METHODS: Sprague Dawley rats were intravitreally injected with ET1. MgAT and TAU were administered as pre-, co-, or posttreatment. Subsequently, the expression of NOS isoforms was detected in retina by immunohistochemistry, retinal nitrotyrosine level was estimated using ELISA, and retinal cell apoptosis was detected by TUNEL staining.
RESULTS: Intravitreal ET1 caused a significant increase in the expressions of nNOS and iNOS while eNOS expression was significantly reduced compared to vehicle treated group. Administration of both MgAT and TAU restored the altered levels of NOS isoform expression, reduced retinal nitrosative stress and retinal cell apoptosis. The effect of MgAT, however, was greater than that of TAU alone.
CONCLUSIONS: MgAT and TAU prevent ET1-induced retinal cell apoptosis by reducing retinal nitrosative stress in Sprague Dawley rats. Addition of TAU to Mg seems to enhance the efficacy of TAU compared to when given alone. Moreover, the pretreatment with MgAT/TAU showed higher efficacy compared to co- or posttreatment.
MATERIALS AND METHODS: Five groups of rats were intravitreally administered with vehicle or Aβ(1-40) in doses of 1.0, 2.5, 5 and 10 nmol. Animals were sacrificed and eyes were enucleated at weeks 1, 2 and 4 post-injection. The retinae were subjected to morphometric analysis and TUNEL staining. Optic nerve sections were stained with toluidine blue and were graded for neurodegenerative effects. The estimation of BDNF and markers of oxidative stress in retina were done using ELISA technique.
RESULTS AND CONCLUSIONS: It was observed that intravitreal Aβ(1-40) causes significant retinal and optic nerve damage up to day 14 post-injection and there was increasing damage with increase in dose. However, on day 30 post-injection both the retinal and optic nerve morphology showed a trend towards normalization. The observations made for retinal cell apoptosis, retinal glutathione, superoxide dismutase activity and BDNF were in accordance with those of morphological changes with deterioration till day 14 and recovery by day 30 post-injection. The findings of this study may provide a guide for selection of appropriate experimental conditions for future studies.
METHODS: Sprague Dawley rats, 180-250 g in weight were divided into four groups. Groups 1, 2, 3 and 4 were intravitreally administered with vehicle and NMDA at the doses 80, 160 and 320 nmol respectively. Seven days after injection, rats were euthanized, and their eyes were taken for optic nerve toluidine blue and retinal hematoxylin and eosin stainings. The TUNEL assay was done for detecting apoptotic cells.
RESULTS: All groups treated with NMDA showed significantly reduced ganglion cell layer (GCL) thickness within inner retina, as compared to control group. Group NMDA 160 nmol showed a significantly greater GCL thickness than the group NMDA 320 nmol. Administration of NMDA also resulted in a dose-dependent decrease in the number of nuclei both per 100 µm GCL length and per 100 µm2 of GCL. Intravitreal NMDA injection caused dose-dependent damage to the optic nerve. The degeneration of nerve fibres with increased clearing of cytoplasm was observed more prominently as the NMDA dose increased. In accordance with the results of retinal morphometry analysis and optic nerve grading, TUNEL staining demonstrated NMDA-induced excitotoxic retinal injury in a dose-dependent manner.
CONCLUSION: Our results demonstrate dose-dependent effects of NMDA on retinal and optic nerve morphology in rats that may be attributed to differences in the severity of excitotoxicity and oxidative stress. Our results also suggest that care should be taken while making dose selections experimentally so that the choice might best uphold study objectives.
METHODS: Male Sprague Dawley rats weighing 200-250 g were grouped into normal rats (N) and diabetic rats. Diabetes was induced by intraperitoneal injection of streptozotocin (55 mg/kg body weight) whereas N similarly received citrate buffer. STZ-injected rats with blood glucose of more than 20 mmol/L were considered diabetic and were divided into vehicle-treated (DV) and TRF-treated (DT) groups. N and DV received vehicle, whereas DT received TRF (100 mg/kg body weight) via oral gavage once daily for 12 weeks. Fundus images were captured at week 0 (baseline), week 6 and week 12 post-STZ induction to estimate vascular diameters. At the end of experimental period, rats were euthanized, and retinal tissues were collected for morphometric analysis and measurement of NFκB, phospho-NFκB (Ser536), HIF-1α using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). Retinal inflammatory and angiogenic cytokines expression were measured by ELISA and real-time quantitative PCR.
RESULTS: TRF preserved the retinal layer thickness (GCL, IPL, INL and OR; p
METHODS: Sprague-Dawley rats were divided into normal control rats (N) which received vehicle, and diabetic rats which either received vehicle (DV) or 100 mg/kg of TRF (DT). Diabetes was induced with intraperitoneal injection of STZ (60 mg/kg body weight). Treatments were given orally, once daily, for 12 weeks after confirmation of hyperglycaemia. Fundus photographs were captured at baseline, 6- and 12-week post-STZ injection and average diameter of retinal veins and arteries were measured. At 12-week post-STZ injection, rats were euthanised, and retinae were collected for measurement of Ang-2 and PKC gene and protein expressions.
RESULTS: Retinal venous and arterial diameters were significantly greater in DV compared to DT at week 12 post-STZ injection (p
METHODS: Diabetes was induced in rats by intraperitoneal injection of streptozotocin and was confirmed by a blood sugar level of at least 20 mmol/L, 48 h, post-injection. Diabetic rats were divided into a group treated with vehicle (DV) and the other treated with TRF (100 mg/kg; DT). A group of non-diabetic rats treated with vehicle (N) served as the control group. All treatments were administered orally for 12 weeks. Rats were then subjected to an assessment of general behaviour in an open field arena and a two-chamber mirror test to assess their visual behaviour. At the end of the experimental period, rats were sacrificed, and their retinas were isolated to measure the expression of pro- (Casp3, Bax) and anti-apoptotic (Bcl2) markers using RT-qPCR and ELISA. TUNEL staining was used to detect the apoptotic retinal cells.
RESULTS: Treatment with TRF lowered the retinal expression of Casp3 protein by 2.26-folds (p
Methods: Excitotoxic retinal injury was induced with intravitreal injection of NMDA in Sprague-Dawley rats. All treatments were given as pre-, co-, and post-treatment with NMDA. Seven days post-injection, the retinas were processed for measurement of the expression of NOS isoforms using immunostaining and enzyme-linked immunosorbent assay (ELISA), retinal 3-NT content using ELISA, retinal histopathological changes using hematoxylin and eosin (H&E) staining, and retinal cell apoptosis using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining.
Results: As observed on immunohistochemistry, the treatment with NMDA caused a 4.53-fold increase in retinal nNOS expression compared to the PBS-treated rats (p<0.001). Among the MgAT-treated groups, only the pretreatment group showed significantly lower nNOS expression than the NMDA-treated group with a 2.00-fold reduction (p<0.001). Among the TAU-treated groups, the pre- and cotreatment groups showed 1.84- and 1.71-fold reduction in nNOS expression compared to the NMDA-treated group (p<0.001), respectively, but remained higher compared to the PBS-treated group (p<0.01). Similarly, iNOS expression in the NMDA-treated group was significantly greater than that for the PBS-treated group (2.68-fold; p<0.001). All MgAT treatment groups showed significantly lower iNOS expression than the NMDA-treated groups (3.58-, 1.51-, and 1.65-folds, respectively). However, in the MgAT co- and post-treatment groups, iNOS expression was significantly greater than in the PBS-treated group (1.77- and 1.62-folds, respectively). Pretreatment with MgAT caused 1.77-fold lower iNOS expression compared to pretreatment with TAU (p<0.05). In contrast, eNOS expression was 1.63-fold higher in the PBS-treated group than in the NMDA-treated group (p<0.001). Among all treatment groups, only pretreatment with MgAT caused restoration of retinal eNOS expression with a 1.39-fold difference from the NMDA-treated group (p<0.05). eNOS expression in the MgAT pretreatment group was also 1.34-fold higher than in the TAU pretreatment group (p<0.05). The retinal NOS expression as measured with ELISA was in accordance with that estimated with immunohistochemistry. Accordingly, among the MgAT treatment groups, only the pretreated group showed 1.47-fold lower retinal 3-NT than the NMDA-treated group, and the difference was significant (p<0.001). The H&E-stained retinal sections in all treatment groups showed statistically significantly greater numbers of retinal cell nuclei than the NMDA-treated group in the inner retina. However, the ganglion cell layer thickness in the TAU pretreatment group remained 1.23-fold lower than that in the MgAT pretreatment group (p<0.05). In line with this observation, the number of apoptotic cells as observed after TUNEL staining was 1.69-fold higher after pretreatment with TAU compared to pretreatment with MgAT (p<0.01).
Conclusions: MgAT and TAU, particularly with pretreatment, reduce retinal cell apoptosis by reducing retinal nitrosative stress. Pretreatment with MgAT caused greater improvement in NMDA-induced changes in iNOS and eNOS expression and retinal 3-NT levels than pretreatment with TAU. The greater reduction in retinal nitrosative stress after pretreatment with MgAT was associated with lower retinal cell apoptosis and greater preservation of the ganglion cell layer thickness compared to pretreatment with TAU.
METHODS: Diabetic rats were treated orally with the vehicle or the ginger extract (75 mg/kg/day) over a period of 24 weeks along with regular monitoring of bodyweight and blood glucose and weekly fundus photography. At the end of the 24-week treatment, the retinas were isolated for histopathological examination under a light microscope, transmission electron microscopy, and determination of the retinal tumor necrosis factor-α (TNF-α), nuclear factor-kappa B (NF-κB), and vascular endothelial growth factor (VEGF) levels.
RESULTS: Oral administration of the ginger extract resulted in significant reduction of hyperglycemia, the diameter of the retinal vessels, and vascular basement membrane thickness. Improvement in the architecture of the retinal vasculature was associated with significantly reduced expression of NF-κB and reduced activity of TNF-α and VEGF in the retinal tissue in the ginger extract-treated group compared to the vehicle-treated group.
CONCLUSIONS: The current study showed that ginger extract containing 5% of 6-gingerol attenuates the retinal microvascular changes in rats with streptozotocin-induced diabetes through anti-inflammatory and antiangiogenic actions. Although precise molecular targets remain to be determined, 6-gingerol seems to be a potential candidate for further investigation.
METHODS: Databases were searched from inception to Aug 2023, comparing molecular targeted therapies (MTT) with conventional chemotherapy, chemotherapy or surgery. Study screening, data extraction, and data analysis were conducted independently by two investigators. The Cochrane Risk of Bias tool 1.0 was used for the quality of the studies.
RESULTS: There was a total of ten eligible studies with 471 participants in the treatment arm and 469 participants in the control arm. Most studies had an unclear risk of bias assessment. Upon network meta-analysis, cetuximab was found to be the most effective regimen for complete response (CR), bevacizumab was found to be the most effective regimen for partial response (PR), nimotuzumab was found to be the most effective regimen for overall survival rate (OS) and progression-free survival (PFS). Pairwise meta-analysis showed that MTT had a significantly better response than conventional therapies in complete response. GRADE analysis reported low certainty of evidence for CR and very low certainty of evidence for other efficacy outcomes. There was a higher chance of bleeding with MTT and was statistically significant.
CONCLUSION: It was observed that targeted therapies were found to be a promising strategy for NPC especially recurrent and/or metastatic NPC, but the most appropriate therapy still needs to be evaluated.
TRIAL REGISTRATION: This study was registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) with a registration number of INPLASY202380024.
METHODS: Databases were searched from January 2020 to September 2023 for randomized clinical trials (RCTs) that used mAbs for the treatment of COVID-19 regardless of disease severity. Study screening, data extraction and data analysis were performed independently by two reviewers. The Cochrane risk of bias 1.0 tool was used for methodological quality assessment.
RESULTS: Sixteen studies were identified for analysis with 9682 participants in the intervention arm and 10 115 participants in the control arm. Seven trials reported hepatoxicity and there was a statistically significant increase in the chance of hepatoxicity among patients treated with mAbs compared to those given standard of care (SoC) or placebo with risk ratio (RR) = 1.70, 95% confidence interval (CI) 1.29-2.24. Five trials reported for neutropenia and there was a statistically significant association of neutropenia with the use of mAbs compared to SoC or placebo with RR = 4.03, 95% CI 1.74-9.34. Ten trials reported any disease-related serious adverse events related to the disease and there was a reduction of risk compared to SoC/placebo, although this reduction was not statistically significant (RR = 0.88, 95% CI 0.70-1.11).
CONCLUSIONS: The use of mAbs was found to be associated with an increased risk of hepatoxicity and neutropenia compared to SoC/placebo among COVID-19 patients with moderate certainty of evidence. Long-term observational studies are recommended to observe post-COVID adverse events related to the use of mAbs.