Chronic kidney disease activates the HDAC6-inflammatory axis in the heart and contributes to myocardial remodeling in mice: inhibition of HDAC6 alleviates chronic kidney disease-induced myocardial remodeling.

Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-ß, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1ß) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling.

Description of an In Vitro Platelet Function Analyzer-PFA-100™.

This manuscript represents a republication of a manuscript originally published in STH in 1995. This republication is to help celebrate 50 years of publishing for STH. The original abstract follows.A new in vitro system for the detection of platelet dysfunction, PFA-100®, has been developed. It provides a quantitative measure of platelet function in anticoagulated whole blood. The system comprises a microprocessor-controlled instrument and a disposable test cartridge containing a biologically active membrane. The instrument aspirates a blood sample under constant vacuum from the sample reservoir through a capillary and a microscopic aperture cut into the membrane. The membrane is coated with collagen and epinephrine or adenosine 5'-diphosphate. The presence of these biochemical stimuli, and the high shear rates generated under the standardized flow conditions, result in platelet attachment, activation, and aggregation, slowly building a stable platelet plug at the aperture. The time required to obtain full occlusion of the aperture is reported as the "closure time." We have found that impairment of von Willebrand factor, or inhibition of platelet receptors glycoprotein Ib or IIb/IIIa with monoclonal antibodies or peptides, resulted in abnormal closure times. An antifibrinogen antibody, in contrast, failed to show any effect. The test appears to be sensitive to platelet adherence and aggregation abnormalities. The PFA-100® system has potential applications in routine evaluation of platelet function in the clinical setting because of its accuracy, case of operation, and rapid turnaround of results.

Total Synthesis of Diterpenoid Quinone Methide Tumor Inhibitor, (+)-Taxodione.

An asymmetric polyene cyclization (92% ee) strategy has been successfully applied for the first asymmetric total synthesis of oxidized abietane, anticancer agent, taxodione (1) sharing a trans-decalin system. Additionally, the total syntheses of pomiferin B (2) and gaultheric acid (3) (a nor-abietane) were achieved utilizing this unified approach.

Scopoletin alleviates high glucose-induced toxicity in human renal proximal tubular cells via inhibition of oxidative damage, epithelial-mesenchymal transition, and fibrogenesis.

BACKGROUND: Recent years of evidence suggest the crucial role of renal tubular cells in developing diabetic kidney disease. Scopoletin (SCOP) is a plant-based coumarin with numerous biological activities. This study aimed to determine the effect of SCOP on renal tubular cells in developing diabetic kidney disease and to elucidate mechanisms. METHODS AND RESULTS: In this study, SCOP was evaluated in vitro using renal proximal tubular (HK-2) cells under hyperglycemic conditions to understand its mechanism of action. In HK-2 cells, SCOP alleviated the high glucose-generated reactive oxygen species (ROS), restored the levels of reduced glutathione, and decreased lipid peroxidation. High glucose-induced alteration in the mitochondrial membrane potential was markedly restored in the SCOP-treated cells. Moreover, SCOP significantly reduced the high glucose-induced apoptotic cell population in the Annexin V-FITC flow cytometry study. Furthermore, high glucose markedly elevated the mRNA expression of fibrotic and extracellular matrix (ECM) components, namely, transforming growth factor (TGF)-ß, alfa-smooth muscle actin (α-SMA), collagen I, and collagen III, in HK-2 cells compared to the untreated cells. SCOP treatment reduced these mRNA expressions compared to the high glucose-treated cells. Collagen I and TGF-ß protein levels were also significantly reduced in the SCOP-treated cells. Further findings in HK-2 cells revealed that SCOP interfered with the epithelial-mesenchymal transition (EMT) in the high glucose-treated HK-2 cells by normalizing E-cadherin and downregulating the vimentin and α-SMA proteins. CONCLUSIONS: In conclusion, SCOP modulates the high glucose-generated renal tubular cell oxidative damage and accumulation of ECM components and may be a promising molecule against diabetic nephropathy.

Diel variation of plankton in the highly impacted freshwater zone of Hooghly estuary in relation to ecological alteration.

Plankton are promising ecological monitoring tool that responds quickly to any sort of aquatic ecological alteration, of which many of them are much susceptible to ecological variations. Therefore, monitoring shifts in plankton composition can indicate changes in water quality and aid to identify potential pollution sources. In the present study, the variation in plankton dynamics in relation to ecological variables were monitored in the freshwater zone of the Hooghly estuary from May 2020 to April 2021. The study was conducted in the interval of every six hours. i.e., at 6 A.M., 12 P.M., 6 P.M., and 12 A.M. The present finding revealed the occurrence of 54 phytoplankton and 20 zooplankton taxa/species. Diel variation revealed that among different time intervals, the highest abundance of phytoplankton was recorded 28,307 cells l-1 at 12 P.M, while the lowest was recorded 10,632 cells l-1 at 6 A.M. However, the highest zooplankton abundance was observed 804 ind l-1 at 6 A.M., and the lowest was recorded 156 ind l-1 at 6 P.M. The ANOVA (p < 0.05) analysis indicated significant diel variation for many planktonic genera. The CCA exhibited that most of the phytoplankton were influenced by multiple water quality variables such as temperature, turbidity, calcium, pH, salinity, DO, and nutrients. However, the majority of the zooplankton were affected by turbidity, total phosphorus, sulphate, calcium and available nitrogen. Significant seasonal variation in plankton composition has also been observed. The present study will help to determine the varying diel pattern of planktons in retort to alterations in the water quality parameters and varying ecological niches.

Electrocatalysis as a key strategy for the total synthesis of natural products.

Electrochemical strategies have been a powerful approach for the synthesis of valuable intermediates, in particular heterocyclic motifs. Because of the mild nature, a wide range of nonclassical bond disconnections have been achieved via in situ-generated radical intermediates in a highly efficient manner. In particular, anodic electrochemical oxidative strategies have been utilized for the total synthesis of many structurally intriguing natural products. In this review article, we have discussed a number of total syntheses of structurally intriguing alkaloids and terpenoids in which electrochemical processes play an important role as a key methodology.

The psychometric properties of the Bangla Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5): preliminary reports from a large-scale validation study.

BACKGROUND: The Posttraumatic Stress Disorder Checklist (PCL-5) is the most widely used screening tool in assessing posttraumatic stress disorder symptoms, based on the Diagnostic and Statistical Manual of Mental disorders (DSM-5) criteria. This study aimed to evaluate the psychometric properties of the newly translated Bangla PCL-5. METHODS: A cross-sectional survey was carried out among 10,605 individuals (61.0% male; mean age: 23.6 ± 5.5 [13-71 years]) during May and June 2020, several months after the onset of the COVID-19 outbreak in Bangladesh. The survey included the Bangla PCL-5 and the PHQ-9 depression scale. We used confirmatory factor analysis to test the four-factor DSM-5 model, the six-factor Anhedonia model, and the seven-factor hybrid model. RESULTS: The Bangla PCL-5 displayed adequate internal consistency (Cronbach's alpha = 0.90). The Bangla PCL-5 score was significantly correlated with scores of the PHQ-9 depression scale, confirming strong convergent validity. Confirmatory factor analyses indicated the models had a good fit to the data, including the four-factor DSM-5 model, the six-factor Anhedonia model, and the seven-factor hybrid model. Overall, the seven-factor hybrid model exhibited the best fit to the data. CONCLUSIONS: The Bangla PCL-5 appears to be a valid and reliable psychometric screening tool that may be employed in the prospective evaluation of posttraumatic stress disorder in Bangladesh.

Pd(0)-Catalyzed Deacylative Allylations (DaA) Strategy and Application in the Total Synthesis of Alkaloids.

Natural product synthesis has been the prime focus for the development of new carbon-carbon bond forming transformations. In particular, the construction of molecules with all-carbon quaternary centers remain one of the most facinating targets. In this regard, transition-metal catalyzed processes have gained imporatnce owing to their mild nature. Towards this, Pd(0)-catalyzed decarboxylative allylations (DcA) is worth mentioning and has emerged as a convenient method for synthesis of molecules even in their enantioenriched form. However, in order to have a flexible approach that facilitate rapid production of derivatives by utilizing commercially available allyl alcohols, the concept of Pd(0)-catalyzed deacylative allylations (DaA) methodology gains popularity. In these reactions, the transfer of an acyl group has a functional role in activating the allylic alcohol (proelectrophile) toward reaction with Pd(0)-catalysts. We present here an Account on newly conceptualized deacylative allylations (DaA) methodology and its applications in the synthesis of various intermediates and building blocks. Further, its potential in the total synthesis of naturally occurring alkaloids have been summarized in this personal account.

Depressive symptoms associated with COVID-19 preventive practice measures, daily activities in home quarantine and suicidal behaviors: Findings from a large-scale online survey in Bangladesh.

BACKGROUND: The world is facing a public health emergency situation caused by the COVID-19 pandemic. Psychological wellbeing among individuals worldwide has been negatively affected by the pandemic especially in low- and middle-income countries such as Bangladesh. The present study aimed to assess the estimate of depressive symptoms and investigated its associations with COVID-19 preventive practice measures, daily activities in home quarantine, and suicidal behaviors in a large-scale Bangladeshi online survey. METHODS: An online-based cross-sectional survey was widely distributed to Bangladeshi citizens. A total of 13,654 participants (61.0% male; mean age = 24.0 years [SD = 6.0]; age range 18-65 years) completed the survey between May and June (2020). The survey included socio-demographics and COVID-19-related questions, along with lifestyle, suicidal, and psychometric measures. Hierarchical regression was performed to determine significant associations between depression and examined variables. RESULTS: The estimate of depressive symptoms during the COVID-19 pandemic was 43.5%. Based on hierarchical regression analysis, depression was significantly associated with not engaging in COVID-19 preventive measures, daily activities in home quarantine (e.g., playing videogames), and suicidal behaviors. CONCLUSIONS: Depressive symptoms appeared to be high during the COVID-19 pandemic in Bangladesh. To fight against the pandemic, mental health issues as well as physical health issues need to be taken into consideration.

Hydrogen sulfide inhibits Ca2+-induced mitochondrial permeability transition pore opening in type-1 diabetes.

Hydrogen sulfide (H2S) attenuates N-methyl-d-aspartate receptor-R1 (NMDA-R1) and mitigates diabetic renal damage; however, the molecular mechanism is not well known. Whereas NMDA-R1 facilitates Ca2+ permeability, H2S is known to inhibit L-type Ca2+ channel. High Ca2+ activates cyclophilin D (CypD), a gatekeeper protein of mitochondrial permeability transition pore (MPTP), thus facilitating molecular exchange between matrix and cytoplasm causing oxidative outburst and cell death. We tested the hypothesis of whether NMDA-R1 mediates Ca2+ influx causing CypD activation and MPTP opening leading to oxidative stress and renal injury in diabetes. We also tested whether H2S treatment blocks Ca2+ channel and thus inhibits CypD and MPTP opening to prevent renal damage. C57BL/6J and Akita (C57BL/6J-Ins2Akita) mice were treated without or with H2S donor GYY4137 (0.25 mg·kg-1·day-1 ip) for 8 wk. In vitro studies were performed using mouse glomerular endothelial cells. Results indicated that low levels of H2S and increased expression of NMDA-R1 in diabetes induced Ca2+ permeability, which was ameliorated by H2S treatment. We observed cytosolic Ca2+ influx in hyperglycemic (HG) condition along with mitochondrial-CypD activation, increased MPTP opening, and oxidative outburst, which were mitigated with H2S treatment. Renal injury biomarker KIM-1 was upregulated in HG conditions and normalized following H2S treatment. Inhibition of NMDA-R1 by pharmacological blocker MK-801 revealed similar results. We conclude that NMDA-R1-mediated Ca2+ influx in diabetes induces MPTP opening via CypD activation leading to increased oxidative stress and renal injury, and H2S protects diabetic kidney from injury by blocking mitochondrial Ca2+ permeability through NMDA-R1 pathway.

A study on knowledge, attitude, and practice regarding mental health illnesses in Amdanga block, West Bengal.

BACKGROUND: The discourse of mental health is getting its due attention after all these years in India. A major threat to the mental health system is the demand side factors, namely, knowledge, attitude, and practice (KAP) of the general population toward this. In spite of growing concern regarding mental health in India, this kind of study to assess the mental health status has been very few in India, more so in West Bengal. OBJECTIVES: With this background, this study was carried out with the objectives to validate the Community Attitude to Mental Illness (CAMI), to assess the different sociodemographic factors among the study population, to assess the KAP regarding mental illness among the study population. METHODS: It was an observational, descriptive study with cross-sectional design done at Amdanga Community Development Block, North 24 Parganas, West Bengal, India, in 2015-16. Questionnaire validation to assess the KAP was the primary objective with obtaining the descriptive data were the second one. CAMI questionnaire was used which was validated for the given area by validation methods such as Cronbach's alpha and structural equation modeling. The resultant questionnaire was used in the field on adult population after a single-stage survey design to collect 730 samples. RESULTS: The test statistics showed that the questionnaire was reasonably valid after a few tweakings. SEM identified well-define domains in the attitude part. 94.9% says that they are willing to live with a people with mental illness. 14.9% has actually done so. Health-care seeking behavior shows that 19.2% will go to a GP in case of any mental illness. Furthermore, attitude toward mental illness showed mixed picture as also knowledge. This study correlated with various studies of developing countries and it was seen that these population showed markedly different attitudes for probability of the patients getting cured than many other countries. Furthermore, stigma was gradually decreasing, as evident from various other studies. CONCLUSION: This study will provide valuable insights into the cognitive and affective aspect of mental illness among these population and thus help in implementing better policies in this regard, as this is fast becoming the talk of the day.

Moderate intensity exercise prevents diabetic cardiomyopathy associated contractile dysfunction through restoration of mitochondrial function and connexin 43 levels in db/db mice.

AIMS: Although the cardiovascular benefits of exercise are well known, exercise induced effects and mechanisms in prevention of cardiomyopathy are less clear during obesity associated type-2 diabetes. The current study assessed the impact of moderate intensity exercise on diabetic cardiomyopathy by examining cardiac function and structure and mitochondrial function. METHODS: Obese-diabetic (db/db), and lean control (db/+) mice, were subjected to a 5 week, 300 m run on a tread-mill for 5 days/week at the speeds of 10-11 m/min. Various physiological parameters were recorded and the heart function was evaluated with M-mode echocardiography. Contraction parameters and calcium transits were examined on isolated cardiomyocytes. At the molecular level: connexin 43 and 37 (Cx43 and 37) levels, mitochondrial biogenesis regulators: Mfn2 and Drp-1 levels, mitochondrial trans-membrane potential and cytochrome c leakage were assessed through western blotting immunohistochemistry and flow cytometry. Ability of exercise to reverse oxygen consumption rate (OCR), tissue ATP levels, and cardiac fibrosis were also determined. RESULTS: The exercise regimen was able to prevent diabetic cardiac functional deficiencies: ejection fraction (EF) and fractional shortening (FS). Improvements in contraction velocity and contraction maximum were noted with the isolated cardiomyocytes. Restoration of interstitial and micro-vessels associated Cx43 levels and improved gap junction intercellular communication (GJIC) were observed. The decline in the Mfn2/Drp-1 ratio in the db/db mice hearts was prevented after exercise. The exercise regimen further attenuated transmembrane potential decline and cytochrome c leakage. These corrections further led to improvements in OCR and tissue ATP levels and reduction in cardiac fibrosis. CONCLUSIONS: Moderate intensity exercise produced significant cardiovascular benefits by improving mitochondrial function through restoration of Cx43 networks and mitochondrial trans-membrane potential and prevention of excessive mitochondrial fission.

DNA hypermethylation in hyperhomocysteinemia contributes to abnormal extracellular matrix metabolism in the kidney.

Hyperhomocysteinemia (HHcy) is prevalent in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Emerging studies suggest that epigenetic mechanisms contribute to the development and progression of fibrosis in CKD. HHcy and its intermediates are known to alter the DNA methylation pattern, which is a critical regulator of epigenetic information. In this study, we hypothesized that HHcy causes renovascular remodeling by DNA hypermethylation, leading to glomerulosclerosis. We also evaluated whether the DNA methylation inhibitor, 5-aza-2'-deoxycytidine (5-Aza) could modulate extracellular matrix (ECM) metabolism and reduce renovascular fibrosis. C57BL/6J (wild-type) and cystathionine-ß-synthase (CBS(+/-)) mice, treated without or with 5-Aza (0.5 mg/kg body weight, i.p.), were used. CBS(+/-) mice showed high plasma Hcy levels, hypertension, and significant glomerular and arteriolar injury. 5-Aza treatment normalized blood pressure and reversed renal injury. CBS(+/-) mice showed global hypermethylation and up-regulation of DNA methyltransferase-1 and -3a. Methylation-specific PCR showed an imbalance between matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 and -2 and also increased collagen and galectin-3 expression. 5-Aza reduced abnormal DNA methylation and restored the MMP-9/TIMP-1, -2 balance. In conclusion, our data suggest that during HHcy, abnormal DNA methylation and an imbalance between MMP-9 and TIMP-1 and -2 lead to ECM remodeling and renal fibrosis.

Detection of base-pair mismatches in DNA using graphene-based nanopore device.

We present a unique way to detect base-pair mismatches in DNA, leading to a different epigenetic disorder by the method of nanopore sequencing. Based on a tight-binding formulation of a graphene-based nanopore device, using the Green's function approach we study the changes in the electronic transport properties of the device as we translocate a double-stranded DNA through the nanopore embedded in a zigzag graphene nanoribbon. In the present work we are not only successful in detecting the usual AT and GC pairs but also a set of possible mismatches in the complementary base pairing.

Hydrogen sulfide mitigates hyperglycemic remodeling via liver kinase B1-adenosine monophosphate-activated protein kinase signaling.

Hyperglycemia (HG) reduces AMPK activation leading to impaired autophagy and matrix accumulation. Hydrogen sulfide (H2S) treatment improves HG-induced renovascular remodeling however, its mechanism remains unclear. Activation of LKB1 by the formation of heterotrimeric complex with STRAD and MO25 is known to activate AMPK. We hypothesized that in HG; H2S induces autophagy and modulates matrix synthesis through AMPK-dependent LKB1/STRAD/MO25 complex formation. To address this hypothesis, mouse glomerular endothelial cells were treated with normal and high glucose in the absence or presence of sodium hydrogen sulfide (NaHS), an H2S donor. HG decreased the expression of H2S regulating enzymes CBS and CSE, and autophagy markers Atg5, Atg7, Atg3 and LC3B/A ratio. HG increased galectin-3 and periostin, markers of matrix accumulation. Treatment with NaHS to HG cells increased LKB1/STRAD/MO25 formation and AMPK phosphorylation. Silencing the encoded genes confirmed complex formation under normoglycemia. H2S-mediated AMPK activation in HG was associated with upregulation of autophagy and diminished matrix accumulation. We conclude that H2S mitigates adverse remodeling in HG by induction of autophagy and regulation of matrix metabolism through LKB1/STRAD/MO25 dependent pathway.

Epigenetic regulation of aortic remodeling in hyperhomocysteinemia.

Hyperhomocysteinemia (HHcy) is prevalent in patients with hypertension and is an independent risk factor for aortic pathologies. HHcy is known to cause an imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), leading to the accumulation of collagen in the aorta and resulting in stiffness and development of hypertension. Although the exact mechanism of extracellular matrix (ECM) remodeling is unclear, emerging evidence implicates epigenetic regulation involving DNA methylation. Our purpose was to investigate whether 5-aza-2'-deoxycytidine (Aza), a DNA methyltransferase (DNMT1) inhibitor, reduces high blood pressure (BP) by regulating aortic ECM remodeling in HHcy. Wild-type and cystathionine ß-synthase (CBS)(+/-) HHcy mice were treated with Aza (0.5 mg/kg body weight). In HHcy mice, Aza treatment normalized the plasma homocysteine (Hcy) level and BP. Thoracic and abdominal aorta ultrasound revealed a reduction in the resistive index and wall-to-lumen ratio. Vascular response to phenylephrine, acetylcholine, and sodium nitroprusside improved after Aza in HHcy mice. Histology showed a marked reduction in collagen deposition in the aorta. Aza treatment decreased the expression of DNMT1, MMP9, TIMP1, and S-adenosyl homocysteine hydrolase (SAHH) and upregulated methylene tetrahydrofolate reductase (MTHFR). We conclude that reduction of DNA methylation by Aza in HHcy reduces adverse aortic remodeling to mitigate hypertension.

MMP-9- and NMDA receptor-mediated mechanism of diabetic renovascular remodeling and kidney dysfunction: hydrogen sulfide is a key modulator.

Previously we reported that matrix metalloproteinase-9 (MMP-9) plays an important role in extracellular matrix (ECM) remodeling in diabetic kidney. Induction of NMDA-R and dysregulation of connexins (Cxs) were also observed. We concluded that this was due to decreased H2S production by downregulation of CBS and CSE enzymes. However, the potential role of H2S to mitigate ECM dysregulation and renal dysfunction was not clearly understood. The present study was undertaken to determine whether H2S supplementation reduces MMP-9-induced ECM remodeling and dysfunction in diabetic kidney. Wild type (C57BL/6J), diabetic (Akita, C57BL/6J-Ins2(Akita)), MMP-9 knockout (MMP-9(-/-), M9KO) and double KO of Akita/MMP-9(-/-) (DKO) mice were treated without or with 0.005 g/l of NaHS (as a source of H2S) in drinking water for 30 days. Decreased tissue production and plasma content of H2S in Akita mice were ameliorated with H2S supplementation. Dysregulated expression of MMP-9, CBS, CSE, NMDA-R1 and Cxs-40, -43 was also normalized in Akita mice treated with H2S. In addition, increased renovascular resistive index (RI), ECM deposition, plasma creatinine, and diminished renal vascular density and cortical blood flow in Akita mice were normalized with H2S treatment. We conclude that diminished H2S production in renal tissue and plasma levels in diabetes mediates adverse renal remodeling, and H2S therapy improves renal function through MMP-9- and NMDA-R1-mediated pathway.

Hyperhomocysteinemia: a missing link to dysfunctional HDL via paraoxanase-1.

Paraoxanase-1 (PON1) is an HDL-associated enzyme that contributes to the antioxidant and antiatherosclerotic properties of HDL. Lack of PON1 results in dysfunctional HDL. HHcy is a risk factor for cardiovascular disorders, and instigates vascular dysfunction and ECM remodeling. Although studies have reported HHcy during atherosclerosis, the exact mechanism is unclear. Here, we hypothesize that dysfunctional HDL due to lack of PON1 contributes to endothelial impairment and atherogenesis through HHcy-induced ECM re-modeling. To verify this hypothesis, we used C57BL6/J and PON1 knockout mice (KO) and fed them an atherogenic diet. The expression of Akt, ADMA, and DDAH, as well as endothelial gap junction proteins such as Cx-37 and Cx-40 and eNOS was measured for vascular dysfunction and inflammation. We observed that cardiac function was decreased and plasma Hcy levels were increased in PON1 KO mice fed the atherogenic diet compared with the controls. Expression of Akt, eNOS, DDAH, Cx-37, and Cx-40 was decreased, and the expression of MMP-9 and ADMA was increased in PON1 KO mice fed an atherogenic diet compared with the controls. Our results suggest that HHcy plays an intricate role in dysfunctional HDL, owing to the lack of PON1. This contributes to vascular endothelial impairment and atherosclerosis through MMP-9-induced vascular remodeling.

Charge transport in a double-stranded DNA: Effects of helical symmetry and long-range hopping.

Within a tight-binding framework, we examine conformation-dependent charge transport properties of the DNA double-helix, including helical symmetry and the possibility of multiple charge conduction pathways. Using techniques based on the Green's function method, we inspect changes in the localization properties of DNA in the presence of long-range hopping, with varying disorder strength. We study three characteristic DNA sequences, two periodic and one random. We observe that, in all cases, due to disorder-induced delocalization, the localization length variation is similar. We also investigate the effect of backbone energetics on current-voltage (I-V) responses, using the Landauer-Büttiker formalism. We find that, in the presence of helical symmetry and long-range hopping, due to environmental effects, DNA can undergo a phase transition from semiconductor to insulator.

Total synthesis of (+)-oridamycins A and B.

We have accomplished a unified strategy to achieve the structurally intriguing indolosesquiterpene alkaloids with diverse biological activity, xiamycin A (1a), xiamycin A methyl ester (1b) and oridamycins A (2a), and B (2b), which possesses a complex 6/6/6/5/6-fused pentacyclic skeleton bearing a carbazole moiety fused with a highly functionalized trans-decalin motif. Lewis acid-mediated epoxy-ene cyclization establishes the required pentacyclic scaffold with the installation of the four contiguous stereogenic centers. Further oxidative cleavage of the vinyl functionality, followed by successive functional group interconversions, completed the total synthesis of the indolosesquiterpene alkaloids.