Synthesis, Crystallographic Characterization and Density Functional Study of Novel Spoke-Molecular Tetravent ethyltriphenylphosphorous Dibromide

A novel molecular tetravent ethyltriphenylphosphorous dibromide ((C6H5) 3PCH2Br2) has been synthesized in toluene and has been characterized by single crystal x-ray crystallography. Theoretical studies have been conducted utilizing DFT (B3LYP/6-311+ G (d, p) level of theory both in gas phase and solution using diverse solvents. Potential surface energy calculations revealed the existence of the tetravelent diionic form as a global minimum except in dimethylsolfoxide where our adduct is more stable. Calculations showed that the Br-Br bond distance is in quadratic variation with the medium dielectric constant. The unusual Br-Br lengthen is reasonably rationalized in terms of charge transfer of electron density from the π clouds in phenyl moieties to the σ* of the dibromine entity. The average harmonic oscillator index of aromaticity of the complex are found suffering a deviation from unity

Investigation of the Ameliorating Effect of Copper Albumin Complex on Lysyl oxidase in monosodium iodoacetate -Induced Knee Osteoarthritis in Rats

Knee osteoarthritis (KOA) is a common type of joint degeneration which causes progressive damage of the joint structure and has less therapeutic options. It has been found that oral consumption of Copper Albumin Complex as anti-inflammatory drug has a positive effect on the treatment of joint deterioration. The present study aimed to investigate the effect of oral administration of Copper Albumin Complex (cu-albumin complex) on Lysyl oxidase (LOX) which acts as a protective factor in KOA. Fifty adult albino rats were divided into 3 groups: negative control (10 normal rats); positive control (20 rats with KOA which left without induction treatment); and treated group (20 rats with KOA which treated with administration of copper albumin complex). Treated and untreated arthritic groups were subdivided equally into mild and severe groups (10 rats for each) according to the severity of clinical signs. KOA was induced by intra-articular injection of monosodium iodoacetate (MIA). At the experimental end, the joints were examined histopathologically and immunohistochemically after cervical dislocation of rats. It was observed that the treatment with CU- was effective in reducing disease severity and in improvement of Lysyl oxidase KOA. It was concluded that Copper albumin complex has a positive effect in the improvement of LOX of Knee joint cartilages of rats affected by osteoarthritis (OA)

In Vivo Investigation of the Ameliorating Effect of Copper Albumin Complex on chondroitin sulfate in Monosodium iodoacetate -Induced Knee Osteoarthritis

Osteoarthritis (OA) is a condition that manifests as cartilage deterioration and subchondral bone sclerosis in the joint tissues. The weight-bearing joint is most severely impacted by OA. According to some research, consuming foods high in copper albumin complex (cu-albumin complex) can help with OA-related joint degeneration and pain relief. The current study's objective to determine how oral administration of the cu-albumin complex as an anti-inflammatory medication affected the development of rat knee osteoarthritis (KOA). Fifty adult albino rats were divided into three groups: negative control untreated (n= 10, no KOA induction); positive untreated control (n= 20, KOA induction); and treated group (n= 20, KOA induction with administration of cu-albumin complex). According to the severity of the clinical symptoms, treated and untreated arthritic groups were equally divided into mild and severe groups (n=10). Monosodium iodoacetate (MIA) was used as intra-articular injection for osteoarthritis induction. Rats were euthanized after a month of the beginning of the experiment, and the joints were examined histopathologically and immunohistochemically. It was indicated that the treatment was effective in reducing KOA severity and in improvement of chondroitin sulfate of the affected cartilages. In conclusion, the structure of the chondroitin sulphate in the knee joint cartilages of KOA-affected rats was modified by the cu-albumin complex

Silencing p75NTR prevents proNGF-induced endothelial cell death and development of acellular capillaries in rat retina

Accumulation of the nerve growth factor precursor (proNGF) and its receptor p75NTR have been associated with several neurodegenerative diseases in both brain and retina. However, whether proNGF contributes to microvascular degeneration remain unexplored. This study seeks to investigate the mechanism by which proNGF/p75NTR induce endothelial cell (EC) death and development of acellular capillaries, a surrogate marker of retinal ischemia. Stable overexpression of the cleavage-resistant proNGF and molecular silencing of p75NTR were utilized in human retinal EC and rat retinas in vivo. Stable overexpression of proNGF decreased NGF levels and induced retinal vascular cell death evident by 1.9-fold increase in acellular capillaries and activation of JNK and cleaved-PARP that were mitigated by p75NTRshRNA. In vitro, overexpression of proNGF did not alter TNF-α level, reduced NGF, however induced EC apoptosis evident by activation of JNK and p38 MAPK, cleaved-PARP. Silencing p75NTR using siRNA restored expression of NGF and TrkA activation and prevented EC apoptosis. Treatment of EC with human-mutant proNGF induced apoptosis that coincided with marked protein interaction and nuclear translocation of p75NTR and the neurotrophin receptor interacting factor. These effects were abolished by a selective p75NTR antagonist. Therefore, targeting p75NTR represents a potential therapeutic strategy for diseases associated with aberrant expression of proNGF

Modulating Expression of Thioredoxin Interacting Protein (TXNIP) Prevents Secondary Damage and Preserves Visual Function in a Mouse Model of Ischemia/Reperfusion

Retinal neurodegeneration, an early characteristic of several blinding diseases, triggers glial activation, resulting in inflammation, secondary damage and visual impairment. Treatments that aim only at neuroprotection have failed clinically. Here, we examine the impact of modulating thioredoxin interacting protein (TXNIP) to the inflammatory secondary damage and visual impairment in a model of ischemia/reperfusion (IR). Wild type (WT) and TXNIP knockout (TKO) mice underwent IR injury by increasing intraocular pressure for 40 min, followed by reperfusion. An additional group of WT mice received intravitreal TXNIP-antisense oligomers (ASO, 100 µg/2 µL) 2 days post IR injury. Activation of Müller glial cells, apoptosis and expression of inflammasome markers and visual function were assessed. IR injury triggered early TXNIP mRNA expression that persisted for 14 days and was localized within activated Müller cells in WT-IR, compared to sham controls. Exposure of Müller cells to hypoxia-reoxygenation injury triggered endoplasmic reticulum (ER) stress markers and inflammasome activation in WT cells, but not from TKO cells. Secondary damage was evident by the significant increase in the number of occluded acellular capillaries and visual impairment in IR-WT mice but not in IR-TKO. Intervention with TXNIP-ASO prevented ischemia-induced glial activation and neuro-vascular degeneration, and improved visual function compared to untreated WT. Targeting TXNIP expression may offer an effective approach in the prevention of secondary damage associated with retinal neurodegenerative diseases

Diabetes and overexpression of proNGF cause retinal neurodegeneration via activation of RhoA pathway.

Our previous studies showed positive correlation between accumulation of proNGF, activation of RhoA and neuronal death in diabetic models. Here, we examined the neuroprotective effects of selective inhibition of RhoA kinase in the diabetic rat retina and in a model that stably overexpressed the cleavage-resistance proNGF plasmid in the retina. Male Sprague-Dawley rats were rendered diabetic using streptozotocin or stably express cleavage-resistant proNGF plasmid. The neuroprotective effects of the intravitreal injection of RhoA kinase inhibitor Y27632 were examined in vivo. Effects of proNGF were examined in freshly isolated primary retinal ganglion cell (RGC) cultures and RGC-5 cell line. Retinal neurodegeneration was assessed by counting TUNEL-positive and Brn-3a positive retinal ganglion cells. Expression of proNGF, p75(NTR), cleaved-PARP, caspase-3 and p38MAPK/JNK were examined by Western-blot. Activation of RhoA was assessed by pull-down assay and G-LISA. Diabetes and overexpression of proNGF resulted in retinal neurodegeneration as indicated by 9- and 6-fold increase in TUNEL-positive cells, respectively. In vitro, proNGF induced 5-fold cell death in RGC-5 cell line, and it induced >10-fold cell death in primary RGC cultures. These effects were associated with significant upregulation of p75(NTR) and activation of RhoA. While proNGF induced TNF-α expression in vivo, it selectively activated RhoA in primary RGC cultures and RGC-5 cell line. Inhibiting RhoA kinase with Y27632 significantly reduced diabetes- and proNGF-induced activation of proapoptotic p38MAPK/JNK, expression of cleaved-PARP and caspase-3 and prevented retinal neurodegeneration in vivo and in vitro. Taken together, these results provide compelling evidence for a causal role of proNGF in diabetes-induced retinal neurodegeneration through enhancing p75(NTR) expression and direct activation of RhoA and p38MAPK/JNK apoptotic pathways