain imaging and its correlation with conventional echocardiographic parameter.

Background: The objectives of this study were to find out of normal reference value for age-dependent longitudinal strain values in children and find its correlation with conventional echocardiographic parameters. Methods: In total, 100 healthy normal children aged between 2 and 15 years were enrolled and divided into three age groups, namely, 2-5 years, 5-10 years, and 10-15 years. Using the GE Vivid 7 ultrasound platform with 4 or 7 MHz probes, both LV and RV global longitudinal strains and conventional echocardiographic parameters were acquired. Results: In normal healthy children, left ventricular GLS values were -20.10 to -19.68 (mean: -19.89), -21.93 to -21.02 (mean: -21.48), and -20.87 to -20.41 (mean: -20.64)) in children aged 2-5 years, 5-10 years, and 10-15 years and right ventricular GLS values were -16.80 to -16.44 (mean: -16.62), -27.85 to -27.27 (mean: -27.56), -28.44 to -27.93 (mean: -28.19) in the above three groups, respectively. No significant increase was noted in the left ventricular strain value from basal to the apical segment from age group 2 years to 15 years and no gender differences were seen. None of the conventional echocardiographic parameters commonly used to assess the left or right ventricular systolic function had a significant correlation with LVGLS and RVGLS. Conclusions: The mean LVGLS values were -19.89, -21.48, and -20.64 and RVGLS were -16.62, -27.56, and -28.19 in healthy normal children aged 2-5 years, 5-10 years, and 10-15 years, respectively, and conventional echocardiographic parameters did not have any significant correlation with these values.

Exploring the acceptance for e-learning among higher education students in India: combining technology acceptance model with external variables.

The concept of e-learning has now become fundamental in student learning process. This concept becomes even more relevant in situations of global crisis such as that arising from COVID-19. Since this pandemic there have been tectonic shifts in the education sector. Effective implementation of e-learning in higher education depends on students' adoption of this technology. So, this study aimed to identify the factors influencing the behavioral intentions and actual usage of students in adopting e-learning. Additionally, it also examined the mediation effects among different latent constructs. Based on technology acceptance model (TAM), an explanatory structural model of technology acceptance was tested along with introduction of three external variables. To do this, a quantitative investigation was conducted using an online survey of higher education students in India, obtaining 570 responses. The structural model was examined through the partial least square structural equation modeling. Results obtained make it possible to validate the proposed model as findings explains the 56.2% variance of actual usage. In addition, it shows the direct and indirect effect of all three selected external variables of personal innovativeness, social factors and self-efficacy on the main constructs of TAM. The findings of this study are relevant for the higher education management, administration, e-learning system developers, marketers and researchers for improving the effective usage of e-learning by developing more focused and customized learning solutions.

Efficacy of Spironolactone in Adult Acne in Polycystic Ovary Syndrome Patients an Original Research.

INTRODUCTION: This prospective clinical trial was designed to assess the effects of a long-term therapy with spironolactone, with and without dietary-induced weight-loss, on clinical features, lipid profile, and insulin levels in women with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: Twenty-five patients (range of age 16-32 year; 13 lean and 12 overweight) fulfilling formal diagnostic criteria for PCOS (oligomenorrhea and/or amenorrhea, biochemical and/or clinical evidence of hyperadrogenism) were studied at baseline and then received oral spironolactone (100 mg/die) for 12 months; association with lifestyle modifications was recommended to all overweight patients. Clinical, endocrine, and metabolic parameters (oral glucose tolerance test [OGTT], lipid profile) were measured at baseline and at the end of the antiandrogen treatment. RESULTS: The therapy was associated with a significant average decline of triglycerides in overweight subjects and with increased high-density lipoprotein-cholesterol levels in lean patients. The insulin levels at 60 min during OGTT, homeostasis model assessment-insulin resistance and area under curve of insulin were significantly lowered in overweight women after 12 months of spironolactone and weight loss and no negative changes in insulin secretion and sensitivity were observed in PCOS women after pharmacological treatment alone. CONCLUSION: The efficacy of spironolactone on the androgenic clinical aspects of PCOS has been confirmed in this study. Furthermore, our data show that long-term treatment with spironolactone exerts no negative effects on lipoprotein profile and glucose metabolism; more relevant beneficial effects on glucose and lipid metabolism were observed when the antiandrogen was associated with weight loss in overweight PCOS women.

Impact of Climatic Variations on Drug-induced Skin Reactions in Two Different Regions of India.

BACKGROUND: Around 2-3% of hospitalizations have been reported due to dermatological adverse drug reactions. Recent studies suggest that climatic variations affect the skin barrier function and extreme conditions aggravate skin disorders. OBJECTIVE: The present study was designed to compare the impact of climatic variations on drug-induced skin reactions in the Northern and Eastern regions of India. METHODS: We performed a one-year retrospective study to evaluate the impact of climatic variations (temperature and humidity) on drug-induced skin reactions in the Eastern (Kalyani, West Bengal) and Northern (Karnal, Haryana) regions. Drug-induced skin reactions were reported month-- wise in both the Eastern and Northern regions. Temperature and humidity levels were also noted month-wise in both regions. The direct correlation between climatic variations and the number of drug reactions were assessed using Pearson's correlation and quadratic regression analysis. RESULTS AND DISCUSSION: Overall, 99 and 81 dermatological adverse drug reactions were reported in tertiary care hospitals in the Northern and Eastern regions, respectively. During the summer season, the humidity level was found to be low in the Northern region as compared to the Eastern region. During this period, drug-induced skin reactions were reported significantly (p<0.05) more in the Northern region as compared to the Eastern region. Furthermore, quadratic regression analysis revealed that climatic variations contributed to drug reaction variability in the Northern region (68.5%) and Eastern region (23.5%). CONCLUSION: Therefore, the difference in the prevalence of drug-induced skin reactions may be related to the different climatic conditions among these two regions. Further studies in controlled climatic conditions should be performed for definitive correlations and to look into possible solutions.

Reactivity and Mechanisms of Photoactivated Heterometallic [RuII NiII ] and [RuII NiII RuII ] Catalysts for Dihydrogen Generation from Water.

Two heterometallic photocatalysts were designed and probed for water reduction. Both [(bpy)2 RuII NiII (L1 )](ClO4 )2 (1) and [(bpy)2 RuII NiII (L2 )2 RuII (bpy)2 ](ClO4 )2 (2) can generate the low-valent precursor involved in hydride formation prior to dihydrogen generation. However, while the bimetallic [RuII NiII ] (1) requires the presence of an external photosensitizer to trigger catalytic activity, the trimetallic [RuII NiII RuII ] (2) displays significant coupling between the catalytic and light-harvesting units to promote intramolecular multielectron transfer and perform photocatalysis at the Ni center. A concerted experimental and theoretical effort proposes mechanisms to explain why 1 is unable to achieve self-supported catalysis, while 2 is fully photocatalytic.

Chrysin rescues rat myocardium from ischemia-reperfusion injury via PPAR-γ/Nrf2 activation.

Pharmacological strategies aimed at co-activating peroxisome proliferator-activated receptor-gamma (PPAR-γ)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway have shown promising results in alleviating myocardial injury. The aim of the study was to evaluate the role of chrysin, a PPAR-γ agonist, in ischemia-reperfusion (IR)-induced myocardial infarction (MI) in rats and to explore the molecular mechanism driving this activity. To evaluate this hypothesis, chrysin (60 mg/kg, orally), PPAR-γ antagonist (GW9662, 1 mg/kg, intraperitoneally), or both were administered to rats for 28 days. On the 29th day, one-stage ligation of left anterior descending coronary artery for 45 min followed by 60 min of reperfusion was performed. Chrysin significantly decreased infarct size and improved cardiac functions following IR-induced MI. This improvement was corroborated by augmented PPAR-γ/Nrf2 expression as confirmed by immunohistochemistry and western blotting analysis. Chrysin exhibited strong anti-oxidant property as demonstrated by increased GSH and CAT levels and decreased 8-OHdG and TBARS levels. Our findings also imply that chrysin significantly inhibited inflammatory response as validated by decreased NF-κB, IKK-ß, CRP, TNF-α and MPO levels. In addition, chrysin decreased TUNEL/DAPI positivity, a marker of apoptotic response and normalized cardiac injury markers. The histopathological and ultrastructural analysis further supported the functional and biochemical outcomes, showing preserved myocardial architecture. Intriguingly, co-administration with GW9662 significantly diminished the cardioprotective effect of chrysin as demonstrated by depressed myocardial function, decreased PPAR-γ/Nrf2 expression and increased oxidative stress. In conclusion, the present study demonstrates that co-activation of PPAR-γ/Nrf2 by chrysin may be crucial for its cardioprotective effect.

Development of hierarchical magnesium oxide anchored cerium oxide nanocomposites with improved magnetic properties and photocatalytic performance.

A facile strategy was introduced for the development of pure MgO and its nanocomposites using different CeO2 contents (3%-7%) to enhance their magnetic properties and photocatalytic performance. Different morphologies (namely nanoflowers and rhombohedral type nanostructures) were obtained using an in situ hydrothermal method at different concentrations of CeO2. X-ray diffraction results revealed that peaks of CeO2 were observed along with peaks of MgO, which confirms the presence of both phases. The crystallite size and particle size were found to increase with changing CeO2 content in the host matrix of MgO. Moreover, the band gap reduces while the magnetic character increases with CeO2 content. The magnetic behaviour of the nanocomposites was elucidated on the basis of oxygen intrinsic defects, which are shown through XPS. EPR measurements were carried out to understand the valence electrons and establish the defects present in the material, which are related to the size of the nanostructures. The degradation of Rose Bengal dye was performed to probe the photocatalytic activity of the MgO@CeO2 nanocomposites. Hence the facile synthesis of these nanostructures conveyed good magnetic properties along with its application towards dye degradation.

Assessment of metal contamination and the associated human health risk from dustfall deposition: a study in a mid-sized town in India.

It is evident from the past studies that dust fallout is a severe concern due to its impact to urban air quality and public health. This study mainly examines the spatial and seasonal variation of dustfall at ambient levels and chemical characterization of its insoluble fraction for Kharagpur Town, India. Dustfall samples were collected monthly for 1 year (July 2014 to June 2015) from four sampling sites. The results showed that the maximum dustfall deposition is found during summer (March to June) and in the range of 2.01 ± 0.36 to 15.74 ± 3.83 ton km-2 month-1, and minimum deposition is during monsoon season (July to October) in the range of 0.42 ± 0.72 to 7.38 ± 5.8 ton km-2 month-1. Selected metals like Sc, V, Cr, Co, Ni, Zn, Y, Zr, Ce, Hf, and Pb were analyzed using the high-resolution inductively coupled mass spectrometer (HR-ICP-MS) technique, and the contamination level of heavy metals was assessed using the geoaccumulation index (Igeo) and enrichment factor (EF). To estimate the sources for the metallic contaminants, principal component analysis (PCA) was conducted. The US EPA health risk assessment model was applied to determine the hazard index and hazard quotient values. The results show the significant level of enrichment for Pb (EF = 41.79) and Cr (EF = 4.39). The Igeo values point out moderate contamination by Pb (Igeo = 2.01) and Cr (Igeo = 1.6) in Kharagpur Town. This study suggests that in the context of noncancer risk of heavy metals as determined by the hazard index (HI) and hazard quotient (HQ) values, ingestion is the main source of exposure to dust in adults and children followed by dermal contact. Considering the inhalation route, carcinogenic risk level of Cr, Co, and Ni for adults and children is lower than the EPA's safe limit (10-6 to 10-4), indicating that cancer risk of these metals due to exposure to dustfall in Kharagpur is negligible.

Regulation of cell-type-specific transcriptomes by microRNA networks during human brain development.

MicroRNAs (miRNAs) regulate many cellular events during brain development by interacting with hundreds of mRNA transcripts. However, miRNAs operate nonuniformly upon the transcriptional profile with an as yet unknown logic. Shortcomings in defining miRNA-mRNA networks include limited knowledge of in vivo miRNA targets and their abundance in single cells. By combining multiple complementary approaches, high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation with an antibody to AGO2 (AGO2-HITS-CLIP), single-cell profiling and computational analyses using bipartite and coexpression networks, we show that miRNA-mRNA interactions operate as functional modules that often correspond to cell-type identities and undergo dynamic transitions during brain development. These networks are highly dynamic during development and over the course of evolution. One such interaction is between radial-glia-enriched ORC4 and miR-2115, a great-ape-specific miRNA, which appears to control radial glia proliferation rates during human brain development.

Febuxostat Modulates MAPK/NF-κBp65/TNF-α Signaling in Cardiac Ischemia-Reperfusion Injury.

Xanthine oxidase and xanthine dehydrogenase have been implicated in producing myocardial damage following reperfusion of an occluded coronary artery. We investigated and compared the effect of febuxostat and allopurinol in an experimental model of ischemia-reperfusion (IR) injury with a focus on the signaling pathways involved. Male Wistar rats were orally administered vehicle (CMC) once daily (sham and IR + control), febuxostat (10 mg/kg/day; FEB10 + IR), or allopurinol (100 mg/kg/day; ALL100 + IR) for 14 days. On the 15th day, the IR-control and treatment groups were subjected to one-stage left anterior descending (LAD) coronary artery ligation for 45 minutes followed by a 60-minute reperfusion. Febuxostat and allopurinol pretreatment significantly improved cardiac function and maintained morphological alterations. They also attenuated oxidative stress and apoptosis by suppressing the expression of proapoptotic proteins (Bax and caspase-3), reducing TUNEL-positive cells, and increasing the level of antiapoptotic proteins (Bcl-2). The MAPK-based molecular mechanism revealed suppression of active JNK and p38 proteins concomitant with the rise in ERK1/ERK2, a prosurvival kinase. Additionally, a reduction in the level of inflammatory markers (TNF-α, IL-6, and NF-κB) was also observed. The changes observed with febuxostat were remarkable in comparison with those observed with allopurinol. Febuxostat protects relatively better against IR injury than allopurinol by suppressing inflammation and apoptosis mediating the MAPK/NF-κBp65/TNF-α pathway.

Clinical significance of cathepsin L and cathepsin B in dilated cardiomyopathy.

Dysregulated expression of lysosomal cysteine cathepsins is associated with adverse cardiac remodeling, a characteristic of several cardiovascular diseases. However, the information regarding the role of cysteine cathepsin L (CTSL) and cathepsin B (CTSB) in dilated cardiomyopathy (DCM) is limited. The present study was aimed to investigate the expression of CTSL and CTSB in animal model of doxorubicin (doxo)-induced cardiomyopathy as well as in peripheral blood samples of DCM patients. Cardiac tissue sections from doxo-treated and control rats were used to study the expression of CTSL and CTSB by enzyme assay and immunohistochemistry (IHC). Peripheral blood mononuclear cells (PBMCs) isolated from DCM patients (n = 29) along with age-matched healthy controls (n = 28) were used to assay enzymatic activity of these cathepsins. Activities of these proteases were further correlated with echocardiographic parameters of DCM patients. A significant increase in CTSL activity and protein expression was observed with no changes in CTSB levels in doxo-treated rats as compared to controls. We also observed a drastic increase in the functional activity of cathepsin L+cathepsin B (CTSL+B), CTSL, and CTSB in DCM patients compared to controls (p ≤ 0.001). Increased levels of these proteases exhibited a statistically significant correlation with reduced left ventricular ejection fraction (LVEF) in DCM patients (ρ = -0.58, p = 0.01). For the first time, this study demonstrates a correlation between increased expression of CTSL and CTSB in PBMCs with severity of left ventricular dysfunction in DCM patients. Thus, these proteases may serve as blood-based biomarker of DCM and prove useful in its management.