- Hydrogen bond-linked pathways of peptide units and polar groups of amino acid residues suitable for electron transfer in cytochrome c proteins. [Journal Article]
- MCMol Cell Biochem 2018 Sep 07
- Electron transfer occurs through heme-Fe across the cytochrome c protein. The current models of long range electron transfer pathways in proteins include covalent σ-bonds, van der Waals forces, and t...
Electron transfer occurs through heme-Fe across the cytochrome c protein. The current models of long range electron transfer pathways in proteins include covalent σ-bonds, van der Waals forces, and through space jump. Hydrogen-bond-linked pathways of delocalized electron units in peptide units and polar side chains of amino acid residues in proteins and internal water molecules are better suited for intramolecular atom-to-atom electron transfer in proteins. Crystal structures of cytochrome c proteins from horse (1HRC), tuna (3CYT), rice (1CCR), and yeast (3CX5) were analyzed using pymol software for 'Hydrogen Bonds' marking the polar atoms within the distance of 2.6-3.3 Å and tracing the atom-to-atom pathways linked by hydrogen bonds. Pathways of hydrogen-bond-linked peptide units, polar side chains of the amino acid residues, and buried water molecules connect heme-Fe through axially coordinated Met80-S and His18-N have been traced in cytochrome c proteins obtained from horse, tuna, rice and yeast with an identical hydrogen-bonded sequence around the heme-Fe: Asn-N-water-O-Tyr-O-Met-S-heme-Fe-His (HN-C=N)-Pro-Asn-Pro-Gly (peptide unit, HN-C=O)-water-O. More than half of the amino acid residues in these pathways are among the conserved list and delocalized electron units, internal water molecules and hydrogen bonds are conspicuous by their presence.
- Estradiol attenuates ischemia reperfusion-induced acute kidney injury through PPAR-γ stimulated eNOS activation in rats. [Journal Article]
- MCMol Cell Biochem 2018 Sep 07
- We investigated the involvement of peroxisome proliferator activated receptor-γ (PPAR-γ)/endothelial nitric oxide synthase (eNOS) pathway in estradiol mediated protection against ischemia reperfusion...
We investigated the involvement of peroxisome proliferator activated receptor-γ (PPAR-γ)/endothelial nitric oxide synthase (eNOS) pathway in estradiol mediated protection against ischemia reperfusion (I/R)-induced acute kidney injury (AKI) in rats. To induce AKI, rats underwent 40 min of bilateral renal ischemia followed by 24 h of reperfusion. I/R-induced kidney damage was quantified by measuring serum creatinine, creatinine clearance, urea nitrogen, uric acid, potassium, fractional excretion of sodium, microproteinuria, and renal oxidative stress (thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione). Hematoxylin eosin stain demonstrated renal histology, while renal expression of apoptotic markers (Bcl-2, Bax), PPAR-γ and eNOS were quantified by immunohistochemistry. Estradiol (1 mg/kg, i.p.) was administered 30 min before I/R in rats. In separate groups, PPAR-γ antagonist, BADGE (30 mg/kg, i.p.), and NOS inhibitor, L-NAME (20 mg/kg, i.p.) were administered prior to estradiol treatment, which was followed by I/R in rats. I/R caused significant renal damage as demonstrated by biochemical (serum/urine), renal oxidative stress and histological changes alongwith increased expression of Bax and decreased levels of Bcl-2, PPAR-γ and eNOS, which were prevented by estradiol. Pre-treatment with BADGE and L-NAME abolished estradiol mediated renoprotection. Notably, I/R + estradiol + BADGE group revealed decreased expression of PPAR-γ and eNOS in renal tissues. In I/R + estradiol + L-NAME group, eNOS expression was reduced while PPAR-γ levels remained unchanged. These results suggest that estradiol modulates PPAR-γ which consequently regulates eNOS expression in rat kidneys. We conclude that estradiol protects against I/R-induced AKI through PPAR-γ stimulated eNOS activation in rats.
- Lasalocid immediately and completely prevents the myocardial damage caused by coronary ischemia reperfusion in rat heart. [Journal Article]
- MCMol Cell Biochem 2018 Sep 06
- Lasalocid, a specific mobile membrane ionophore for calcium, dopamine and norepinephrine was assayed in its capacity to reduce or maintain unaltered the cardiovascular function in conditions of immin...
Lasalocid, a specific mobile membrane ionophore for calcium, dopamine and norepinephrine was assayed in its capacity to reduce or maintain unaltered the cardiovascular function in conditions of imminent myocardial injury. In experiments of coronary blockade and reperfusion carried out in rat heart, it was found that when administered from 5 to 30 minutes prior to the induction of coronary blockade, at a concentration of 2 mg/kg of body weight, the ionophore immediately, simultaneously, and completely interrupts the blood pressure decay, cardiac frequency increase, electrical ventricular tachycardia and fibrillation, as well as the fall of mitochondrial oxidative phosphorylation and decay of mitochondrial oxygen uptake provoked by the induced myocardial injury. It appears that the molecular mode of action of the lasalocid is associated with its unique ability to transport both calcium and the catecholamines, dopamine and norepinephrine, across mitochondrial and bimolecular lipid membranes, as well as through synaptic cell membrane terminals from rat heart, myocardial fibers of the heart and heart chromaffin membrane vesicles. It is suggested that for the potential medical use of lasalocid to detain incoming ischemic myocardial damage, there exists a need to develop a personal electronic device able to simultaneously monitor, detect, and inform on the very early and simultaneous signs of cardiac alterations of electrical, mechano-chemical, metabolic and hydraulic nature, all which precede heart failure and to administer the lasalocid.
- The mitochondrial Nod-like receptor NLRX1 modifies apoptosis through SARM1. [Journal Article]
- MCMol Cell Biochem 2018 Sep 06
- NLRX1, the mitochondrial NOD-like receptor (NLR), modulates apoptosis in response to both intrinsic and extrinsic cues. Insights into the mechanism of how NLRX1 influences apoptosis remain to be dete...
NLRX1, the mitochondrial NOD-like receptor (NLR), modulates apoptosis in response to both intrinsic and extrinsic cues. Insights into the mechanism of how NLRX1 influences apoptosis remain to be determined. Here, we demonstrate that NLRX1 associates with SARM1, a protein with a toll/interleukin-1 receptor (TIR)-containing domain also found in adaptor proteins downstream of toll-like receptors, such as MyD88. While a direct role of SARM1 in innate immunity is unclear, the protein plays essential roles in Wallerian degeneration (WD), a type of neuronal catabolism occurring following axonal severing or damage. In non-neuronal cells, we found that endogenous SARM1 was equally distributed in the cytosol and the mitochondrial matrix, where association with NLRX1 occurred. In these cells, the apoptotic role of NLRX1 was fully dependent on SARM1, indicating that SARM1 was downstream of NLRX1 in apoptosis regulation. In primary murine neurons, however, Wallerian degeneration induced by vinblastine or NGF deprivation occurred in SARM1- yet NLRX1-independent manner, suggesting that WD requires the cytosolic pool of SARM1 or that NLRX1 levels in neurons are too low to contribute to WD regulation. Together, these results shed new light into the mechanisms through which NLRX1 controls apoptosis and provides evidence of a new link between NLR and TIR-containing proteins.
- Induction of HRR genes and inhibition of DNMT1 is associated with anthracycline anti-tumor antibiotic-tolerant breast carcinoma cells. [Journal Article]
- MCMol Cell Biochem 2018 Sep 03
- The aim of the study was to understand the role of homologous recombination repair (HRR) pathway genes in development of chemotolerance in breast cancer (BC). For this purpose, chemotolerant BC cells...
The aim of the study was to understand the role of homologous recombination repair (HRR) pathway genes in development of chemotolerance in breast cancer (BC). For this purpose, chemotolerant BC cells were developed in MCF-7 and MDA MB 231 cell lines after treatment with two anthracycline anti-tumor antibiotics doxorubicin and nogalamycin at different concentrations for 48 h with differential cell viability. The drugs were more effective in MCF-7 (IC50: 0.214-0.242 µM) than in MDA MB 231 (IC50: 0.346-0.37 µM) as shown by cell viability assay. The drugs could reduce the protein expression of PCNA in the cell lines. Increased mRNA/protein expression of the HRR (BRCA1, BRCA2, FANCC, FANCD2, and BRIT1) genes was seen in the cell lines in the presence of the drugs at different concentrations (lower IC50, IC50, and higher IC50) irrespective of the cell viability (68-41%). Quantitative methylation assay showed an increased percentage of hypomethylation of the promoters of these genes after drug treatment in the cell lines. Similarly, chemotolerant neoadjuvant chemotherapy (NACT) treated primary BC samples showed significantly higher frequency of hypomethylation of the genes than the pretherapeutic BC samples. The drugs in different concentrations could reduce m-RNA and protein expression of DNMT1 (DNA methyltransferase 1) in the cell lines. Similar phenomenon was also evident in the NACT samples than in the pretherapeutic BC samples. Thus, our data indicate that reduced DNMT1 expression along with promoter hypomethylation and increased expression of the HRR genes might have importance in chemotolerance in BC.
- Stimulation role of epinephrine in transcription of the melatonin synthesis key enzyme AANAT in the pineal gland of broilers. [Journal Article]
- MCMol Cell Biochem 2018 Sep 03
- Melatonin is a crucial neurohormone synthesized in the pineal gland that influences the physiology of animals. The molecular mechanism of norepinephrine control of the synthesis of melatonin is well ...
Melatonin is a crucial neurohormone synthesized in the pineal gland that influences the physiology of animals. The molecular mechanism of norepinephrine control of the synthesis of melatonin is well documented; however, few reports have described the effects of epinephrine on the synthesis of melatonin. In this study, the effect of epinephrine on melatonin synthesis was investigated by adding different concentrations of epinephrine or norepinephrine to broiler pineal glands cultured in vitro. In addition, we investigated how epinephrine regulates the synthesis of melatonin and the transcription of the key melatonin synthesis enzyme AANAT. We determined the abundance of melatonin, norepinephrine, and epinephrine in broiler serum and the mRNA expression levels of key enzymes under different light conditions. The minimum concentrations of epinephrine and norepinephrine required to recover the melatonin synthesis rhythm in pineal cells were 10-13 and 10-11 mol/L, respectively. Under various light durations, epinephrine reached maximum levels two hours earlier than melatonin. These results demonstrate for the first time that epinephrine can increase the synthesis of melatonin by increasing the transcription of AANAT.
- Mesenchymal stem cells attenuate sepsis-induced liver injury via inhibiting M1 polarization of Kupffer cells. [Journal Article]
- MCMol Cell Biochem 2018 Sep 03
- Sepsis is a leading cause of death in intensive care units that can result in acute hepatic damage. Animal experiments and clinical trials have shown that mesenchymal stem cell (MSC) therapy has some...
Sepsis is a leading cause of death in intensive care units that can result in acute hepatic damage. Animal experiments and clinical trials have shown that mesenchymal stem cell (MSC) therapy has some beneficial in several liver diseases. However, the protective effects of MSC therapy on sepsis-induced hepatic damage and associated mechanisms are not completely understood. The aim of the present study was to investigate the effects of MSCs on sepsis-induced liver injury and underlying mechanisms. A rat model of sepsis-induced liver injury was established by cecal ligation and puncture, and serum alanine aminotransferase and aspartate transaminase activities as well as liver histological changes were measured. Inflammatory cytokines, Kupffer cell M1 phenotype markers, and associated signal molecules were also determined in septic rats and in lipopolysaccharide (LPS)-treated Kupffer cells. Our results showed that injection of MSCs attenuated sepsis-induced liver injury. Treatment with MSCs inhibited activation of Kupffer cells towards M1 phenotype, attenuated TNF-α and IL-6 expression, and promoted IL-4 and IL-10 expression in septic rats and LPS-treated Kupffer cells. Furthermore, MSCs also inhibited the nuclear translocation of nuclear factor-kappa B in LPS-challenged Kupffer cells and the liver of septic rats. These results indicated that MSCs attenuated sepsis-induced liver injury through suppressing M1 polarization of Kupffer cells.
- Potential therapeutic roles of 10-dehydrogingerdione and/or pentoxifylline against calcium deposition in aortic tissues of high dietary cholesterol-fed rabbits. [Journal Article]
- MCMol Cell Biochem 2018 Sep 01
- The present study aimed to investigate the inhibitory effects of 10-dehydrogingerdione (10-DHGD) and pentoxifylline (PTX) either individually or in combined form on calcium deposition in high cholest...
The present study aimed to investigate the inhibitory effects of 10-dehydrogingerdione (10-DHGD) and pentoxifylline (PTX) either individually or in combined form on calcium deposition in high cholesterol diet (HCD)-fed rabbits as compared to atorvastatin (ATOR), and to clarify the underlying mechanisms. Three-months-old male New Zealand white rabbits received either normal chow or HCD for 12 weeks. The latter group was subdivided into five groups and concurrently treated either with vehicle (dyslipidemic control), ATOR, 10-DHGD, PTX or combined 10-DHGD and PTX. Blood samples and aortic tissue were collected for biochemical and histological analyses. HCD-fed rabbits displayed dyslipidemia, inflammation, atherosclerotic lesions, and calcium deposition in aortas as compared to normal group. This was associated with up-regulation of bone morphogenetic protein-2 (BMP-2), wingless-type MMTV integration site family 3A (Wnt3a) mRNA levels and osteopontin expression in their aortic tissue, along with higher serum alkaline phosphatase and osteocalcin levels. Furthermore, a marked decrease in osteoprotegerin, along with a significant increase in receptor activator of NF-κB(RANK) levels, was found in aortic tissue of dyslipidemic rabbits. 10-DHGD and PTX monotherapy significantly modulated the afore-mentioned calcification markers and attenuated aortic calcification to greater extent than ATOR. Combination of 10-DHGD and PTX exerted more anti-calcifying effect than either individual drug. Our findings suggested therapeutic roles of 10-DHGD and PTX against aortic calcium deposition in dyslipidemic rabbits, likely mediated by HDL-raising effect and attenuation of associated inflammation. Combination of 10-DHGD and PTX may represent a promising therapeutic strategy for aortic calcification associated with atherosclerosis.
- TDCPP protects cardiomyocytes from H2O2-induced injuries via activating PI3K/Akt/GSK3β signaling pathway. [Journal Article]
- MCMol Cell Biochem 2018 Sep 01
- Tris (1, 3-dichloro-2-propyl) phosphate (TDCPP) is a major type of organophosphorus flame retardants, and long-term exposure to TDCPP to normal cells or tissues under physiological conditions can ind...
Tris (1, 3-dichloro-2-propyl) phosphate (TDCPP) is a major type of organophosphorus flame retardants, and long-term exposure to TDCPP to normal cells or tissues under physiological conditions can induce toxic effects. But how TDCPP leads to the adverse effects is not yet clear, and the effect of TDCPP under pathological conditions such as reactive oxygen species assault is not well understood. The present study aimed to explore the potential effect of TDCPP against H2O2-induced oxidative stress in H9c2 cardiomyoblasts and rat neonatal cardiomyocytes. We found that H2O2-treatment decreased cell viability and increased lactate dehydrogenase and malondialdehyde generation of H9c2 cells. However, TDCPP could alleviate these effects. TDCPP alleviated Ca2+-overload caused by H2O2 through decreasing store-operated calcium entry. More importantly, TDCPP remarkably decreased H2O2-induced dephosphorylation of Akt and GSK3β, and through this pathway TDCPP mitigated the H2O2-induced apoptosis and detrimental autophagy. Collectively, via mitigating Ca2+-overload and activating the Akt/GSK3β signaling pathway, TDCPP may have a role in protecting cardiomyocytes from oxidative stress.
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- Vitamin D improves vascular function and decreases monoamine oxidase A expression in experimental diabetes. [Journal Article]
- MCMol Cell Biochem 2018 Aug 30
- The active form of vitamin D, 1,25-dihydroxycholecalciferol (1,25(OH)2D3), was reported to improve vascular function in patients with diabetes, yet the underlying mechanisms remain to be fully elucid...
The active form of vitamin D, 1,25-dihydroxycholecalciferol (1,25(OH)2D3), was reported to improve vascular function in patients with diabetes, yet the underlying mechanisms remain to be fully elucidated. Monoamine oxidase (MAO), a mitochondrial enzyme, with two isoforms (A and B) that generates hydrogen peroxide (H2O2) as by-product, has been recently reported to contribute to the pathogenesis of endothelial dysfunction in diabetes. The present study assessed the interaction between vitamin D and MAO in the vascular wall in the setting of type 1 experimental diabetes. To this aim, diabetes was induced in male Wistar rats via a single injection of streptozotocin (STZ, 50 mg/kg, IP) and 1 month later thoracic aortas were harvested and used for organ bath studies and H2O2 measurements. MAO expression was assessed by immunohistochemistry and RT-PCR. Endothelial function was evaluated in isolated aortic rings in the absence vs. presence of 1,25(OH)2D3 (100 nM, 24 h incubation). In diabetic animals, we found a significant reduction in the endothelial-dependent relaxation to acetylcholine and an increased expression of the MAO-A isoform, respectively. Vitamin D significantly improved vascular function, mitigated oxidative stress and decreased MAO-A expression in diabetic vascular preparations. In conclusion, MAO-A is induced in diabetic aortas and vitamin D can improve diabetes-induced endothelial dysfunction by modulating the MAO-A expression.