Upregulation of cytosolic NADP+-dependent isocitrate dehydrogenase by hyperglycemia protects renal cells against oxidative stress

Hyperglycemia-induced oxidative stress is widely recognized as a key mediator in the pathogenesis of diabetic nephropathy, a complication of diabetes. We found that both expression and enzymatic activity of cytosolic NADP⁺-dependent isocitrate dehydrogenase (IDPc) were upregulated in the renal cortexes of diabetic rats and mice. Similarly, IDPc was induced in murine renal proximal tubular OK cells by high hyperglycemia, while it was abrogated by co-treatment with the antioxidant N-Acetyl-Cysteine (NAC). In OK cells, increased expression of IDPc by stable transfection prevented hyperglycemia-mediated reactive oxygen species (ROS) production, subsequent cellular oxidative stress and extracellular matrix accumulation, whereas these processes were all stimulated by decreased IDPc expression. In addition, production of NADPH and GSH in the cytosol was positively correlated with the expression level of IDPc in OK cells. These results together indicate that upregulation of IDPc in response to hyperglycemia might play an essential role in preventing the progression of diabetic nephropathy, which is accompanied by ROS-induced cellular damage and fibrosis, by providing NADPH, the reducing equivalent needed for recycling reduced glutathione and low molecular weight antioxidant thiol proteins.     

The In vitro antioxidant properties of chinese highland lichens

Antioxidant properties of 46 lichen species collected from high-UV exposed alpine areas of southwestern China were evaluated for their therapeutic utilization. Anti-linoleic acid peroxidation activity, 1, 1-diphenyl-2-picryl-hydrazyl (DPPH) scavenging activity, reducing power and the total phenolic contents were assessed in methanol extract of the lichens in vitro. Extracts of Peltigera praetextata and Sticta nylanderiana exhibited potent activity in all antioxidant tests. Especially, extracts of S. nylanderiana exhibited 1.37 times higher anti-linoleic acid peroxidation activity than ascorbic acid used as a positive control. It also showed the strongest free radical scavenging activity among all the tested species with an inhibition of 90.4% at the concentration of 330microgram/ml. Potent reducing power was also detected in the lichen extract compared with BHA. Generally, the antioxidant lichens contained large amount of phenolic contents. The activity-guided bioautographic TLC and HPLC analysis are used to find out the compounds responsible for the potent antioxidant activities of S. nylanderiana extract. The analysis demonstrated that lecanoric acid is one of the effective antioxidant compounds in S. nylanderiana. The results suggested that several highland lichens can be used as a novel bioresource for natural antioxidants.     

Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome

Mutations in the human Notch ligand jagged 1 (JAG1) result in a multi-system disorder called Alagille syndrome (AGS). AGS is chiefly characterized by a paucity of intrahepatic bile ducts (IHBD), but also includes cardiac, ocular, skeletal, craniofacial and renal defects. The disease penetration and severity of the affected organs can vary significantly and the molecular basis for this broad spectrum of pathology is unclear. Here, we report that Jag1 inactivation in the portal vein mesenchyme (PVM), but not in the endothelium of mice, leads to the hepatic defects associated with AGS. Loss of Jag1 expression in SM22α-positive cells of the PVM leads to defective bile duct development beyond the initial formation of the ductal plate. Cytokeratin 19-positive cells are detected surrounding the portal vein, yet they are unable to form biliary tubes, revealing an instructive role of the vasculature in liver development. These findings uncover the cellular basis for the defining feature of AGS, identify mesenchymal Jag1-dependent and -independent stages of duct development, and provide mechanistic information for the role of Jag1 in IHBD formation.     

Addressing the threats to biodiversity from oil-palm agriculture

Oil-palm agriculture is the greatest immediate threat to biodiversity in Southeast Asia. Despite the efforts of environmentalists, oil palm continues to expand across the tropics. Those concerned about the impacts of oil palm on biodiversity must face some harsh social, economic, and ecological realities: (i) oil palm has been a very profitable crop; (ii) palm oil is used in so many products that simple, direct actions, such as boycotts, are unlikely to succeed; (iii) there is currently insufficient demand for certified sustainable palm oil and inadequate political clout from environmental groups in two of the biggest markets for palm oil—China and India—to slow the rate of forest conversion; and (iv) oil-palm agriculture has improved the lives of poor rural communities in Southeast Asia (although it has also disenfranchised some indigenous communities). To address the threats posed by oil-palm agriculture to biodiversity, environmentalists must change the behavior of the palm oil business through: (i) regulations to curb undesirable activities (e.g., a ban on converting forests to oil palm); (ii) financial incentives to promote desirable behavior (e.g., production of certified, sustainable oil palm); (iii) financial disincentives designed to discourage undesirable behavior (e.g., consumer pressure on major manufacturers and retailers to use palm oil that does not come from plantations created at the expense of forests); and (iv) the promotion of alternative, more biodiversity-friendly uses of forested land that might otherwise be converted to oil palm. There is no single best approach for dealing with the oil-palm crisis in Southeast Asia; a mixture of regulations, incentives, and disincentives targeted at all sectors of the oil-palm industry is necessary to protect the region’s rapidly disappearing forests.     

Lupane-type triterpenoids from the steamed leaves of Acanthopanax koreanum and their inhibitory effects on the LPS-stimulated pro-inflammatory cytokine production in bone marrow-derived dendritic cells

Two new compounds, (20R)-3α-hydroxy-29-dimethoxylupan-23,28-dioic acid (1) and 3α-hydroxylup-20(29)-ene-23,28-dioic acid 28-O-[β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl] ester (2), and eight known lupane-type triterpenoids (3-10), were isolated from steamed leaves of Acanthopanax koreanum. Chemical structures were determined using a combination of spectroscopic analyses and chemical reactivity. Compounds 1-10 were evaluated for their inhibitory activities on lipopolysaccharide (LPS)-stimulated interleukin (IL)-12 production in bone marrow-derived dendritic cells (BMDCs). Compound 1 exhibited inhibitory activity with IC(50) value of 26.5 μM on IL-12 production, compared with IC(50) value of 29.6 μM for the positive control. Compound 1 also showed significant suppression of LPS-stimulated IL-6 and tumor necrosis factor-alpha (TNF-α) production.     

Synthesis and evaluation of tricyclic derivatives containing a non-aromatic amide as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)

Highly potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors, including 9-hydroxy-1,2-dihydro-4H-thiopyrano[3,4-c]quinolin-5(6H)-one derivatives with a non-aromatic A-ring, were synthesized. Among the derivatives, 12a showed low nanomolar enzyme and cellular activity (IC₅₀ = 42 nM, ED₅₀ = 220 nM) with good water solubility. Further, 12a exhibited microsomal stability in vitro and brain permeability in vivo.     

Discovery of aminopyridines substituted with benzoxazole as orally active c-Met kinase inhibitors

We report the synthesis and biological evaluation of aminopyridines substituted with benzoxazole. The SAR of the aminopyridines was explored to improve the inhibitory activity against c-Met and to decrease hERG affinity. These studies led to the discovery of amide 24 which showed good c-Met inhibitory potency, low affinity to hERG and favorable pharmacokinetic properties in rats.     

Non-invasive Determination of the Optimized Atrioventricular Delay in Patients with Implanted Biventricular Pacing Devices

Background

Biventricular (BiV) is extensively used in the treatment of congestive heart failure but so far no recommendations for optimized programming of atrioventricular-delay (AVD) settings have been proposed. Can AVD optimization be performed using a simple formula based on non-invasive doppler-echocardiography?

Methods

25 patients (ejection fraction 30±8%) received BiV ICDs. Doppler-echocardiographic evaluation of diastolic and systolic flow was performed for different AVDs (30ms to 150ms) and different stimulation sites (left ventricular (LV), right ventricular and BiV). The optimal atrioventricular delay was calculated applying a simple formula based on systolic and diastolic mechanical delays determined during doppler-echocardiography.

Results

The mean optimal AVD was calculated to be 112±29ms (50 to 180ms) for BiV, 95±30ms (65 to 150ms) for LV and 75±28ms (40 to 125ms) for right ventricular pacing with wide interindividual variations. Compared to suboptimal AVDs diastolic optimization improved preejection and ejection intervals independent to pacing site. Optimization of the AVD significantly increased ejection time during BiV pacing (279ms versus 266ms; p<0.05). Compared to LV or right ventricular pacing BiV pacing produced the shortest mean pre-ejection and longest ejection intervals as parameters of improved systolic ventricular contractile synchrony. Diastolic filling times were longest during BiV pacing compared to LV or RV pacing.

Conclusions

Individual programming of BiV pacing devices increases hemodynamic benefit when implementing the inter-individually widely varying electromechanical delays. Optimization applying a simple formula not only improves diastolic ventricular filling but also increases systolic functional parameters.     

Lower limb dynamics change for children while walking with backpack loads to modulate shock transmission to the head

Backpack load carriage increases ground reaction forces and increases the stiffness in the upper extremity that can cause transmission of higher amount of forces from the lower extremity to the head. This study investigated the effect of load carriage and placement of load on the back on the shock transmission mechanisms amongst children. Fifteen primary school boys with mean age 10.01 (±1.31) years, mean height 136.40 (±10.08) cm and mean mass 31.83 (±7.13) kg completed the study. Subjects carried 10%, 15% and 20% bodyweight (BW) loads on two locations on the back, namely upper and lower. Results showed a significant reduction in pelvic and trunk rotation in the transverse plane and an increase in the upper body stiffness for loads exceeding 15% of BW. The lower limb results showed a reduction in the first peak force and cadence and a significant change in the walking velocity and time to the first peak force for 20% load. No significant differences were found for the load configuration but the upper configuration showed slightly higher shock transmission. The changes in the lower limb dynamics indicated that there are locomotion mechanisms in place amongst children to modulate shock transmission to the head.     

Hard Ticks as Vectors Tested Negative for Severe Fever with Thrombocytopenia Syndrome in Ganghwa-do,Korea during 2019–2020

This study aimed to characterize the seasonal abundance of hard ticks that transmit severe fever with thrombocytopenia syndrome virus from April to November 2019 and 2020 on Ganghwa-do, Incheon Metropolitan City, Korea. The ticks were collected at grassland, grave site, copse and mountain road using a collection trap method. The ixodid hard ticks comprising three species (Haemaphysalis longicornis, H. flava, and Ixodes nipponensis) collected were 6,622 in 2019 and 3,811 in 2020. H. longicornis was the most frequent (97.9% in 2019 and 96.0% in 2020), followed by H. flava (2.0% and 3.0% in 2019 and 2020, respectively) and I. nipponensis (less than 0.1%). Our study demonstrated that seasonal patterns of the tick populations examined for two years were totally unsimilar. The hard ticks tested using RT-qPCR were all negative for severe fever with thrombocytopenia syndrome virus.