This study investigated the mechanisms by which D-pinitol induces vasodilation in mouse mesenteric arteries. The results showed that D-pinitol caused concentration-dependent vasodilation that was endothelium-dependent and nitric oxide (NO)-mediated. D-pinitol increased phosphorylation of eNOS at its active site and decreased phosphorylation at its inactive site. It also increased NO production in mesenteric arteries through a mechanism involving calcium-calmodulin activation of eNOS. Administration of D-pinitol reduced systolic blood pressure in mice. These findings suggest D-pinitol causes vasodilation by activating eNOS and increasing NO bioavailability through calcium-calmodulin.
Neuroprotective effect of myricetin in Parkinson's diseaseVIJAYRAJA DHANRAJ
The document discusses the neuroprotective effects of myricetin isolated from the brown seaweed Turbinaria ornata. It begins with an introduction on Parkinson's disease and current treatment strategies. It then describes the collection and extraction of T. ornata to obtain its methanolic extract (TOME). Various in vitro assays were performed on TOME to analyze its antioxidant properties and identify bioactive compounds, leading to the isolation and characterization of myricetin. The study aims to evaluate the neuroprotective effects of myricetin in both in vitro cell line models and an in vivo Drosophila melanogaster model of Parkinson's disease induced by rotenone, through assessing markers of oxidative stress, inflammation, apoptosis, and neurodegeneration
This study investigated the protective effects of Salacia oblanga and quercetin on cyclophosphamide-induced chromosome aberrations in rat bone marrow cells. Rats were treated with Salacia oblanga or quercetin for 15 days, then given cyclophosphamide on days 14 and 15. Cyclophosphamide is known to induce chromosome aberrations and oxidative stress. The study found that quercetin completely prevented cyclophosphamide-induced chromosome aberrations, while Salacia oblanga partially prevented them. Both treatments decreased oxidative stress caused by cyclophosphamide. The results suggest that Salacia oblanga and quercetin can protect against the genotoxic and oxidative effects of cyclophosph
1) A study investigated the vasodilatory and toxic effects of a crude extract of Ruta graveolens (Ruta) on rat aortas and CRL1730 endothelial cells.
2) The Ruta extract generated vasodilation in rat aortas at subtoxic concentrations, partially dependent on the endothelium. It caused a loss of cell viability in CRL1730 cells at high concentrations but did not induce oxidative stress or DNA fragmentation.
3) The results suggest Ruta extract regulates vascular tone through a complex, partially endothelium-dependent mechanism and has vasodilatory activity at subtoxic levels without damaging cell membranes or viability.
Histopathological effects of nanosilver (Ag-NPs) in liver after dermal exposu...Nanomedicine Journal (NMJ)
Objective(s):
With the advent of nanotechnology, significant progress has been made in the area of nanoscale materials such as nanosilver (Ag-Nps). These nanoparticles have a wide range of applications and been used for antimicrobial purposes for more than a century. However, little
attention has been paid to the toxicity of nanosilver wound dressing. This study was designed to investigate the possible histopathological toxicity of Ag-NPs in liver of mice during wound healing.
Materials and Methods:
A group of 50 female BALB/c mice of about 8 weeks were randomly divided into two groups: Ag-NPs and control groups (n=25). After creating similar wound on the backs of all animals, the wound bed was treated in Ag-NPs group, with a volume of 50 microliters of the nanosilver solution (10ppm) ,and in control group, with the same amount of distilled water. The experiment lasted for 14 days. Histopathaological samplings of liver were conducted on days 2, 7 and 14 of the experiment.
Results:
Histopathological studies demonstrated time-dependent changes in mice liver treated with Ag-NPs compared to control group. Some changes include dilation in central venous, hyperemia, cell swelling, increase of Kupffer and inflammatory cells.
Conclusion:
This study suggests that use of nanosilver for wound healing may cause a mild toxicity, as indicated by time-dependent toxic responses in liver tissue. However, this issue will have to be considered more extensively in further studies
This study investigated the gastroprotective effects of coenzyme Q10 (CoQ10) in indomethacin-induced gastric injury in rats and the role of matrix metalloproteinase 9 (MMP-9). Rats pretreated with CoQ10 before indomethacin showed significantly reduced gastric damage, increased prostaglandin E2 levels, and decreased MMP-9 and myeloperoxidase activities compared to rats given indomethacin alone. Pretreating rats with a nitric oxide inhibitor before CoQ10 attenuated the gastroprotective effect of CoQ10. The results suggest that regulation of MMP-9 is one mechanism of CoQ10's gastroprotective effect and that
Objective: To study the effects of resveratrol in neuronal structures in traumatic brain injury (TBI).
Study Design: Thirty rats were categorized as (1) control group (n=10), saline solution administered i.p. for 14 days, (2) TBI group (n=10), trauma induced by weight-drop model on brain, and (3) TBI+Resveratrol group (n=10), 15 minutes after injury the rats were given resveratrol (10 μmoL/kg/i.p.) for 14 days. At the end of the experiment the cerebellum was excised for routine paraffin tissue protocol. Blood samples were tested for serum biochemical markers (MDA, SOD, CAT, and GSH-x).
Results: SOD, GPx, and CAT values were lowest in the TBI group. MDA and histological scores of dilations in vessels, inflammation, degeneration in neurons, apoptosis in microglia, ADAMTS8, and GFAP expressions were highest in the TBI group. Sections of the control group showed normal cerebellar histology. The trauma group showed degenerated ganglion layer, pyknotic and apoptotic Purkinje cell nuclei. Vascular thrombus was seen in the substantia alba and substantia grisea. In the Trauma+Resveratrol group, most pa- thologies observed in the TBI group were improved. In the control group, GFAP protein was expressed in granular cells, axons, dendrites, Purkinje cells, and microglia cells. In the trauma group, increased GFAP expression was observed in glial processes, neurons, and Purkinje cells. In the Trauma+Resveratrol group, GFAP was expressed in molecular layer and glial processes. In the control group, ADAMTS-4 activity was observed in granulosa layer, glial cells, and Purkinje cells. In the trauma group, ADAMTS-4 expression was positive in Purkinje cells and glial cells. In the Trauma+ Resveratrol group, ADAMTS-4 was expressed in Purkinje cells, granular cells, and glial cells.
Conclusion: GFAP and ADAMTS-4 proteins may be involved in regeneration of damaged astroglial cells and other glial cells, Purkinje cells, and synaptic extensions. We suggest that antioxidative drugs such as resveratrol may be alternative target agents in neurological disease.
Keywords: ADAMTS-4, brain, cerebellum, GFAP, rat, resveratrol, traumatic brain injury
This study investigated the effects of gallic acid on testicular injury caused by ischemia-reperfusion in a rat testicular torsion model. Forty rats were divided into four groups: a control group, a torsion group, a torsion/detorsion group, and a torsion/detorsion plus gallic acid group. Biochemical markers and immunohistochemical staining for caspase-3 and TNF-α were analyzed. The results showed that gallic acid treatment decreased oxidative stress markers, reduced apoptosis and inflammation, and helped protect testicular tissue compared to the torsion/detorsion group without treatment. The study suggests that gallic acid may be a potential therapeutic agent for testicular ischemia-reperfusion injury.
Neuroprotective effect of myricetin in Parkinson's diseaseVIJAYRAJA DHANRAJ
The document discusses the neuroprotective effects of myricetin isolated from the brown seaweed Turbinaria ornata. It begins with an introduction on Parkinson's disease and current treatment strategies. It then describes the collection and extraction of T. ornata to obtain its methanolic extract (TOME). Various in vitro assays were performed on TOME to analyze its antioxidant properties and identify bioactive compounds, leading to the isolation and characterization of myricetin. The study aims to evaluate the neuroprotective effects of myricetin in both in vitro cell line models and an in vivo Drosophila melanogaster model of Parkinson's disease induced by rotenone, through assessing markers of oxidative stress, inflammation, apoptosis, and neurodegeneration
This study investigated the protective effects of Salacia oblanga and quercetin on cyclophosphamide-induced chromosome aberrations in rat bone marrow cells. Rats were treated with Salacia oblanga or quercetin for 15 days, then given cyclophosphamide on days 14 and 15. Cyclophosphamide is known to induce chromosome aberrations and oxidative stress. The study found that quercetin completely prevented cyclophosphamide-induced chromosome aberrations, while Salacia oblanga partially prevented them. Both treatments decreased oxidative stress caused by cyclophosphamide. The results suggest that Salacia oblanga and quercetin can protect against the genotoxic and oxidative effects of cyclophosph
1) A study investigated the vasodilatory and toxic effects of a crude extract of Ruta graveolens (Ruta) on rat aortas and CRL1730 endothelial cells.
2) The Ruta extract generated vasodilation in rat aortas at subtoxic concentrations, partially dependent on the endothelium. It caused a loss of cell viability in CRL1730 cells at high concentrations but did not induce oxidative stress or DNA fragmentation.
3) The results suggest Ruta extract regulates vascular tone through a complex, partially endothelium-dependent mechanism and has vasodilatory activity at subtoxic levels without damaging cell membranes or viability.
Histopathological effects of nanosilver (Ag-NPs) in liver after dermal exposu...Nanomedicine Journal (NMJ)
Objective(s):
With the advent of nanotechnology, significant progress has been made in the area of nanoscale materials such as nanosilver (Ag-Nps). These nanoparticles have a wide range of applications and been used for antimicrobial purposes for more than a century. However, little
attention has been paid to the toxicity of nanosilver wound dressing. This study was designed to investigate the possible histopathological toxicity of Ag-NPs in liver of mice during wound healing.
Materials and Methods:
A group of 50 female BALB/c mice of about 8 weeks were randomly divided into two groups: Ag-NPs and control groups (n=25). After creating similar wound on the backs of all animals, the wound bed was treated in Ag-NPs group, with a volume of 50 microliters of the nanosilver solution (10ppm) ,and in control group, with the same amount of distilled water. The experiment lasted for 14 days. Histopathaological samplings of liver were conducted on days 2, 7 and 14 of the experiment.
Results:
Histopathological studies demonstrated time-dependent changes in mice liver treated with Ag-NPs compared to control group. Some changes include dilation in central venous, hyperemia, cell swelling, increase of Kupffer and inflammatory cells.
Conclusion:
This study suggests that use of nanosilver for wound healing may cause a mild toxicity, as indicated by time-dependent toxic responses in liver tissue. However, this issue will have to be considered more extensively in further studies
This study investigated the gastroprotective effects of coenzyme Q10 (CoQ10) in indomethacin-induced gastric injury in rats and the role of matrix metalloproteinase 9 (MMP-9). Rats pretreated with CoQ10 before indomethacin showed significantly reduced gastric damage, increased prostaglandin E2 levels, and decreased MMP-9 and myeloperoxidase activities compared to rats given indomethacin alone. Pretreating rats with a nitric oxide inhibitor before CoQ10 attenuated the gastroprotective effect of CoQ10. The results suggest that regulation of MMP-9 is one mechanism of CoQ10's gastroprotective effect and that
Objective: To study the effects of resveratrol in neuronal structures in traumatic brain injury (TBI).
Study Design: Thirty rats were categorized as (1) control group (n=10), saline solution administered i.p. for 14 days, (2) TBI group (n=10), trauma induced by weight-drop model on brain, and (3) TBI+Resveratrol group (n=10), 15 minutes after injury the rats were given resveratrol (10 μmoL/kg/i.p.) for 14 days. At the end of the experiment the cerebellum was excised for routine paraffin tissue protocol. Blood samples were tested for serum biochemical markers (MDA, SOD, CAT, and GSH-x).
Results: SOD, GPx, and CAT values were lowest in the TBI group. MDA and histological scores of dilations in vessels, inflammation, degeneration in neurons, apoptosis in microglia, ADAMTS8, and GFAP expressions were highest in the TBI group. Sections of the control group showed normal cerebellar histology. The trauma group showed degenerated ganglion layer, pyknotic and apoptotic Purkinje cell nuclei. Vascular thrombus was seen in the substantia alba and substantia grisea. In the Trauma+Resveratrol group, most pa- thologies observed in the TBI group were improved. In the control group, GFAP protein was expressed in granular cells, axons, dendrites, Purkinje cells, and microglia cells. In the trauma group, increased GFAP expression was observed in glial processes, neurons, and Purkinje cells. In the Trauma+Resveratrol group, GFAP was expressed in molecular layer and glial processes. In the control group, ADAMTS-4 activity was observed in granulosa layer, glial cells, and Purkinje cells. In the trauma group, ADAMTS-4 expression was positive in Purkinje cells and glial cells. In the Trauma+ Resveratrol group, ADAMTS-4 was expressed in Purkinje cells, granular cells, and glial cells.
Conclusion: GFAP and ADAMTS-4 proteins may be involved in regeneration of damaged astroglial cells and other glial cells, Purkinje cells, and synaptic extensions. We suggest that antioxidative drugs such as resveratrol may be alternative target agents in neurological disease.
Keywords: ADAMTS-4, brain, cerebellum, GFAP, rat, resveratrol, traumatic brain injury
This study investigated the effects of gallic acid on testicular injury caused by ischemia-reperfusion in a rat testicular torsion model. Forty rats were divided into four groups: a control group, a torsion group, a torsion/detorsion group, and a torsion/detorsion plus gallic acid group. Biochemical markers and immunohistochemical staining for caspase-3 and TNF-α were analyzed. The results showed that gallic acid treatment decreased oxidative stress markers, reduced apoptosis and inflammation, and helped protect testicular tissue compared to the torsion/detorsion group without treatment. The study suggests that gallic acid may be a potential therapeutic agent for testicular ischemia-reperfusion injury.
The study investigated the protective effects of losartan, an angiotensin II type 1 receptor blocker, on intestinal ischemia-reperfusion injury in rats. Forty rats were divided into four groups: sham operation, ischemia, ischemia/reperfusion (I/R), and I/R + losartan treatment. Biochemical markers and histopathological analysis of the jejunum tissue were performed. Losartan treatment reduced oxidative stress markers, inflammation, and apoptosis compared to the I/R group. This suggests losartan may protect against intestinal damage caused by ischemia-reperfusion injury.
The cellular uptake of antisense oligonucleotid of E6 mRNA into cervical canc...Nanomedicine Journal (NMJ)
Abstract
Objective(s):
Although several chemical and physical methods for gene delivery have been introduced, their cytotoxicity, non-specific immune responses and the lack of biodegradability remain the main issues. In this study, hydroxyapatite nanoparticles (NPs) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)-modified hydroxyapatite NPs was coated with antisense oligonucleotide of E6 mRNA, and their uptakes into the cervical cancer cell line were evaluated.
Materials and Methods:
Calcium nitrate and diammonium phosphate were used for the synthesis of the hydroxyapatite nanoparticle. Thus, they were coated with polyethylene glycol (PEG), DOPE and antisense oligonucleotide of E6 mRNA using a cross-linker. Then, hydroxyapatite NPs and DOPE-modified hydroxyapatite NPs were incubated 48 hours with cervical cancer cells and their uptakes were evaluated by fluorescent microscopy.
Results:
The hydroxyapatite NPs had different shapes and some agglomeration with average size of 100 nm. The results showed DOPE-modified hydroxyapatite NPs had higher uptake than hydroxyapatite NPs (P<0.05).
Conclusions:
Hydroxyapatite NPs conjugated with DOPE are a good choice for gene delivery and silencing of viral genes in cervical cancer cells, but their efficacy should be addressed more in future studies.
This study evaluated the immunostimulatory and antioxidant properties of Phoenix dactylifera, commonly known as dates. Mice were injected with various concentrations of a Phoenix dactylifera extract. Results showed that the extract significantly increased phagocytic activity and reduced the half-life of carbon in the blood, indicating enhanced function of the reticuloendothelial system. The extract also significantly increased levels of the antioxidant glutathione in the liver. The concentration of 50 mg/kg produced the highest effects on phagocytosis and glutathione. Therefore, the study suggests that Phoenix dactylifera has immune-stimulating and antioxidant activities, with 50 mg/kg having the strongest impact.
Inhibition mmp 2 and mmp-9 of different molecule weigh function by membrane s...Van-Tinh Nguyen
The study investigated the effects of digests produced from abalone (Haliotis discus hannai) intestine on the expression of matrix metalloproteinases (MMPs) in human fibrosarcoma cells. Abalone intestine was digested using a simulated gastrointestinal system to produce abalone intestine gastrointestinal digests (AIGIDs). These were separated into fractions of different molecular weights. Two fractions, AIGID II and AIGID III, inhibited the expression and activity of MMP-2 and MMP-9 in human fibrosarcoma cells, as well as cell migration. Both fractions attenuated expression of the p65 subunit of nuclear factor kappa B. The study suggests these abalone intestine digest fractions may have potential
Review paper osteoarthritis and its possible treatmentsvalrivera
1. Osteoarthritis is the most common type of arthritis and affects millions of people and dogs each year. There are some potential treatments but no single definitive treatment.
2. Studies have found that glucosamine/chondroitin sulfate supplements provided benefits for dogs with osteoarthritis, including improved mobility and reduced pain. Long term use of supplements showed better results than traditional NSAID treatments.
3. Research is also exploring inhibitors of enzymes like MMPs that degrade cartilage. Early studies found that COL-3 inhibitor helped reduce breakdown of ligaments in arthritic dog knees.
This document summarizes the results of a study that investigated the dose-dependent effects of ginger in inhibiting oxidative stress and genotoxicity in streptozotocin-induced diabetic rats. Male rats were divided into several groups, including a control group, diabetic non-treated group, and diabetic groups treated with 0.5%, 1%, or 5% ginger powder. Ginger treatment was found to reduce blood glucose and lipid levels, modulate antioxidant enzymes, and reduce DNA damage and genotoxicity in a dose-dependent manner compared to untreated diabetic rats. The study suggests that ginger exerts protective effects against diabetes by reducing oxidative stress and genotoxicity in a dose-response manner.
This study investigated the effects of spinal cord injury on the bladder tissue of rats. Twenty rats were divided into a control group and spinal cord injury (SCI) group. The SCI group exhibited statistically higher levels of oxidative stress markers (MDA, MPO), epithelial degeneration, vascular dilation, inflammation, and expression of VEGF and APAF-1 compared to the control group. The SCI group also had lower levels of the antioxidant GSH. Histological examination of the SCI group showed degeneration of epithelial cells, thickened fibrosis, dilated blood vessels, and increased VEGF and APAF-1 expression compared to the control group. The results suggest that spinal cord injury leads to increased oxidative stress, inflammation and apoptosis in
Objective: To investigate the changes in the retina due to deltamethrin toxicity and the process in cell inflammation and apoptosis.
Study Design: Sixteen Wistar albino rats were randomly divided into two groups as control (n=8) and deltamethrin (n=8) groups. Saline was given to the control group, and 0.5 mL of 5 mg/kg deltamethrin was given to the deltamethrin group for 14 days each. Blood was collected for biochemical analysis. Retinal tissue was processed for histological examination.
Results: Compared to the control group, MDA levels were high while GSH and CAT levels were low in the deltamethrin group. Histopathological analysis showed spaces between the pigment epithelium, irregularity in the delimiting membrane, degenerated ganglion, cone and bacillus cell, pyknotic nuclei, thinned inner limitation membrane, and thickened vascular wall. The control group showed FAS expression in the pigment layer limiting membranes, in the nuclei of many cone and bacillus cells, and ganglion cells in the control group sections. In the deltamethrin group, FAS expression was observed in the inner and outer limiting membranes of the pigment epithelium, cone and bacillus cells, and ganglion cell nuclei. In the control group, negative NOS expression in the pigment epithelium and outer limiting membranes, internal limitation membrane, and ganglion cells in the cone and bacillus cell nuclei were observed. In the deltamethrin group, NOS expression was positive in the pigment epithelium, cone and bacillus, and ganglion cell nuclei.
Conclusion: We suggest that deltamethrin toxicity induced apoptotic process due to increased inflammation in the retina and may cause visual impairment as a result of neural damage.
Keywords: deltamethrin, FAS, insecticides, NOS, nitric oxide synthase, retina
IOSR Journal of Pharmacy (IOSRPHR), www.iosrphr.org, call for paper, research...iosrphr_editor
IOSR Journal of Pharmacy (IOSRPHR), www.iosrphr.org, call for paper, research paper publishing, where to publish research paper, journal publishing, how to publish research paper, Call for research paper, international journal, publishing a paper, call for paper 2012, journal of pharmacy, how to get a research paper published, publishing a paper, publishing of journal, research and review articles, Pharmacy journal, International Journal of Pharmacy, hard copy of journal, hard copy of certificates, online Submission, where to publish research paper, journal publishing, international journal, publishing a paper
Objective: To identify interstitial cells of Cajal (ICC) in the common bile duct of Kunming mice.
Study Design: Common bile ducts obtained from the Kunming mice were prepared for immunohistochemical investigations using the c-kit antibody. Immunoelectron microscopy was used to detect the expression of c-kit in the ICC of the common bile duct. Transmission electron microscopy showed ultrastructure of ICC in the murine bile duct. Reverse transcription–polymerase chain reaction (RT-PCR) and western blot were used to confirm the expression of mRNA specific for the c-kit gene and production of c-kit protein in the Kunming mice common bile duct.
Results: Immunohistochemistry revealed that ICC in the murine common bile duct are c-kit positive and the ICC are located in the tela submucosa and the tunica muscularis of the murine common bile duct and do not connect with each other. Immunoelectron microscopy confirmed the expression of Kit by ICC in the murine common bile duct. Transmission electron microscopy showed that ICC in the murine common bile duct have long processes, abundant mitochondria, plenty of smooth endoplasmic reticulum (sER), a lot of lysosomes, and dense bodies. The caveolae of ICC are distinctive. At the same time, RT-PCR indicated that the Kunming mice common bile duct expressed mRNA specific for the c-kit gene, and western blot analysis showed the evidence of production of c-kit protein in the Kunming mice common bile duct.
Conclusion: ICC are found in the Kunming mice common bile duct, which is likely to lead to the development of motility study of the common bile duct.
Keywords: common bile duct; electron microscopy; immuno-electron microscopy; interstitial cells of Cajal; intestines; smooth muscle; tyrosine kinase receptor (c-kit)
This document summarizes a study that evaluated the toxic effects of orally administering titanium dioxide nanoparticles (TiO2 NPs) to male Wistar rats. The rats were divided into control and experimental groups that received 50 or 100 mg/kg body weight of TiO2 NPs daily for 14 days. Blood samples were analyzed for biochemical markers of liver and kidney function. The results showed elevated levels of markers indicating liver damage and renal toxicity in the experimental groups, suggesting oral exposure to TiO2 NPs can negatively impact the liver and kidneys.
Effect of Antioxidant status on liver following Atrazine exposure and its pro...IOSR Journals
The efficacy of Andrographis paniculata (AP) extract was studied on atrazine induced hepatic damage in rats. Ethanolic extract of AP (150mg/kg body weight) was found to protect the male wistar rats from hepato toxic action of atrazine as evidence by significant reduction in the level of lipid peroxidation and increased the antioxidant defense system activity in the atrazine intoxicated rats. However, AP treatment ameliorated the effects of atrazine suggesting it as potential antioxidant against atrazine induced oxidative stress.
Abstract
Objective(s):
Zinc oxide nanoparticles (ZNP) are increasingly used in sunscreens, biosensors, food additives and pigments. In this study the effects of ZNP on liver of rats was investigated.
Materials and Methods:
Experimental groups received 5, 50 and 300 mg/kg ZNP respectively for 14 days. Control group received only distilled water. ALT, AST and ALP were considered as biomarkers to indicate hepatotoxicity. Lipid peroxidation (MDA), SOD and GPx were detected for assessment of oxidative stress in liver tissue. Histological studies and TUNEL assay were also done.
Results:
Plasma concentration of zinc (Zn) was significantly increased in 5 mg/kg ZNP-treated rats. Liver concentration of Zn was significantly increased in the 300 mg/kg ZNP-treated animals. Weight of liver was markedly increased in both 5 and 300 mg/kg doses of ZNP. ZNP at the doses of 5 mg/kg induced a significant increase in oxidative stress through the increase in MDA content and a significant decrease in SOD and GPx enzymes activity in the liver tissue. Administration of ZNP at 5 mg/kg induced a significant elevation in plasma AST, ALT and ALP. Histological studies showed that treatment with 5 mg/kg of ZNP caused hepatocytes swelling, which was accompanied by congestion of RBC and accumulation of inflammatory cells. Apoptotic index was also significantly increased in this group. ZNP at the dose of 300 mg/kg had poor hepatotoxicity effect.
Conclusion:
It is concluded that lower doses of ZNP has more hepatotoxic effects on rats, and recommended to use it with caution if there is a hepatological problem.
Objective: To evaluate the results of the effect of nebivolol on tibial bone defect and graft application in new bone development in the rat.
Study Design: Thirty Wistar albino rats were divided into 3 groups. In the Control group, tibia bone defect was created without any treatment. In the Defect+ Graft group, allograft treatment was performed by forming a 6 mm tibial bone defect. In the Defect+Graft+ Nebivolol group, alloplastic bone graft was placed in the calvarial bone defect and then nebivolol (0.34 mg/mL solution/day) treatment was intraperitoneally applied for 28 days.
Results: Histopathological examination revealed inflammation in the defect area, congestion in the vessels, degeneration in collagen fibers, and an increase in osteoclast cells. There was an increase in inflammation and blood vessel structure in graft application, and osteoblastic activity matrix formation after reorganization nebivolol application in collagen fibers. Osteonectin expression was positive in the collagen fiber and matrix, starting in the Graft group, in osteoblasts, whereas in the Nebivolol group, osteoblasts increased in osteocytes and new bone formation.
Conclusion: Nebivolol is thought to have a positive effect on osteoinductive bone growth factors and contribute to the cell-matrix interaction, in addition to the supporting effect of the graft with its antioxidative effect.
Keywords: allograft; bone; bone regeneration; disease models, animal; nebivolol; orthopedic procedures; osteonectin; rats; tibia; tibial defect
Protective role of co q10 or l carnitine on the integrity of the myocardium i...Prof. Hesham N. Mustafa
Doxorubicin (DOX) is a chemotherapeutic agent used for treatment of different cancers and its clinical usage is hindered by the oxidative injury-related cardiotoxicity. This work aims to declare if the harmful effects of DOX on heart can be alleviated with the use of Coenzyme Q10 (CoQ10) or L-carnitine. The study was performed on seventy two female Wistar albino rats divided into six groups, 12 animals each: Control group; DOX group (10mg/kg); CoQ10 group (200mg/kg); L-carnitine group (100mg/kg); DOX+CoQ10 group; DOX+L-carnitine group. CoQ10 and L-carnitine treatment orally started 5days before a single dose of 10mg/kg DOX that injected intraperitoneally (IP) then the treatment continued for 10days. At the end of the study, serum biochemical parameters of cardiac damage, oxidative stress indices, and histopathological changes were investigated. CoQ10 or L-carnitine showed a noticeable effects in improving cardiac functions evidenced reducing serum enzymes as serum interleukin-1 beta (IL-1 β), tumor necrosis factor alpha (TNF-α), leptin, lactate dehydrogenase (LDH), Cardiotrophin-1, Troponin-I and Troponin-T. Also, alleviate oxidative stress, decrease of cardiac Malondialdehyde (MDA), Nitric oxide (NO) and restoring cardiac reduced glutathione levels to normal levels. Both corrected the cardiac alterations histologically and ultrastructurally. With a visible improvements in α-SMA, vimentin and eNOS immunohistochemical markers. CoQ10 or L-carnitine supplementation improves the functional and structural integrity of the myocardium.
Keywords: Cardiotoxicity; CoQ10 and L-carnitine; Dox; Vimentin; eNOS.
Objective(s):
There is a rising use of gold nanoparticles (AuNPs) in goods and in the medical fields but there is concern about the toxicity of them. So in this study spherical AuNPs with 3 different concentrations were applied for investigating their effects in vivo.
Materials and Methods:
40 male albino mice were randomly divided into sham, control, 25 ppm, 50 ppm, 100 ppm groups and were treated by intraperitoneal injection for period of 14 days. Blood was taken for measuring of glutamate oxaloacetate transaminase and glutamate pyruvate transaminase (SGOT and SGPT) enzyme levels and Complete Blood Count (CBC).
Results:
After the treatment and comparing groups with sham group, in 50 ppm group significant increases on RBC, HCT, HGB, MCHC and in 25 ppm group significant increase on MCHC and significant decrease on MCV and in 100 ppm group significant increase on MCHC were observed. Also in 50 ppm group an increase on SGOT enzyme level was observed. However, it was nonsignificant.
Conclusion:
By observing the abnormality on the RBC count and SGOT enzyme level in the 50 ppm group, we concluded a slight toxicity effect for AuNPs and the threat potential of their use in human.
The study investigated the effects of methoxychlor (MXC), an organochlorine pesticide, on liver and kidney function in rats and the potential protective effects of propolis. Rats were exposed to MXC, propolis, or both for 6 or 12 months. MXC exposure significantly increased liver enzymes and oxidative stress markers in the liver and caused histological damage. It also increased kidney dysfunction biomarkers and caused tubular degeneration. Co-administration of propolis with MXC ameliorated many of the toxic effects of MXC on the liver and kidney, decreasing oxidative stress and normalizing biomarker levels. The study suggests that propolis has protective effects against MXC-induced toxicity in
This document summarizes a proteomic analysis of the excretory/secretory (ES) proteins of Toxoplasma gondii, the causative agent of toxoplasmosis. 34 proteins were identified from the ES proteins of the RH strain of T. gondii using LC/MS/MS analysis and spectral counting methods. The three most abundant proteins identified were GRA1, GRA7, and GRA2. A variety of other proteins were also identified, including micronemal proteins, rhoptry proteins, and dense granule proteins, which play important roles in T. gondii host cell invasion and survival within host cells. This analysis provides new insights into the ES proteome of T
1) Rats treated with 3-nitropropionic acid (3-NP), a model of Huntington's disease, exhibited weight loss, gait abnormalities, and striatal lesions.
2) The study found a dose-dependent reduction in complex-I activity in the cerebral cortex of 3-NP treated rats, as measured spectrophotometrically and by blue native-polyacrylamide gel electrophoresis.
3) Succinate driven State 3 respiration was significantly inhibited both in vivo and in isolated mitochondria from the cortex of 3-NP treated rats, suggesting complex-I dysfunction in addition to inhibition of complex-II and succinate dehydrogenase activity contributes to cortico-striatal lesions in this model
This study examined the effects of prolonged simvastatin (SIM) treatment on ischemia-reperfusion (I/R) induced acute kidney injury in rats. Rats were divided into four groups: sham, ischemia, I/R, and I/R+SIM treated. The I/R group showed intense inflammation, necrosis, and apoptosis in kidney tissue. The I/R+SIM group showed reduced inflammation and tissue damage. Biochemical analysis found increased oxidative stress and inflammation markers in the ischemia and I/R groups compared to control, but levels in the I/R+SIM group were similar to control. Histological analysis also showed more damage in ischemia and I/R groups versus control, while the I/R+
1) The study examined the effects of the inhalation anesthetic isoflurane on muscarinic receptor-mediated excitation and contraction of intestinal smooth muscle.
2) It found that isoflurane strongly inhibited the muscarinic cation current in mouse intestinal cells, reducing carbachol-activated current by 63% and GTPγS-induced current by 44%.
3) Isoflurane also inhibited carbachol-induced contractions of ileum and colon smooth muscle tissues by approximately 30%. The results suggest isoflurane acts by inhibiting muscarinic receptors and G-proteins rather than directly blocking TRPC channels.
In vivo modulation of dopaminergic nigrostriatal pathways by cytisine derivat...Georgi Daskalov
This study examined the ability of the nicotinic receptor agonist cytisine and two halogenated derivatives (3-bromocytisine and 5-bromocytisine) to stimulate dopamine release in vivo and protect against dopamine depletion in a rat model of Parkinson's disease. Microdialysis experiments showed that cytisine, 5-bromocytisine, and nicotine were more effective than 3-bromocytisine at inducing striatal dopamine release. Administration of cytisine and 5-bromocytisine before and after an intranigral injection of 6-hydroxydopamine significantly prevented the decrease in striatal dopamine levels, but 3-bromocytisine did not provide protection. These results suggest that the efficacy
The study investigated the protective effects of losartan, an angiotensin II type 1 receptor blocker, on intestinal ischemia-reperfusion injury in rats. Forty rats were divided into four groups: sham operation, ischemia, ischemia/reperfusion (I/R), and I/R + losartan treatment. Biochemical markers and histopathological analysis of the jejunum tissue were performed. Losartan treatment reduced oxidative stress markers, inflammation, and apoptosis compared to the I/R group. This suggests losartan may protect against intestinal damage caused by ischemia-reperfusion injury.
The cellular uptake of antisense oligonucleotid of E6 mRNA into cervical canc...Nanomedicine Journal (NMJ)
Abstract
Objective(s):
Although several chemical and physical methods for gene delivery have been introduced, their cytotoxicity, non-specific immune responses and the lack of biodegradability remain the main issues. In this study, hydroxyapatite nanoparticles (NPs) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)-modified hydroxyapatite NPs was coated with antisense oligonucleotide of E6 mRNA, and their uptakes into the cervical cancer cell line were evaluated.
Materials and Methods:
Calcium nitrate and diammonium phosphate were used for the synthesis of the hydroxyapatite nanoparticle. Thus, they were coated with polyethylene glycol (PEG), DOPE and antisense oligonucleotide of E6 mRNA using a cross-linker. Then, hydroxyapatite NPs and DOPE-modified hydroxyapatite NPs were incubated 48 hours with cervical cancer cells and their uptakes were evaluated by fluorescent microscopy.
Results:
The hydroxyapatite NPs had different shapes and some agglomeration with average size of 100 nm. The results showed DOPE-modified hydroxyapatite NPs had higher uptake than hydroxyapatite NPs (P<0.05).
Conclusions:
Hydroxyapatite NPs conjugated with DOPE are a good choice for gene delivery and silencing of viral genes in cervical cancer cells, but their efficacy should be addressed more in future studies.
This study evaluated the immunostimulatory and antioxidant properties of Phoenix dactylifera, commonly known as dates. Mice were injected with various concentrations of a Phoenix dactylifera extract. Results showed that the extract significantly increased phagocytic activity and reduced the half-life of carbon in the blood, indicating enhanced function of the reticuloendothelial system. The extract also significantly increased levels of the antioxidant glutathione in the liver. The concentration of 50 mg/kg produced the highest effects on phagocytosis and glutathione. Therefore, the study suggests that Phoenix dactylifera has immune-stimulating and antioxidant activities, with 50 mg/kg having the strongest impact.
Inhibition mmp 2 and mmp-9 of different molecule weigh function by membrane s...Van-Tinh Nguyen
The study investigated the effects of digests produced from abalone (Haliotis discus hannai) intestine on the expression of matrix metalloproteinases (MMPs) in human fibrosarcoma cells. Abalone intestine was digested using a simulated gastrointestinal system to produce abalone intestine gastrointestinal digests (AIGIDs). These were separated into fractions of different molecular weights. Two fractions, AIGID II and AIGID III, inhibited the expression and activity of MMP-2 and MMP-9 in human fibrosarcoma cells, as well as cell migration. Both fractions attenuated expression of the p65 subunit of nuclear factor kappa B. The study suggests these abalone intestine digest fractions may have potential
Review paper osteoarthritis and its possible treatmentsvalrivera
1. Osteoarthritis is the most common type of arthritis and affects millions of people and dogs each year. There are some potential treatments but no single definitive treatment.
2. Studies have found that glucosamine/chondroitin sulfate supplements provided benefits for dogs with osteoarthritis, including improved mobility and reduced pain. Long term use of supplements showed better results than traditional NSAID treatments.
3. Research is also exploring inhibitors of enzymes like MMPs that degrade cartilage. Early studies found that COL-3 inhibitor helped reduce breakdown of ligaments in arthritic dog knees.
This document summarizes the results of a study that investigated the dose-dependent effects of ginger in inhibiting oxidative stress and genotoxicity in streptozotocin-induced diabetic rats. Male rats were divided into several groups, including a control group, diabetic non-treated group, and diabetic groups treated with 0.5%, 1%, or 5% ginger powder. Ginger treatment was found to reduce blood glucose and lipid levels, modulate antioxidant enzymes, and reduce DNA damage and genotoxicity in a dose-dependent manner compared to untreated diabetic rats. The study suggests that ginger exerts protective effects against diabetes by reducing oxidative stress and genotoxicity in a dose-response manner.
This study investigated the effects of spinal cord injury on the bladder tissue of rats. Twenty rats were divided into a control group and spinal cord injury (SCI) group. The SCI group exhibited statistically higher levels of oxidative stress markers (MDA, MPO), epithelial degeneration, vascular dilation, inflammation, and expression of VEGF and APAF-1 compared to the control group. The SCI group also had lower levels of the antioxidant GSH. Histological examination of the SCI group showed degeneration of epithelial cells, thickened fibrosis, dilated blood vessels, and increased VEGF and APAF-1 expression compared to the control group. The results suggest that spinal cord injury leads to increased oxidative stress, inflammation and apoptosis in
Objective: To investigate the changes in the retina due to deltamethrin toxicity and the process in cell inflammation and apoptosis.
Study Design: Sixteen Wistar albino rats were randomly divided into two groups as control (n=8) and deltamethrin (n=8) groups. Saline was given to the control group, and 0.5 mL of 5 mg/kg deltamethrin was given to the deltamethrin group for 14 days each. Blood was collected for biochemical analysis. Retinal tissue was processed for histological examination.
Results: Compared to the control group, MDA levels were high while GSH and CAT levels were low in the deltamethrin group. Histopathological analysis showed spaces between the pigment epithelium, irregularity in the delimiting membrane, degenerated ganglion, cone and bacillus cell, pyknotic nuclei, thinned inner limitation membrane, and thickened vascular wall. The control group showed FAS expression in the pigment layer limiting membranes, in the nuclei of many cone and bacillus cells, and ganglion cells in the control group sections. In the deltamethrin group, FAS expression was observed in the inner and outer limiting membranes of the pigment epithelium, cone and bacillus cells, and ganglion cell nuclei. In the control group, negative NOS expression in the pigment epithelium and outer limiting membranes, internal limitation membrane, and ganglion cells in the cone and bacillus cell nuclei were observed. In the deltamethrin group, NOS expression was positive in the pigment epithelium, cone and bacillus, and ganglion cell nuclei.
Conclusion: We suggest that deltamethrin toxicity induced apoptotic process due to increased inflammation in the retina and may cause visual impairment as a result of neural damage.
Keywords: deltamethrin, FAS, insecticides, NOS, nitric oxide synthase, retina
IOSR Journal of Pharmacy (IOSRPHR), www.iosrphr.org, call for paper, research...iosrphr_editor
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Objective: To identify interstitial cells of Cajal (ICC) in the common bile duct of Kunming mice.
Study Design: Common bile ducts obtained from the Kunming mice were prepared for immunohistochemical investigations using the c-kit antibody. Immunoelectron microscopy was used to detect the expression of c-kit in the ICC of the common bile duct. Transmission electron microscopy showed ultrastructure of ICC in the murine bile duct. Reverse transcription–polymerase chain reaction (RT-PCR) and western blot were used to confirm the expression of mRNA specific for the c-kit gene and production of c-kit protein in the Kunming mice common bile duct.
Results: Immunohistochemistry revealed that ICC in the murine common bile duct are c-kit positive and the ICC are located in the tela submucosa and the tunica muscularis of the murine common bile duct and do not connect with each other. Immunoelectron microscopy confirmed the expression of Kit by ICC in the murine common bile duct. Transmission electron microscopy showed that ICC in the murine common bile duct have long processes, abundant mitochondria, plenty of smooth endoplasmic reticulum (sER), a lot of lysosomes, and dense bodies. The caveolae of ICC are distinctive. At the same time, RT-PCR indicated that the Kunming mice common bile duct expressed mRNA specific for the c-kit gene, and western blot analysis showed the evidence of production of c-kit protein in the Kunming mice common bile duct.
Conclusion: ICC are found in the Kunming mice common bile duct, which is likely to lead to the development of motility study of the common bile duct.
Keywords: common bile duct; electron microscopy; immuno-electron microscopy; interstitial cells of Cajal; intestines; smooth muscle; tyrosine kinase receptor (c-kit)
This document summarizes a study that evaluated the toxic effects of orally administering titanium dioxide nanoparticles (TiO2 NPs) to male Wistar rats. The rats were divided into control and experimental groups that received 50 or 100 mg/kg body weight of TiO2 NPs daily for 14 days. Blood samples were analyzed for biochemical markers of liver and kidney function. The results showed elevated levels of markers indicating liver damage and renal toxicity in the experimental groups, suggesting oral exposure to TiO2 NPs can negatively impact the liver and kidneys.
Effect of Antioxidant status on liver following Atrazine exposure and its pro...IOSR Journals
The efficacy of Andrographis paniculata (AP) extract was studied on atrazine induced hepatic damage in rats. Ethanolic extract of AP (150mg/kg body weight) was found to protect the male wistar rats from hepato toxic action of atrazine as evidence by significant reduction in the level of lipid peroxidation and increased the antioxidant defense system activity in the atrazine intoxicated rats. However, AP treatment ameliorated the effects of atrazine suggesting it as potential antioxidant against atrazine induced oxidative stress.
Abstract
Objective(s):
Zinc oxide nanoparticles (ZNP) are increasingly used in sunscreens, biosensors, food additives and pigments. In this study the effects of ZNP on liver of rats was investigated.
Materials and Methods:
Experimental groups received 5, 50 and 300 mg/kg ZNP respectively for 14 days. Control group received only distilled water. ALT, AST and ALP were considered as biomarkers to indicate hepatotoxicity. Lipid peroxidation (MDA), SOD and GPx were detected for assessment of oxidative stress in liver tissue. Histological studies and TUNEL assay were also done.
Results:
Plasma concentration of zinc (Zn) was significantly increased in 5 mg/kg ZNP-treated rats. Liver concentration of Zn was significantly increased in the 300 mg/kg ZNP-treated animals. Weight of liver was markedly increased in both 5 and 300 mg/kg doses of ZNP. ZNP at the doses of 5 mg/kg induced a significant increase in oxidative stress through the increase in MDA content and a significant decrease in SOD and GPx enzymes activity in the liver tissue. Administration of ZNP at 5 mg/kg induced a significant elevation in plasma AST, ALT and ALP. Histological studies showed that treatment with 5 mg/kg of ZNP caused hepatocytes swelling, which was accompanied by congestion of RBC and accumulation of inflammatory cells. Apoptotic index was also significantly increased in this group. ZNP at the dose of 300 mg/kg had poor hepatotoxicity effect.
Conclusion:
It is concluded that lower doses of ZNP has more hepatotoxic effects on rats, and recommended to use it with caution if there is a hepatological problem.
Objective: To evaluate the results of the effect of nebivolol on tibial bone defect and graft application in new bone development in the rat.
Study Design: Thirty Wistar albino rats were divided into 3 groups. In the Control group, tibia bone defect was created without any treatment. In the Defect+ Graft group, allograft treatment was performed by forming a 6 mm tibial bone defect. In the Defect+Graft+ Nebivolol group, alloplastic bone graft was placed in the calvarial bone defect and then nebivolol (0.34 mg/mL solution/day) treatment was intraperitoneally applied for 28 days.
Results: Histopathological examination revealed inflammation in the defect area, congestion in the vessels, degeneration in collagen fibers, and an increase in osteoclast cells. There was an increase in inflammation and blood vessel structure in graft application, and osteoblastic activity matrix formation after reorganization nebivolol application in collagen fibers. Osteonectin expression was positive in the collagen fiber and matrix, starting in the Graft group, in osteoblasts, whereas in the Nebivolol group, osteoblasts increased in osteocytes and new bone formation.
Conclusion: Nebivolol is thought to have a positive effect on osteoinductive bone growth factors and contribute to the cell-matrix interaction, in addition to the supporting effect of the graft with its antioxidative effect.
Keywords: allograft; bone; bone regeneration; disease models, animal; nebivolol; orthopedic procedures; osteonectin; rats; tibia; tibial defect
Protective role of co q10 or l carnitine on the integrity of the myocardium i...Prof. Hesham N. Mustafa
Doxorubicin (DOX) is a chemotherapeutic agent used for treatment of different cancers and its clinical usage is hindered by the oxidative injury-related cardiotoxicity. This work aims to declare if the harmful effects of DOX on heart can be alleviated with the use of Coenzyme Q10 (CoQ10) or L-carnitine. The study was performed on seventy two female Wistar albino rats divided into six groups, 12 animals each: Control group; DOX group (10mg/kg); CoQ10 group (200mg/kg); L-carnitine group (100mg/kg); DOX+CoQ10 group; DOX+L-carnitine group. CoQ10 and L-carnitine treatment orally started 5days before a single dose of 10mg/kg DOX that injected intraperitoneally (IP) then the treatment continued for 10days. At the end of the study, serum biochemical parameters of cardiac damage, oxidative stress indices, and histopathological changes were investigated. CoQ10 or L-carnitine showed a noticeable effects in improving cardiac functions evidenced reducing serum enzymes as serum interleukin-1 beta (IL-1 β), tumor necrosis factor alpha (TNF-α), leptin, lactate dehydrogenase (LDH), Cardiotrophin-1, Troponin-I and Troponin-T. Also, alleviate oxidative stress, decrease of cardiac Malondialdehyde (MDA), Nitric oxide (NO) and restoring cardiac reduced glutathione levels to normal levels. Both corrected the cardiac alterations histologically and ultrastructurally. With a visible improvements in α-SMA, vimentin and eNOS immunohistochemical markers. CoQ10 or L-carnitine supplementation improves the functional and structural integrity of the myocardium.
Keywords: Cardiotoxicity; CoQ10 and L-carnitine; Dox; Vimentin; eNOS.
Objective(s):
There is a rising use of gold nanoparticles (AuNPs) in goods and in the medical fields but there is concern about the toxicity of them. So in this study spherical AuNPs with 3 different concentrations were applied for investigating their effects in vivo.
Materials and Methods:
40 male albino mice were randomly divided into sham, control, 25 ppm, 50 ppm, 100 ppm groups and were treated by intraperitoneal injection for period of 14 days. Blood was taken for measuring of glutamate oxaloacetate transaminase and glutamate pyruvate transaminase (SGOT and SGPT) enzyme levels and Complete Blood Count (CBC).
Results:
After the treatment and comparing groups with sham group, in 50 ppm group significant increases on RBC, HCT, HGB, MCHC and in 25 ppm group significant increase on MCHC and significant decrease on MCV and in 100 ppm group significant increase on MCHC were observed. Also in 50 ppm group an increase on SGOT enzyme level was observed. However, it was nonsignificant.
Conclusion:
By observing the abnormality on the RBC count and SGOT enzyme level in the 50 ppm group, we concluded a slight toxicity effect for AuNPs and the threat potential of their use in human.
The study investigated the effects of methoxychlor (MXC), an organochlorine pesticide, on liver and kidney function in rats and the potential protective effects of propolis. Rats were exposed to MXC, propolis, or both for 6 or 12 months. MXC exposure significantly increased liver enzymes and oxidative stress markers in the liver and caused histological damage. It also increased kidney dysfunction biomarkers and caused tubular degeneration. Co-administration of propolis with MXC ameliorated many of the toxic effects of MXC on the liver and kidney, decreasing oxidative stress and normalizing biomarker levels. The study suggests that propolis has protective effects against MXC-induced toxicity in
This document summarizes a proteomic analysis of the excretory/secretory (ES) proteins of Toxoplasma gondii, the causative agent of toxoplasmosis. 34 proteins were identified from the ES proteins of the RH strain of T. gondii using LC/MS/MS analysis and spectral counting methods. The three most abundant proteins identified were GRA1, GRA7, and GRA2. A variety of other proteins were also identified, including micronemal proteins, rhoptry proteins, and dense granule proteins, which play important roles in T. gondii host cell invasion and survival within host cells. This analysis provides new insights into the ES proteome of T
1) Rats treated with 3-nitropropionic acid (3-NP), a model of Huntington's disease, exhibited weight loss, gait abnormalities, and striatal lesions.
2) The study found a dose-dependent reduction in complex-I activity in the cerebral cortex of 3-NP treated rats, as measured spectrophotometrically and by blue native-polyacrylamide gel electrophoresis.
3) Succinate driven State 3 respiration was significantly inhibited both in vivo and in isolated mitochondria from the cortex of 3-NP treated rats, suggesting complex-I dysfunction in addition to inhibition of complex-II and succinate dehydrogenase activity contributes to cortico-striatal lesions in this model
This study examined the effects of prolonged simvastatin (SIM) treatment on ischemia-reperfusion (I/R) induced acute kidney injury in rats. Rats were divided into four groups: sham, ischemia, I/R, and I/R+SIM treated. The I/R group showed intense inflammation, necrosis, and apoptosis in kidney tissue. The I/R+SIM group showed reduced inflammation and tissue damage. Biochemical analysis found increased oxidative stress and inflammation markers in the ischemia and I/R groups compared to control, but levels in the I/R+SIM group were similar to control. Histological analysis also showed more damage in ischemia and I/R groups versus control, while the I/R+
1) The study examined the effects of the inhalation anesthetic isoflurane on muscarinic receptor-mediated excitation and contraction of intestinal smooth muscle.
2) It found that isoflurane strongly inhibited the muscarinic cation current in mouse intestinal cells, reducing carbachol-activated current by 63% and GTPγS-induced current by 44%.
3) Isoflurane also inhibited carbachol-induced contractions of ileum and colon smooth muscle tissues by approximately 30%. The results suggest isoflurane acts by inhibiting muscarinic receptors and G-proteins rather than directly blocking TRPC channels.
In vivo modulation of dopaminergic nigrostriatal pathways by cytisine derivat...Georgi Daskalov
This study examined the ability of the nicotinic receptor agonist cytisine and two halogenated derivatives (3-bromocytisine and 5-bromocytisine) to stimulate dopamine release in vivo and protect against dopamine depletion in a rat model of Parkinson's disease. Microdialysis experiments showed that cytisine, 5-bromocytisine, and nicotine were more effective than 3-bromocytisine at inducing striatal dopamine release. Administration of cytisine and 5-bromocytisine before and after an intranigral injection of 6-hydroxydopamine significantly prevented the decrease in striatal dopamine levels, but 3-bromocytisine did not provide protection. These results suggest that the efficacy
This study developed a new model using Drosophila melanogaster larvae to study chemotherapy-induced peripheral neuropathy (CIPN). The goals were to examine the effects of Taxol and Cisplatin chemotherapy drugs on mitochondrial dynamics and function, and determine if pretreatment with another drug could prevent the effects of chemotherapy. Behavioral assays showed that as drug concentration increased, motor and sensory function decreased and mortality rose. Imaging of larval neurons found that the chemotherapy drugs reduced mitochondrial movement, especially at higher Cisplatin doses. The results provide preliminary evidence that this model could help uncover mechanisms of CIPN and identify potential treatments.
This study investigated the role of neuronal apoptosis in volumetric changes of the hippocampus in diabetes mellitus type 1 rats. The key findings were:
1. The volume of the dentate gyrus and CA3 region was reduced in diabetic and vitamin C-treated rats compared to controls, indicating volume reduction can occur independently of neuronal loss.
2. The number of apoptotic neurons in the dentate gyrus and CA3 was significantly higher in diabetic rats compared to other groups, showing neuronal apoptosis is increased by diabetes.
3. A response index using the ratio of dentate gyrus to CA3 volumes and neuronal densities provided a predictive model, with the curves meeting at a critical point of 0
The study aimed to examine the protective effects of taxifolin on cisplatin-induced kidney damage in rats. Rats were divided into three groups: a healthy control group, a cisplatin group, and a taxifolin-cisplatin group. The cisplatin group was given cisplatin only, while the taxifolin-cisplatin group was given both taxifolin and cisplatin. After 14 days, biomarkers of kidney damage were measured in blood and tissue samples. Histological examination of kidney tissue was also performed. The results showed that cisplatin increased oxidative stress markers and kidney damage, while taxifolin prevented these effects of cisplatin and reduced kidney damage. The study demonstrated
1) The document describes four studies related to sepsis and the immune response.
2) The first study finds that autophagy plays a protective role in organ dysfunction in a mouse sepsis model, with autophagy induced in several organs over 24 hours after cecal ligation and puncture.
3) The second study finds that TNFα decreases heart rate, contractile force, and speeds of contraction and relaxation in an isolated perfused rat heart, and that these effects are partially reversible.
IDN5706 is a semi-synthetic derivative of hyperforin that has neuroprotective effects. The document reports on experiments examining the effects of IDN5706 on field excitatory postsynaptic potentials (fEPSPs) in mouse hippocampal slices. The results suggest that IDN5706 activates TRPC3/6/7 channels, improving synaptic response and protecting against reductions in fEPSPs caused by amyloid beta oligomers. IDN5706 also improved spatial memory in mice, and this effect was blocked by a TRPC channel blocker. Computational modeling further supported the idea that IDN5706 activates TRPC channels.
The role of curcumin in streptozotocin induced hepatic damage and the trans-d...Prof. Hesham N. Mustafa
Diabetic patients frequently suffer from non-alcoholic steatohepatitis. The current study aimed to investigate the role of curcumin and the response of hepatic stellate cells in streptozotocin (STZ)-induced hepatic damage. Sixty male rats were divided into three groups. The normal control injected with a citrate buffer vehicle and the diabetic control group which was injected intraperitoneally (IP) with a single-dose of streptozotocin (50mg/kg body weight) and a diabetic group was treated with an oral dose of curcumin at 80 mg/kg body weight daily for 60 days. Curcumin effectively counteracts oxidative stress-mediated hepatic damage and improves biochemical parameters. Alpha-smooth muscle actin (α-SMA) was significantly reduced, and insulin antibodies showed strong positive immunoreactivity with curcumin administration. These results optimistically demonstrate the potential use of curcumin, which is attributed to its antiradical/antioxidant activities and its potential β-cell regenerative properties. Also, it has the capability to encourage the trans-differentiation of hepatic stellate cells into insulin-producing cells for a period of time. In addition, as it is an anti-fibrotic mediator that inhibits hepatic stellate cell activation and the transition to myofibroblast-like cells, this suggests the possibility of considering curcumin's novel therapeutic effects in reducing hepatic dysfunction in diabetic patients.
Oral toxic exposure of titanium dioxide nanoparticles on serum biochemical ch...Nanomedicine Journal (NMJ)
Abstract
Objective(s):
Titanium dioxide (TiO2) nanoparticles (NPs) are widely used in commercial food additives and cosmetics worldwide. Uptake of these nanoparticulate into humans by different routes and may exhibit potential side effects, lags behind the rapid development of nanotechnology. Thus, the present study designed to evaluate the toxic effect of mixed rutile and anatase TiO2 NPs on serum biochemical changes in rats.
Materials and Methods:
In this study, adult male Wistar rats were randomly allotted into the experimental and control groups (n=6), which were orally administered with 50 and 100 mg/kg body weight of TiO2 NPs. Toxic effects were assessed by the changes of serum biochemical parameters such as glucose, total protein, albumin, globulin, cholesterol, triglyceride, high density lipoprotein, alanine transaminase, aspartate transaminase, alkaline phosphatase, total bilirubin, blood urea nitrogen, uric acid and creatinine. All the serum biochemical markers were experimented in rats, after 14-days of post exposure.
Results:
Changes of the serum specific parameters indicated that liver and kidney were significantly affected in both experimental groups. The changes between the levels of total protein, glucose, aspartate transaminase, alanine transaminase and alkaline phosphatase indicate that TiO2 NPs induces liver damage. Significant increase in the blood urea nitrogen and uric acid indicates the renal damage in the TiO2 NPs treated rats.
Conclusion:
The data shows that the oral administration of TiO2 NPs (<100nm) may lead to hepatic and renal toxicity in experimental rats.
This study investigated whether S-methylcysteine (SMC), a metabolite of monohalomethanes, contributes to their neurotoxicity. The researchers found that:
1) High concentrations of SMC (10-2 M) reduced synaptic responses in hippocampal slices, an effect that was partially reversible.
2) In organotypic hippocampal cultures, 24 hour exposure to 5x10-5 M SMC compromised membrane integrity in the dentate gyrus, while lower concentrations increased population spike amplitudes and repetitive discharges without affecting membrane integrity.
3) In dissociated hippocampal neurons, SMC reduced GABA-induced currents, acting as a competitive GABAA receptor antagonist with
2014 increasing survival study of kidney hek-293 tOscar Moreno
This document summarizes a study that examined the effects of magnetic field stimulation on the growth of Human Embryonic Kidney 293 cells (HEK-293T cells). The cells were exposed to magnetic field vortices at frequencies between 100-2500 Hz and field intensities of 1.13-4.13 mT. A nanofluid containing gadolinium was also added to the cells. Flow cytometry analysis after 72 hours found that cell survival increased by 12.89% in the exposed cells compared to the unexposed control cells. The results suggest that magnetic field stimulation may activate cellular mechanisms that promote increased cell survival. Further experiments are still needed to fully understand the magnetic effects on cell growth.
This study investigated the genotoxic potential of paracetamol and its reactive metabolite NAPQI. The key findings were:
1. Neither paracetamol nor NAPQI caused mutations in Salmonella typhimurium bacteria, though NAPQI was cytotoxic to the bacteria.
2. Radiolabeled paracetamol bound covalently to DNA in mouse liver microsomal incubations and hepatic DNA from mice given a hepatotoxic dose.
3. NAPQI caused DNA single-strand breaks in treated liver cells, and paracetamol induced increased DNA repair synthesis in mouse liver cells, both at cytotoxic concentrations.
Taken together, these results show that while par
Effects of extract of Drymaria cordata on isolated rat liver MMPT poreGloria Okenze
This study investigated the effects of extract of Drymaria cordata, a medicinal plant, on the mitochondrial membrane permeability transition pore (MMPT pore) using isolated rat liver mitochondria. The objectives were to determine if the extract could induce opening of the MMPT pore. Fractions of the methanol extract were tested for their effects on mitochondrial swelling, ATPase activity, and lipid peroxidation in the presence and absence of calcium. The chloroform fraction was found to be the most potent at inducing MMPT pore opening and inhibiting lipid peroxidation. This suggests the chloroform fraction contains compounds that could modulate apoptosis by affecting the mitochondrial membrane and MMPT pore. Further studies are needed to identify active compounds and fully characterize
Subcutaneous administration of toluene to rabbits for 6 weeks resulted in significant increases in liver enzyme levels and histopathological changes in the liver tissue. Liver sections from toluene-treated rabbits showed congested central veins, flattening and vacuolation of hepatocytes, and disarrangement of hepatic architecture. In contrast, liver sections from control rabbits appeared normal. Toluene exposure is known to cause oxidative stress and damage cell membranes in the liver through its metabolism.
Morphological and functional state of immune organs in rats with experimental...QUESTJOURNAL
This study examined the morphological and functional changes in the immune organs (thymus and spleen) of rats with experimentally induced type 1 diabetes mellitus (DM-1). Rats with DM-1 showed initial pathological changes in these organs, including increased medulla in the thymus and increased white pulp in the spleen, indicating early inflammatory and degenerative processes. Treatment with the phytopreparation BNO 10.30 was found to help restore cell structure in the thymus and spleen by stimulating immune function. The results demonstrate the importance of early detection of immune organ changes in patients with type 1 diabetes.
Isolation, in vitro antidiabetic, antioxidant activity and molecular docking ...iosrjce
The document describes the isolation and characterization of two pentacyclic triterpenoids, friedelin and 3β-friedelinol, from the stem bark of Syzygium alternifolium. The compounds were tested for their antidiabetic and antioxidant activities. Friedelin and 3β-friedelinol showed significant inhibition of α-glucosidase and α-amylase enzymes, decreasing plasma glucose levels and demonstrating antidiabetic effects. They also exhibited antioxidant properties by scavenging free radicals in the DPPH inhibition assay. Molecular docking studies confirmed the binding of friedelin and 3β-friedelinol to α-glucosidase and
The document discusses a study that investigated the effects of Strobilanthes crispus extracts on atherosclerosis in hypercholesterolemic rabbits. Rabbits were divided into four groups: one receiving a high cholesterol diet only, one receiving the diet plus simvastatin, one receiving the diet plus S. crispus extract, and a control group. Histological analysis found lesser thickening of the aorta in the S. crispus and simvastatin groups compared to the high cholesterol group. Liver tissue from the S. crispus group showed no fatty or inflammatory changes seen in the other groups. The results support that S. crispus may slow atherosclerosis development through hypocholesterolemic effects.
1) The study examines the role of tissue plasminogen activator (tPA) and plasmin in promoting axonal regrowth after spinal cord injury (SCI) via degradation of chondroitin sulfate proteoglycans (CSPGs).
2) It finds that tPA and plasmin are upregulated after SCI and can degrade CSPG core proteins. Mice lacking tPA show attenuated neurite outgrowth and recovery after SCI, even with chondroitinase ABC (ChABC) treatment to degrade CSPG sugar chains.
3) Coadministration of ChABC and plasmin enhanced recovery in tPA-deficient mice and further supported recovery in wild-type mice with S
Similar to Activation of e_nos_by_d-pinitol_induces_an_endothe(1) (20)
Animais de Laboratório.pptx Para estudos básicos em ciências biomédicasNilberto Nascimento
O documento discute o enriquecimento ambiental, diagnóstico de prenhez e sinais de estresse em animais. Ele fornece informações sobre como melhorar o bem-estar de animais em cativeiro.
Apresentação FESBE - 2.pptx Farmacologia de Produtos NaturaisNilberto Nascimento
O documento descreve um módulo temático sobre o potencial cardioprotetor de moléculas derivadas de plantas, coordenado por Nilberto Robson Falcão do Nascimento da UECE. O documento discute o uso de fitoterápicos e fitofármacos, com ênfase na pesquisa de compostos naturais com atividades antiarrítmica, antiagregante plaquetária, vasoprotetora e cardioprotetora realizada no Laboratório de Farmacologia Cardiovascular e Renal da UECE.
Este documento fornece um resumo das atividades de pesquisa realizadas no Instituto de Ciências Biomédicas (ISCB) da Universidade Estadual do Ceará. Ele lista os pesquisadores e suas linhas de pesquisa, laboratórios, produções científicas, projetos aprovados, patentes, ensaios clínicos realizados e eventos promovidos pelo ISCB ao longo dos anos.
This document discusses the discovery and development of beta-lactam antibiotics. It describes Howard Florey injecting penicillin into a mouse's tail, and Selman Waksman receiving the Nobel Prize for his research that led to the discovery of streptomycin. It also shows images of William Feldman and H. Corwin Hinshaw, who were the first to test streptomycin as a revolutionary treatment for tuberculosis. The document outlines the phases of drug development from preclinical testing in animals through post-marketing studies. It lists the types of toxicology studies required including single dose toxicity, repeat dose toxicity, reproductive toxicity, genotoxicity, safety pharmacology, carcinogenicity, and toxicokinetics.
- The document discusses inositol and its potential role as a biomarker for type 2 diabetes. It summarizes research on inositol isomers like D-chiro-inositol and myo-inositol and their relationship to insulin resistance and glucose metabolism.
- Researchers developed methods to analyze inositol levels in urine and saliva samples using HPLC and refractive index detection. After trying different columns and solvent systems, they achieved separation of glucose, chiro-inositol and myo-inositol. Validation studies were conducted and the method was applied to analyze rat kidney samples.
- Inositol may act as an insulin mediator and levels of different isomers in body fluids have
1) The study investigated the expression of myo-inositol cotransporters (SMIT-1, SMIT-2, HMIT) in central and peripheral nervous tissues during the development of experimental diabetes using a streptozotocin-induced diabetic rat model.
2) Results found downregulation of SMIT-1, SMIT-2, and HMIT expression in most central nervous system tissues over time with diabetes. In peripheral nerves, SMIT-1 expression decreased while HMIT expression increased in sciatic nerve and dorsal root ganglia.
3) Protein expression of SMIT-1 and HMIT in sciatic nerve gradually decreased with longer diabetes duration
O documento descreve os principais componentes e funções do sistema cardiovascular, incluindo o coração, vasos sanguíneos e linfáticos, circulações pulmonar e sistêmica, e estrutura e função dos capilares. É detalhado o papel do sistema na circulação de gases, nutrientes, hormônios e células imunes, assim como a estrutura das camadas das artérias, veias e capilares.
O documento fornece informações sobre o Biotério das Universidades Públicas Estaduais do Ceará, incluindo estatísticas sobre graduação, pós-graduação, pesquisa, inovação e rankings acadêmicos entre 2015-2018. Além disso, detalha a infraestrutura do biotério, investimentos, produção projetada de animais, e impactos acadêmicos, tecnológicos e econômicos esperados.
1. O documento descreve o sistema cardiovascular, incluindo sua estrutura, funções e desenvolvimento.
2. É detalhado o aparelho circulatório, coração e vasos sanguíneos, assim como os sistemas arterial, venoso e linfático.
3. As estruturas do coração, como paredes, camadas, válvulas e sistemas de condução de impulsos são explicadas.
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Activation of e_nos_by_d-pinitol_induces_an_endothe(1)
1. ORIGINAL RESEARCH
published: 22 May 2018
doi: 10.3389/fphar.2018.00528
Edited by:
Karl Tsim,
Hong Kong University of Science
and Technology, Hong Kong
Reviewed by:
Adriana Georgescu,
Institute of Cellular Biology
and Pathology, Romania
Xiao Yu Tian,
The Chinese University of Hong Kong,
Hong Kong
Maria Luisa Del Moral,
Universidad de Jaén, Spain
*Correspondence:
Steyner F. Cortes
sfcortes@icb.ufmg.br
Specialty section:
This article was submitted to
Ethnopharmacology,
a section of the journal
Frontiers in Pharmacology
Received: 27 September 2017
Accepted: 02 May 2018
Published: 22 May 2018
Citation:
Moreira LN, Silva JF, Silva GC,
Lemos VS and Cortes SF (2018)
Activation of eNOS by D-pinitol
Induces an Endothelium-Dependent
Vasodilatation in Mouse Mesenteric
Artery. Front. Pharmacol. 9:528.
doi: 10.3389/fphar.2018.00528
Activation of eNOS by D-pinitol
Induces an Endothelium-Dependent
Vasodilatation in Mouse Mesenteric
Artery
Luciana N. Moreira1, Josiane F. Silva2, Grazielle C. Silva2, Virgínia S. Lemos2 and
Steyner F. Cortes1
*
1
Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte,
Brazil, 2
Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
D-pinitol is a cyclitol present in several edible plant species and extensively investigated
for the treatment of metabolic diseases in humans, as food supplement, and
demonstrated protective effects in the cardiovascular system. For these reasons, the
present work aimed at investigating the mechanisms involved in the vascular effects
of D-pinitol in mouse mesenteric artery. Mesenteric arteries from male C57BL/6 mice
were mounted in a wire myograph. Nitrite was measured by the 2,3-diaminonaphthalene
(DAN) method. Protein expression and phosphorylation were measured by Western blot.
The systolic blood pressure (SBP) was measured by tail-cuff plethysmography. D-pinitol
induced a concentration-dependent vasodilatation in endothelium-intact, but not in
endothelium-denuded arteries. Nω-Nitro-L-arginine methyl ester (300 µM) abolished
the effect of D-pinitol, while 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 µM)
shifted the concentration-response curve to the right. KN-93 (1 µM) blunted the
vasodilator effect of D-pinitol, but H-89 (0.1 µM) did not change it. 1-[2-(Trifluoromethyl)
phenyl]imidazole (300 µM), indomethacin (10 µM), celecoxib (5 µM), wortmannin
(1 µM), ruthenium red (10 µM), tiron (10 µM), MnTMPyP (30 µM), MPP (0.1 µM), PHTPP
(0.1 µM), and atropine (1 µM) did not change the effect of D-pinitol. D-pinitol increased
the concentration of nitrite, which was inhibited by L-NAME and calmidazolium (10 µM).
D-pinitol increased the phosphorylation level of eNOS activation site at Ser1177 and
reduced the phosphorylation level of its inactivation site at Thr495. In normotensive mice,
the intraperitoneal administration of D-pinitol (10 mg/kg) induced a significant reduction
of the SBP after 30 min. The present results led us to conclude that D-pinitol has an
endothelium- and NO-dependent vasodilator effect in mouse mesenteric artery through
a mechanism dependent on the activation of eNOS by the calcium-calmodulin complex,
which can explain its hypotensive effect in mice.
Keywords: calcium-calmodulin complex, D-pinitol, endothelium, mesenteric artery, nitric oxide synthase
INTRODUCTION
Inositols are cyclohexane polyols also known as cyclitols. They are arranged in nine stereoisomers:
scyllo, myo, neo, chiro, cis, mucus, and allo (Thomas et al., 2016). Inositols play an important role in
cell physiology as precursors of second messengers involved in the secretory processes, metabolism,
contraction, and proliferation (Thomas et al., 2016). Moreover, inositols have some clinical uses
Frontiers in Pharmacology | www.frontiersin.org 1 May 2018 | Volume 9 | Article 528
2. Moreira et al. eNOS-Dependent Cardiovascular Effects of D-pinitol
in the treatment of polycystic ovary syndrome and have been
considered as an option as a food supplement for treatment or
prevention of gestational and type 2 diabetes mellitus (Facchinetti
et al., 2015; Celentano et al., 2016). The improvement in the
metabolic parameters observed after the use of inositols in
polycystic ovary syndrome, and type 2 diabetes mellitus suggests
that they may have a protective effect on the cardiovascular
system (Cussons et al., 2006).
D-pinitol (3-O-methyl-D-chiro-inositol) is a cyclitol
present in several edible plants, including soybean and carob
(Kawai and Kumazawa, 1982; Baumgartner et al., 1986). The
chemical similarity suggests that pinitol is a natural source of
D-chiro-inositol in vivo (Davis et al., 2000). Pinitol has been
described as an antidiabetic drug, with insulin-like effect in an
animal model of diabetes (Bates et al., 2000), and the ability to
potentiate the activity of insulin through the translocation of
glucose transporter 4 in skeletal muscle of mice (Dang et al.,
2010). In humans with type 2 diabetes mellitus, treatment
with pinitol improved the glycemic control, reduced the
adipocytokine level, and reduced the metabolic parameters
associated with cardiovascular risk (Kim et al., 2005, 2012). In
the cardiovascular system, D-pinitol was shown to prevent the
endothelial dysfunction induced by diabetes in rat aorta and
mesenteric arteries (Nascimento et al., 2006). This protective
effect was attributed to its antioxidant effect, which seemed to be
responsible for the preservation of nitric oxide (NO) signaling.
It is noteworthy that the polycystic ovary syndrome is also
associated with an endothelium dysfunction (Paradisi et al.,
2001) and the treatment with cyclitols may also have a protective
effect in this disease (Croze and Soulage, 2013).
D-pinitol has been extensively investigated for the treatment
of metabolic diseases in humans, and as a food supplement, for
these reasons, a more detailed investigation of the vascular effect
of this cyclitol is necessary. Therefore, the present work aimed at
investigating the vascular effect of D-pinitol in small mesenteric
arteries from mice.
MATERIALS AND METHODS
Animals
Sixty-six male C57BL/6 mice, aged 10–12 weeks, were used
in the present study. The experiments were performed in
accordance with the recommendations of the ethics committee
of the Universidade Federal de Minas Gerais. The experimental
protocols were approved by the Animal Ethics Committee
(protocol 170/2014).
Vascular Reactivity
Mice were euthanized by decapitation, the abdomen was cut,
and the mesenteric bed was quickly removed and placed in a
dissecting plate with physiological salt solution (PSS) with the
following composition (mM): NaCl 119.0; KCl 4.7; KH2PO4 0.4;
NaHCO3 14.9; MgSO4.7H2O 1.17; CaCl2.2H2O 2.5; and glucose
5.5. A segment of the second branch of the mesenteric artery was
dissected, and the adipose and connective tissues were removed.
The arteries were sectioned into rings (1.6–2.0 mm long) with
an internal diameter ranging from 150 to 250 µm. The rings
were mounted in a wire myograph (620M, DMT, Denmark),
kept in carbogen aerated PSS at 37◦C. After mounting, the
artery was stretched to a length that yielded a circumference
equivalent to 90% of that given by an internal pressure of
100 mmHg; this required a load of approximately 200 mg. The
vessel was maintained for an equilibration period of 60 min.
The mechanical activity was recorded isometrically as previously
described (Silva et al., 2016). The functionality of the arteries
was observed by the contraction induced by phenylephrine
(3 µM) and by the vasodilator effect induced by acetylcholine
(ACh, 10 µM) in arteries pre-contracted with phenylephrine.
Arteries with ACh-induced vasodilatation higher than 70% were
considered with functional endothelium. In some experimental
procedures, the endothelium was removed by rubbing the
lumen slightly with the tungsten wire. The removal of the
endothelium was confirmed by the absence of vasodilatation
induced by ACh in precontracted arteries. The vasodilator
effect of D-pinitol was evaluated by concentration-response
curves (1 nM to 100 µM) in mesenteric arteries in the presence
and the absence of a functional endothelium pre-contracted
with phenylephrine (3 µM). The participation of nitric oxide
synthase (NOS) was investigated in arteries pretreated with
Nω-nitro-L-arginine-methyl-ester (L-NAME; 300 µM), a
non-selective inhibitor of NOS, and 1-(2-trifluoromethylphenyl)
imidazole (TRIM; 300 µM), a selective inhibitor of neuronal
NOS (nNOS). The activation of guanylate cyclase was
investigated with 1H- [1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one
(ODQ; 10 µM). The involvement of cyclooxygenase
(COX) 1 and 2, phosphatidylinositol-3-kinase (PI3K),
Ca2+/calmodulin-dependent kinase II (CaMKII), and
non-selective cationic channels was verified in arteries
pretreated with indomethacin (10 µM), celecoxib (5 µM),
wortmannin (1 µM), KN-93 (1 µM), and ruthenium red (10
µM), respectively. Tiron (10 µM) and MnTMPyP (30 µM), a
cell-permeable analog of superoxide dismutase, were used to
investigate the action of antioxidant drugs on the vasodilator
effect of D-pinitol. The participation of muscarinic receptors and
α and β estrogen receptors was investigated in arteries pretreated
with atropine (1 µM), MPP (0.1 µM), and PHTPP (0.1 µM),
respectively.
Nitrite Measurement in Mouse
Mesenteric Artery
The assessment of NO production in the mesenteric artery was
performed indirectly by the measurement of nitrite (NO2
−)
using the fluorescence method with 2,3-diaminonaphthalene
(DAN), according to Silva et al. (2016). The mesenteric artery
branches were placed in PSS, at 37◦C in 5% CO2 atmosphere.
Samples were collected in the absence (basal) or the presence of
D-pinitol (20 µM) or ACh (10 µM). The involvement of NOS
and calmodulin in the production of nitrite was evaluated in the
presence of L-NAME (300 µM) and calmidazolium (10 µM),
respectively. 150 µl samples were collected, added to 150 µl of
purified water, followed by the immediate addition of 15 µl fresh
DAN solution (0.05 mg/l in 0.62 M HCl) in 96-well opaque
Frontiers in Pharmacology | www.frontiersin.org 2 May 2018 | Volume 9 | Article 528
3. Moreira et al. eNOS-Dependent Cardiovascular Effects of D-pinitol
black plates (CostarR
, United States). The reaction proceeded
for 10 min at room temperature and protected from light. After
this period, the reaction was stopped with 5 µl of NaOH (2.8
N) and the absorbance determined using a spectrofluorometer
(Fluoroskan Ascent FL, Thermo Scientific) at 365 and 415 nm,
as respective excitation and emission wavelengths. The nitrite
concentration in the samples was calculated using a standard
curve with predetermined concentrations of sodium nitrite in
each experiment and normalized by the amount of protein in
the branches. The results were expressed in [nitrite] nM/µg of
protein.
Western Blot Analysis of eNOS
Phosphorylation
Western blot analysis was performed as previously described
(Silva et al., 2016), with some modifications. Briefly, a pool of
mesenteric resistance arteries from six animals was stabilized
in PSS aerated with a carbogenic mixture (95% O2 and 5%
CO2) at 37◦C. D-pinitol (20 µM) was added and after 5,
15, or 30 min, the arteries were collected, and frozen at
−80◦C. Arteries that were not stimulated by D-pinitol were
used to determine the basal level of phosphorylation (time
zero). After, the tissues were homogenized in the presence of
lysis buffer (150 mM NaCl; 50 mM Tris; 5 mM EDTA.2Na;
and 1 mM MgCl2) plus 0.3% Triton X-100, 0.5% SDS, and
protease inhibitors cocktail (Sigma FastR
, Sigma), supplemented
with a cocktail of protease inhibitors (20 mM NaF, 0.1 mM
Na3VO4, and 0.1 mM PMSF). 30 µg of protein were applied
on the SDS-PAGE gel (sodium dodecyl sulfate polyacrylamide)
7.5%. Then, proteins were transferred to a PVDF membrane
(Millipore, United States) and the membranes were blocked (3%
albumin in TBS enriched with 0.1% Tween 20) before overnight
incubation with the specific primary antibody: anti-eNOS (1:750;
mouse monoclonal; Santa Cruz Biotechnology Inc., Santa Cruz,
CA, United States), anti β-actin (1:1000, mouse monoclonal;
Santa Cruz Biotechnology Inc.), anti-phospho-eNOS-Ser1177
(1:500; goat polyclonal; Santa Cruz Biotechnology Inc.), and
anti-phospho-eNOS-Thr495 (1:500, goat polyclonal; Santa Cruz
Biotechnology Inc.). The immunocomplexes were detected by
a chemiluminescence assay (ECL Plus kit; Amersham, Les Ulis,
France) and the densitometry analyses were done using the
software ImageJ 1.48v.
Systolic Blood Pressure Measurement
The systolic blood pressure (SBP) was measured by the tail-cuff
plethysmography (Gross and Luft, 2003) using MRBP system
(IITC Life Science, Los Angeles, CA, United States). Conscious
mice were conditioned in restraints in a warming chamber
controlled at 32◦C for 10 min. The measurements were taken
at 10, 30, and 60 min after the intraperitoneal administration
of D-pinitol (10 mg/kg) or saline. The basal SBP was measured
10 min before the administration of D-pinitol.
Statistical Analysis
Statistical analyses were performed using GraphPad Prism 4
program. Vasodilator data were represented as the percentage of
reduction in the sustained contraction induced phenylephrine
(3 µM). Two-way ANOVA followed by Bonferroni post-test
was used to analyze the cumulative concentration-response
curves and the reduction in the SBP induced by D-pinitol.
One-way ANOVA was used for the statistical analysis of nitrite
dosage and Western blot data. All results were expressed as
mean ± standard error of the mean (SEM) and found to be
significant if P < 0.05.
RESULTS
Vascular Reactivity
In the presence of a functional endothelium, D-pinitol induced
a concentration-dependent vasodilator effect. The maximal
vasodilator effect (Emax) achieved was 21.4 ± 2.4% (Figure 1A).
However, in the absence of a functional endothelium, the
vasodilator effect of D-pinitol was abolished (Figure 1A).
The non-selective inhibition of eNOS with L-NAME blunted
the vasodilator effect of D-pinitol (Figure 1B) while the
selective inhibition of nNOS with TRIM did not alter its
vasodilator effect (Figure 1C). The inhibition of guanylate
cyclase with ODQ induced a significant shift to the right on
the concentration-response curve of D-pinitol (Figure 1D).
The inhibition of COX-1 with indomethacin (Figure 2A),
COX-2 with celecoxib (Figure 2B), PI3K with wortmannin
(Figure 2C), and non-selective calcium channels blockade with
ruthenium red (Figure 2D) did not change the vasodilator effect
of D-pinitol. KN-93, a selective inhibitor of CaMKII, blunted
the vasodilator effect of D-pinitol (Figure 3A), while H-89,
a selective inhibitor of PKA, did not change it (Figure 3B).
Antioxidant drugs such as Tiron (Figure 4A) and MnTMPyP
(Figure 4B), a cell-permeable analog of SOD, did not alter the
concentration-response curve to D-pinitol in endothelium-intact
mesenteric arteries. Preincubation of arteries with atropine, MPP,
and PHTPP did not change the concentration-response curve to
D-pinitol (Supplementary Figure S1).
Nitrite Measurement in Mouse
Mesenteric Artery
D-pinitol increased more than threefold the amount of nitrite
in comparison with the basal level in mouse mesenteric
artery (Figure 5A). L-NAME blunted the increase induced by
D-pinitol while calmidazolium induced a significant reduction
(Figure 5A). A similar effect was observed with ACh (10 µM),
which was also inhibited by L-NAME and calmidazolium
(Figure 5B).
Western Blot Analysis of eNOS
Phosphorylation
D-pinitol increased the phosphorylation level of the activation
site of eNOS at Ser1177 5 and 15 min after the stimulation of
endothelium-intact mesenteric arteries (Figure 6A). Besides, the
level of phosphorylation of the inactivation site of eNOS at Thr495
was decreased 15 and 30 min after the stimulation of the arteries
with D-pinitol (Figure 6B).
Frontiers in Pharmacology | www.frontiersin.org 3 May 2018 | Volume 9 | Article 528
4. Moreira et al. eNOS-Dependent Cardiovascular Effects of D-pinitol
FIGURE 1 | Endothelium- and nitric oxide-dependent vasodilator effect of D-pinitol in mice mesenteric artery. The concentration-dependent vasodilator effect of
D-pinitol was investigated in the presence (E+) or absence (E-) of a functional endothelium (A), in the presence of L-NAME (B), TRIM (C), and ODQ (D). The inset
demonstrates a representative trace of the concentration-dependent vasodilator effect of D-pinitol, where each mark represent a concentration. All results are
expressed as mean ± SEM of five experiments. ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus E+.
Systolic Blood Pressure Measurement
D-pinitol induced a significant reduction in the SBP of
normotensive mice (Figure 7). The significant reduction in the
SBP was observed 30 min after the administration of D-pinitol in
comparison to the saline SBP at 30 min and to the SBP observed
before the administration of D-pinitol.
DISCUSSION
D-pinitol has been extensively investigated for the treatment
of metabolic diseases in humans, as food supplement, and
demonstrated protective effects in the cardiovascular system. The
present study demonstrated that D-pinitol induces a vasodilator
effect in mice mesenteric arteries by a mechanism dependent
on the production of endothelium-derived NO through the
activation of the calcium-calmodulin complex.
Previous studies with D-pinitol have demonstrated that this
cyclitol has vascular endothelium protective effects (Nascimento
et al., 2006). The present work described a new biological
effect of D-pinitol as a vasodilator drug and contributed
to the understanding of its mechanism of action. Although
20–30% of vasodilator effect seems to be relatively small
if compared with ACh, this level of effect is compatible
with physiological vasodilator mediators, such as angiotensin
(1–7) (Neves et al., 2003; Lemos et al., 2005) and substance
P (Beny and Brunet, 1988) that play an important role in the
control of vascular tone and blood pressure. It is noteworthy
remember that the vascular resistance is inversely proportional to
the radius of the vasculature at the fourth potency, meaning that
a small change in the diameter of the artery results in a significant
reduction in the vascular resistance. This is relevant since this
cyclitol induced a significant vasodilator effect at concentrations
as low as 10 nM and has been tested for the treatment of different
pathologies, notably diabetes, at doses as high as 1,200 mg/day
by the oral route, reaching plasma concentration above 1 µM
(Campbell et al., 2004; Kim et al., 2005; Kang et al., 2006).
Therefore, it is plausible to think that the concentrations used in
this study are achieved in the systemic circulation during chronic
treatment with therapeutic doses of D-pinitol.
The endothelium plays an important role in the cardiovascular
system. It functions as a semipermeable barrier between the blood
and the vessel wall, regulating vital functions such as vascular
tone, response to inflammatory stimuli, and blood coagulation
(Triggle et al., 2003; Aird, 2007; Otsuka et al., 2012). The control
of vascular tone by the endothelium is due to the synthesis
and release of mediators such as NO, prostacyclin, and other
endothelium-derived relaxant factors (EDRFs). Some of these
EDRFs induce endothelium-derived hyperpolarization (EDH) of
vascular smooth muscle, such as H2O2 and epoxyeicosatrienoic
acids (Medhora et al., 2001; Matoba et al., 2002; Chadha et al.,
2011). In this study, removal of the endothelium abolished the
Frontiers in Pharmacology | www.frontiersin.org 4 May 2018 | Volume 9 | Article 528
5. Moreira et al. eNOS-Dependent Cardiovascular Effects of D-pinitol
FIGURE 2 | Cyclooxygenase 1 and 2, phosphatidylinositol 3-kinase, and transient receptor potential channels are not involved in the vasodilator effect of D-pinitol in
mice mesenteric arteries. The concentration-dependent vasodilator effect of D-pinitol was investigated in mesenteric arteries with a functional endothelium in the
absence (Control) and presence of indomethacin (A), celecoxib (B), wortmannin (C), and ruthenium red (D). All results are expressed as mean ± SEM of five
experiments.
FIGURE 3 | Ca2+/calmodulin-dependent kinase II, but not protein kinase A, is involved in the vasodilator effect of D-pinitol in mice mesenteric arteries.
The concentration-dependent vasodilator effect of D-pinitol was investigated in mesenteric arteries with a functional endothelium in the absence (control) and
presence of KN-93 (A) and H-89 (B). All results are expressed as mean ± SEM of five experiments. ∗∗∗P < 0.001 versus respective control.
vasodilator effect of D-pinitol, demonstrating the involvement
of the EDRFs in the vasodilator effect of this drug. The
involvement of eNOS in the formation of EDRF participating in
the control of the vascular tone is already well accepted. However,
several studies have demonstrated the presence of nNOS in the
endothelium of mice mesenteric arteries and aorta, validating its
Frontiers in Pharmacology | www.frontiersin.org 5 May 2018 | Volume 9 | Article 528
6. Moreira et al. eNOS-Dependent Cardiovascular Effects of D-pinitol
FIGURE 4 | The vasodilator effect of D-pinitol in mice mesenteric arteries is not associated with the formation of reactive oxygen species. The
concentration-dependent vasodilator effect of D-pinitol was investigated in mesenteric arteries with a functional endothelium in the absence (control) and presence of
tiron (A) or MnTMPyP (B). All results are expressed as mean ± SEM of five experiments.
FIGURE 5 | D-pinitol increases the formation of nitrite through a mechanism dependent on the activation of endothelial nitric oxide synthase (eNOS) by the
calcium-calmodulin complex. The formation of nitrite was measured in endothelium-intact mesenteric arteries in the absence (basal) or presence of D-pinitol
(control/ A) or acetylcholine (ACh; control; B). The involvement of eNOS and calmodulin was evaluated in mesenteric arteries stimulated with D-pinitol or ACh in the
presence of L-NAME and calmidazolium, respectively. All results are expressed as mean ± SEM of five experiments. ∗∗∗P < 0.001 versus basal. †P < 0.05, and
†††P < 0.001 versus control.
participation in the control of the vascular tone (Capettini et al.,
2008, 2010; Takaki et al., 2008; Silva et al., 2016). The inhibition
of the vasodilator effect of D-pinitol by L-NAME and the absence
of inhibitory effect by TRIM, suggest the endothelium-dependent
effect of D-pinitol occurs through the activation of eNOS, and
that nNOS is not involved. The reduction of the vasodilator effect
of D-pinitol by ODQ, a selective inhibitor of guanylate cyclase,
supports the participation NO as the eNOS-derived EDRF in the
vasodilator effect of this cyclitol in mice mesenteric arteries. In
addition, the absence of effect of COX inhibitors rules out the
participation of prostacyclin in the vasodilator effect of D-pinitol.
eNOS can be activated by calcium-independent and
-dependent mechanisms (Fleming, 2010). The calcium-
independent mechanism of the activation of eNOS involves
the PI3K/Akt pathway (Dimmeler et al., 1999; Fulton et al.,
1999). Wortmannin, a selective inhibitor of PI3K (Arcaro and
Wymann, 1993), prevents the phosphorylation and activation of
Akt and inhibits increased levels of cGMP in vascular smooth
muscle (Dimmeler et al., 1999). In the present work, wortmannin
did not change the vasodilator effect of D-pinitol, suggesting that
the PI3K/Akt pathway is not involved in the activation of eNOS
by this cyclitol in mesenteric arteries. The calcium-dependent
mechanism involves the increase in intracellular calcium
concentration resulting from the release of intracellular stores
of calcium or the influx through the plasmatic membrane of
endothelial cells (Fleming, 2010; Forstermann and Sessa, 2012).
The transient receptor potential channels (TRPs) are considered
non-selective channels that allow the influx of calcium, sodium,
Frontiers in Pharmacology | www.frontiersin.org 6 May 2018 | Volume 9 | Article 528
7. Moreira et al. eNOS-Dependent Cardiovascular Effects of D-pinitol
FIGURE 6 | D-pinitol activates the endothelial nitric oxide synthase (eNOS) phosphorylating and dephosphorylating its respective activation and inactivation sites.
Western-blots for time-course of the phosphorylation level of Ser1177 (A), the activation site of eNOS, and the dephosphorylation level of Thr495 (B), the inactivation
site of eNOS, were performed in endothelium-intact mesenteric arteries, in the absence (basal) and presence of D-pinitol (20 µM). All results are expressed as
mean ± SEM of five experiments. ∗P < 0.05 and ∗∗P < 0.01 versus basal.
FIGURE 7 | D-pinitol (10 mg/kg; i.p.) reduces the systolic blood pressure
(SBP) in normotensive mice. All results are expressed as mean ± SEM of six
experiments. ∗∗P < 0.01 versus saline at 30 min. ††P < 0.01 versus the SBP
measured before the administration of D-pinitol.
and magnesium (Pedersen et al., 2005; Owsianik et al., 2006).
In the endothelial cells the vanilloid TRPs (TRPV), inhibited
by ruthenium red, have been described as the main TRPs
involved in the endothelium-dependent vasodilatation in
mouse mesenteric artery (Zhang et al., 2009). The absence of
a significant modification in the concentration-response curve
of D-pinitol in the presence of ruthenium red suggests that
the TRPVs are not involved in the vasodilatation induced by
this cyclitol. Thus, the calcium-dependent mechanism of eNOS
activation induced by D-pinitol can be related to the release
of the intracellular calcium stores or by the influx of calcium
through other channels. The calcium-dependent mechanism
occurs through the formation of calcium-calmodulin complex
(Matsubara et al., 1996; Fleming, 2010). This mechanism is
inhibited by calmidazolium, a calmodulin antagonist (Busse and
Mulsch, 1990). In the present work, the effect of calmidazolium
was not investigated in the vasodilator effect of D-pinitol as
this drug inhibited the contraction induced by phenylephrine.
However, calmidazolium significantly inhibited the production
of nitrite induced by D-pinitol, in a similar way as observed
with ACh. Therefore, D-pinitol seems to activate eNOS by a
calcium-dependent mechanism.
The phosphorylation of Ser1177 is associated with the
activation of eNOS (Michel et al., 1993; Gallis et al.,
1999). Kinases such as protein kinase B (PKB), adenosine
monophosphate-activated protein kinase (AMPK), protein
kinase A (PKA) and CaMKII can be involved in the activation
of eNOS (Schneider et al., 2003; Fisslthaler and Fleming, 2009;
Forstermann and Sessa, 2012). The absence of inhibitory effect
for H-89 demonstrates that PKA is not involved in the vasodilator
effect of D-pinitol. The inhibition of the vasodilator effect of
D-pinitol by KN-93 confirms the participation of CaMKII in
the activation of eNOS and supports a calcium-dependent
mechanism for D-pinitol. In order to confirm the activation of
eNOS, the level of phosphorylation of Ser1177 was investigated
in the presence of D-pinitol by Western blot. The significant
increase in the level of phosphorylation of Ser1177 at 5 and
15 min after the stimulation with D-pinitol confirms the ability of
this cyclitol to activate eNOS. Additionally, the activity of eNOS
is also regulated by inactivation sites, such as Thr495 (Fleming
et al., 2001). Substances with the ability to activate eNOS
reduce the phosphorylation of this site. As observed by Western
Frontiers in Pharmacology | www.frontiersin.org 7 May 2018 | Volume 9 | Article 528
8. Moreira et al. eNOS-Dependent Cardiovascular Effects of D-pinitol
blot the stimulation with D-pinitol was able to reduce the
level of phosphorylation of Thr495 significantly, once more
confirming the ability of this cyclitol to activate eNOS. This is
an important point since Nascimento et al. (2006) suggested
that the mechanism involved in the increased bioavailability of
NO induced by D-pinitol in arteries from diabetic animals was
related to its antioxidant property, while the direct vasodilator
effect of D-pinitol was not demonstrated in this previous report.
The absence of effect of antioxidant drugs such as tiron and
MnTMPyP on the vasodilator effect of D-pinitol, associated to
the profile of phosphorylation discussed above, demonstrate
that D-pinitol increases the production of NO and induces
its vasodilator effect by activation of eNOS rather than by its
antioxidant action.
Finally, the present study also demonstrates that D-pinitol is
able to reduce the SBP in normotensive mice. This observation is
in line with the vasodilator effect of D-pinitol described above,
which suggests a significant reduction in the systemic vascular
resistance and blood pressure. A previous report demonstrated
that the administration of D-pinitol reduced the cardiovascular
risk factors in patients with type 2 diabetes mellitus, including
the reduction in the SBP and diastolic blood pressure (Kim et al.,
2005). These observations suggest that D-pinitol has a significant
effect on the cardiovascular system and may be investigated
as an antihypertensive drug. However, attention should be
taken if D-pinitol is used as food supplement, considering
that high amounts of this cyclitol can significantly reduce the
blood pressure and may produce hypotension in normotensive
subjects.
The present study allows us to conclude that D-pinitol
has an endothelium- and NO-dependent vasodilator effect
by a mechanism of action involving the calcium-calmodulin
complex activation of eNOS, which might be responsible for its
hypotensive effect.
AUTHOR CONTRIBUTIONS
LM, JS, and GS performed research and contributed to the writing
of the manuscript. VL and SC designed research and reviewed the
manuscript to the submission version.
ACKNOWLEDGMENTS
We thank the Conselho Nacional de Desenvolvimento Científico
e Tecnológico (CNPq, Brazil; 308383/2014-1), Fundação de
Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG,
Brazil; PPM-00551-11), and Coordenação de Aperfeiçoamento
de Pessoal de Nível Superior (CAPES, Brazil; PNPD 2841/2010)
for financial support.
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fphar.
2018.00528/full#supplementary-material
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