Novel dual-function GC/MS aided ultrasound-assisted hydrodistillation for the valorization of Citrus sinensis by-products: phytochemical analysis and anti-bacterial activities.

A huge-amount of citrus by-products is being wasted every-year. There is a high-need to utilize these by-products with high-efficiency. This study focuses on the essential oil (EO) isolation from the zest of Citrus sinensis (CS) by-products, using a novel dual-function gas-chromatography mass-spectrometry optimized ultrasound-assisted hydrodistillation-prototype (DF-GC/MS-HUS). The CS-EO was GC-analyzed by MS-detector (GC/MS) and optimized by flame-ionization detector (GC/FID). Ultrasound-assisted hydrodistillation (HUS) had a dual-function in CS-EO isolation by utilizing an adequate-energy to break-open the oil-containing glands, and by functioning-as a dispersing-agent to emulsify the organic-phase. The most effective DF-GC/MS-HUS optimized-conditions were isolation under 38 °C and 10 min of 28.9 Hz sonication. The main-components of CS-EO were limonene, ß-myrcene, and α-pinene (81.32%, 7.55%, and 4.20%) in prototype, compared to (60.23%, 5.33%, and 2.10%) in the conventional-method, respectively. The prototype CS-EO showed natural antibacterial-potentials, and inhibited the bio-film formation by Staphylococcus aureus, Listeria monocytogenes, and E. coli more-potent than the conventional-method. Compared to conventional-method, the prototype-method decreased the isolation-time by 83.3%, lowered energy-consumption, without carbon-dioxide production, by reducing isolation-temperatures by more-than half, which protected the thermolabile-components, and increased the quantity by 2514-folds, and improved the quality of CE-EO composition and its antibacterial-potentials. Therefore, the DF-GC/MS-HUS prototype method is considered a novel green-technique that minimized the energy-utilization with higher-efficiency.

Modulators of diabetic neuropathy and inflammation from Saponaria officinalis: Isolation of active phytochemicals and potential mechanisms of action.

Background and aim: Natural metabolites are rich in neuroactive and anti-inflammatory phytochemicals. Soapwort or Saponaria officinalis (Sap) has been utilized for its immunomodulatory and ant-rheumatic properties. Thus, the aim is to exploit Sap phytochemically and to investigate Sap isolated active phytochemicals effect to modulate diabetic neuropathy and inflammation, and their possible mechanisms of action. Experimental procedure: Bio-guided chromatographic fractionation and phytochemical isolation of the most abundant Sap phytochemicals utilizing RP-HPLC, 13C, and 1H NMR, in-vivo models of diabetes, diabetic neuropathy, and inflammation were used. Glucometers, HbA1c micro-columns, in-vivo hind-paw edema, tail-flick, hot plate, and Von-Frey filaments methods were utilized to investigate the acute, subchronic, and long term diabetes, inflammation, hyperalgesia, and mechanical allodynia. In-vivo antioxidant, inhibitory alpha-amylase, and alpha-glucosidase, and serum insulin levels, IL-6, IL-10, and TNF-alpha cytokines levels were utilized to investigate Sap mechanisms of action. Results and conclusion: The phytochemical post-hydrolysis RP-HPLC investigation results show six major peaks; Quillaic acid (12.5%), Quillaic acid 22 ß-OH (11.25%), Gypsogenin (21.25%), Phytolaccinic acid (18.75%), Phytolaccinic acid (17.50%), and Echynocystic acid (15.10%). The bio-guided chromatographic fractionation investigation utilizing reversed phase HPLC, 13C and 1H NMR has shown that Quillaic acid (QA) is the most abundant and biologically active compound. Sap 20 mg/kg has shown the highest potency in normalization of blood glucose level (BGL) acutely (6-h), subchronically (eight-days), and longer-term (eight-weeks) correlated to Sap 10 and 7 mg/kg, and QA 0.7, 1.0, 2.0 mg/kg. The highest amelioration of diabetic neuropathy (thermal hyperalgesia and mechanical allodynia) was Sap 20 mg/kg. The anti-inflammatory potentials of Sap 20 mg/kg have shown dominance in decreasing carrageenan-induced in-vivo hind-paw edema. The anti-nociceptive mechanism of action might be due to Sap insulin secretagogue and the in-vivo antioxidant potentials. The reduction of IL-6 cytokines and TNF-alpha, along with the elevation of the IL-10 cytokine level might be the underlying Sap anti-inflammatory mechanism. Phytochemically, QA has shown to be the most abundant and biologically active compound in Sap extract. Sap has shown significant (p < 0.05) anti-diabetic, anti-diabetic neuropathy, and anti-inflammatory effects. Our results provide new insights into the potential effects of Saponaria and Quillaic acid as future alternative therapies against diabetic neuropathy and inflammation.

Transdermal Delivery of Capsaicin Nanoemulgel: Optimization, Skin Permeation and In Vivo Activity against Diabetic Neuropathy.

Purpose: Diabetic somatic neuropathy is one of the most prevalent complications in type 1 diabetes mellitus (T1D). Many treatments were investigated to alleviate the pain associated with this condition. Capsaicin is a naturally occurring lipophilic alkaloid that proved to be an effective and safe treatment of chronic painful disorders. Despite the known therapeutic benefits of capsaicin, the conventional topical formulations have limited bioavailability. Therefore, the current study aims to develop capsaicin nanoemulgel to increase skin permeation and enhance its activity against neuropathic pain. Methods: Low-energy emulsification method was used to prepare nanoemulsions, using eucalyptus oil as the oily phase, Tween 80 as a surfactant, propylene glycol, ethanol and isopropyl alcohol as co-surfactants. Pseudo-ternary phase diagrams were constructed to investigate and optimize the formulation. Subsequently, the optimum formulation was formulated as a nanoemulgel and investigated for, skin permeation using Franz diffusion cell, and diabetic neuropathy (DN) management using alloxan-induced diabetic mice. Results: The selected nanoemulsion containing 0.05% capsaicin is composed of 8 % oil, 24 % S mix (Tween 80: isopropyl alcohol 2:1 w/w) and 68 % water. It is characterized by nanosized globules (28.15 ± 0.24 nm) with a relatively low polydispersity index (0.27 ± 0.05). The nanoemulgel revealed circa 4-fold increase in capsaicin cumulative permeation when compared to the conventional gel, and an improvement in its antinociceptive properties was observed in the treated diabetic mice (P < 0.05). Conclusion: The selected capsaicin nanoemulgel would be a promising transdermal formulation that may alleviate diabetic neuropathy in T1D patients.

Nasal trabeculo-ciliary angle and relative lens vault as predictors for intraocular pressure reduction following phacoemulsification.

PURPOSE: To evaluate quantitative relationships between biometric measurements and expected intraocular pressure reduction following phacoemulsification. DESIGN: A prospective, comparative clinical study. METHODS: Forty nine candidates for phacoemulsification were included. Intraocular pressure was measured preoperatively and after 7 and 30 days. Ocular biometrics were measured using optical biometry and ultrasound biomicroscopy preoperatively and 1 month postoperatively. RESULTS: Patients were sub-grouped into open-angle glaucoma (12 eyes), angle-closure glaucoma (18 eyes), and cataract-only groups (19 eyes). The mean intraocular pressure reduction was -1.67 ± 2.73, -13.11 ± 7.98, and -7.50 ± 3.58 mmHg in the cataract-only, angle-closure glaucoma, and open-angle glaucoma groups (p = 0.001). The delta-intraocular pressure at day 7 showed positive correlations with lens vault and relative-lens vault (p = 0.005 and 0.001). It showed negative correlations with lens position, relative-lens position, anterior chamber depth, aqueous depth, and nasal and temporal angles in addition to lens thickness, anterior vault, nasal trabeculo-ciliary angle, and temporal-trabeculo-ciliary angle at the end of the follow-up period. Regression analysis revealed significant associations between preoperative intraocular pressure and both nasal-trabeculo-ciliary angle and anterior vault (p = 0.038 and 0.019) and delta-intraocular pressure and both nasal-trabeculo-ciliary angle and relative-lens vault (p = 0.001 and ≤0.001) with an area under the curve of 0.71 for relative-lens vault. For every degree decrease in nasal-trabeculo-ciliary angle, there was an expected 0.33 mmHg intraocular pressure reduction with no expected change if nasal-trabeculo-ciliary angle decreased to <22°. CONCLUSIONS: The relationship between anterior-segment-biometrics could determine intraocular pressure behavior after phacoemulsification. The preoperative nasal-trabeculo-ciliary angle and relative-lens vault could be significant predictors for postoperative intraocular pressure reduction.

Electron microscopic comparison of the donor cut edges using femtosecond laser-assisted keratoplasty versus conventional keratoplasty.

PURPOSE: To describe and compare the histological changes in the cut edges of the remaining donor corneal rim using femtosecond laser-assisted keratoplasty (FAK) versus conventional penetrating keratoplasty (PK) via light and transmission electron microscopic examination. METHODS: This was a prospective observational study of 10 eyes; 5 FAK (top-hat technique) and 5 conventional PK. Main outcomes were histological findings at the cut edge of the donor corneal rim (at 3, 6, 9, and 12 o'clock). RESULTS: Cellular and ultra-cellular changes in the form of stromal edema, disorganized collagen fibers, and nuclear changes were more prominent in the FAK eyes as compared to the conventional PK ones. CONCLUSION: FAK induces more collateral damage in the cut edge of corneal donor graft at cellular and ultra-cellular levels, compared to conventional trephination. Further studies are required to investigate the clinical ramifications of this observation.

Post-remission retinal microvascular and choroidal thickness changes in eyes with Behcet's disease posterior uveitis: an OCTA longitudinal study.

PURPOSE: To investigate the retinal microvascular and choroidal thickness changes in eyes with active Behcet's disease posterior uveitis and post-remission. PATIENTS AND METHODS: A prospective longitudinal observational analytic study where patients with active Behcet's posterior uveitis (BU) were assessed by optical coherence tomography angiography (OCTA) and enhanced depth imaging OCT during activity and after remission, for retinal microvascular and subfoveal choroidal thickness (SFCT) changes. RESULTS: 26 eyes of 20 patients were included. With remission of active posterior uveitis, capillary density in both layers increased, only being significant in the superficial capillary plexus (SCP) 1.81 ± 3.57% (p = 0.025), while the foveal avascular zone (FAZ) area increased by 0.036 ± 0.069 mm (p = 0.023). CONCLUSION: OCTA can be used to monitor the activity of Behcet's posterior uveitis. Comparing the retinal microvascular changes during activity and after remission, the superficial capillary plexus was found to be more indicative of the activity status, while the deep capillary plexus and foveal avascular zone area-being more irreversible-are more useful as prognostic indicators. Subfoveal choroidal thickness, on the other hand, proved to be a consistent indictor of visual function; however, its change doesn't accurately reflect the activity status.

Identification of phytochemicals from North African plants for treating Alzheimer's diseases and of their molecular targets by in silico network pharmacology approach.

BACKGROUND: The global social expenses of Alzheimer's disease (AD) have been increased to US$1 trillion due to high cost, side-effects, and low efficiency of the current AD-therapies. Another reason is the lack of preventive drugs and the low-income situation of Asian and African countries. Accordingly, patients rather prefer traditional herbal remedies. Network-pharmacology has been a well-established method for the visualization and the construction of disorder target protein-drug framework. This could aid in the identification of drugs molecular-mechanisms. AIM: The aim of this study is to investigate the phytochemical constituents that could target Alzheimer's disease from the North African plants. This could be done by exploring their possible mechanisms of action through molecular network pharmacology-based approach. EXPERIMENTAL PROCEDURE: The Phytochemical-compounds of North-African plants (NAP) have been accessed from open-databank. ADME-screening has been conducted for filtering of the NAP phytochemical-constituents utilizing Qikprop-software. The open STITCH databank has been utilized for the prediction of the phytochemical-constituents target-proteins; UniProt and TDD-DB databanks have been utilized for distinguishing AD-related proteins. Phytochemical constituent-target protein (C-T) and plant-phytochemical constituent-target protein (P-C-T) frameworks have been assembled utilizing Cytoscape to interpret the anti-Alzheimer's disease mechanism of action of the targeted phytochemical constituents. RESULTS: The NAP 6842 phytochemical-constituents (from more than 1000 plants) have been exposed to ADME and CNS modulating filtration, generating 94 phytochemical-constituents which have been subjected to target-prediction investigation. The 94 phytochemical-constituents and the 4 AD-identified targets have been associated through 155 edges which formed the main pathways related to AD. Cuparene, alpha-selinene, beta-sesquiphellandrene, calamenene, 2-4-dimethylheptane, undecane, n-tetradecane, hexadecane, nonadecane, n-eicosane, and heneicosane have had C-T network highest combined-score, whilst the proteins MAO-B, HMG-CoA, BACE1, and GCR have been the most enriched ones by comprising the uppermost combined-scores of C-T. Hypericum perforatum, Piper nigrum, Juniperus communis, Levisticum officinale, Origanum vulgare acquired the uppermost number of P-C-Target interactions. CONCLUSION: The phytochemical-targets prediction of NAP utilizing molecular-network pharmacology-based investigation has paved the way for networking multi-target, multi-constituent, and multi-pathway mechanisms. This may introduce potential future targets for the regulation and the management of Alzheimer's disease. TAXONOMY CLASSIFICATION BY EVISE: Alzheimer's disease, Network pharmacology, In-silico computer based approach.

Evaluation of peripapillary atrophy in early open-angle glaucoma using autofluorescence combined with optical coherence tomography.

PURPOSE: To quantitatively analyze α-zone and ß-zone peripapillary atrophy (PPA) in patients having early primary open-angle glaucoma (POAG) using fundus autofluorescence (FAF) in conjunction with spectral domain optical coherence tomography, colored photography and perimetry. DESIGN: This is an observational cross-sectional case-control study. METHODS: This study included 100 eyes (54 patients) of early to moderate POAG and 100 normal eyes (50 subjects). Ophthalmological examination, OCT for the optic nerve and FAF were performed. The extent of α-PPA and ß-PPA was measured. RESULTS: The extent of α-PPA and ß-PPA as measured by FAF had higher values in POAG group as compared to control group (p values 0.003 and ≤ 0.001 for the total nasal and temporal extents, respectively). However, the nasal alpha and temporal beta zones showed more values in POAG patients as compared to normal controls (p values 0.002 and 0.024). The difference between the total extents of either zones alone was not significant. B-scan OCT was able to positively detect both zones. Detecting the alpha zone was significantly higher in the control group, while beta zone detection was significantly higher in the POAG group (p values ≤ 0.001). CONCLUSION: The sensitivity of alpha zone detection was equal using colored photographs, FAF and B-scan OCT. FAF showed superior results in estimating the beta zone extent although OCT was more accurate in the anatomical delineation of Bruch's membrane and RPE termination. The nasal alpha and temporal beta zone extents could be taken as early indices for evaluating early glaucomatous optic neuropathy.

Alloxan-induced diabetic thermal hyperalgesia, prophylaxis and phytotherapeutic effects of Rheum ribes L. in mouse model.

Rheum ribes L., known as Syrian rhubarb, is used in traditional Lebanese folk medicine for the treatment of diabetes. The present study aims to investigate the activities of R. ribes aqueous extract for glucose homeostasis, in vivo antioxidant and diabetic neuropathy protection in mice. The acute and the subacute effects of various doses of R. ribes on blood glucose and in vivo antioxidant activity utilizing serum catalase level (CAT) were studied in alloxan-diabetic mice. The high doses significantly lowered glucose level and increased serum CAT in alloxan-diabetic mice. Pretreatment with the extract prior to alloxination, protected the mice from acquiring diabetes and diabetic neuropathy. Treatment with the extract for 8 weeks alleviated hyperalgesia in diabetic mice. Our findings provide clinicians with promising drugs intended for the management of the symptoms of diabetic complications. The protective activity of R. ribes against acquiring diabetes and diabetic neuropathy might pave the way for preparing a prophylactic treatment for diabetes risk groups.

Optical coherence tomography indices for diagnosis of chronic glaucoma in patients with diabetes mellitus: a pilot study.

PURPOSE: To evaluate optical coherence tomography (OCT) parameters in patients with concomitant type-2 diabetes mellitus (DM) and primary open angle glaucoma (POAG) compared with patients with either of these diseases. METHODS: Sixty eyes (52 patients) were divided into three groups. The first group included nonglaucomatous diabetic patients, the second included patients with POAG without DM, and the third included patients with both POAG and DM. Spectral domain OCT evaluation of the retinal nerve fiber layer (RNFL), ganglion cell complex (GCC), and optic disc parameters was performed. Visual field (VF) was measured for structural and functional correlation. RESULTS: Significant differences were found in average RNFL, inferior RNFL, average GCC, inferior GCC, rim area, focal loss volume (FLV%), and global loss volume (GLV%) (P = 0.014, 0.001, 0.027, 0.006, 0.009, 0.043, and 0.001, respectively). The concomitant presence of DM and glaucoma was a risk factor for decreased average RNFL, inferior RNFL, rim area, and inferior GCC, and for increased GLV% (P = 0.034, 0.002, 0.014, 0.015, and 0.003, respectively). The inferior RNFL thickness had the largest significant area under the curve (P = 0.726; 90% sensitivity) at a specificity greater than 80% with a cutoff value of 105.38 µm (P = 0.005) compared with average RNFL, inferior GCC, rim area, and GLV% (P = 0.073, 0.25, 0.23, and 0.1, respectively). VF demonstrated the predominance of nasal scotomata in the diabetic group and arcuate scotoma in the glaucoma group (P < 0.001 and 0.03, respectively). CONCLUSIONS: OCT could be a valuable tool for the detection and follow-up of POAG in diabetic patients. The inferior RNFL thickness could be a sensitive and a specific predictor for glaucoma diagnosis and progression in diabetic patients without retinopathy.

Peripapillary capillary density in acute angle closure crisis and angle closure suspect: A structure, flow and function correlation study.

PURPOSE: to describe peripapillary vascular changes using Optical Coherence Tomography Angiography (OCT-A) in patients with acute angle closure crisis (AACC) and primary-angle closure-suspects (PACS) in comparison to normal controls. METHODS: This cross-sectional/case-control/non-randomized study was conducted at Cairo University Hospitals. It included 21 eyes following AACC, 21 eyes of PACS and 32 eyes of age-matched-controls. Participants underwent visual field (VF) examination, retinal nerve fiber layer (RNFL) assessment using spectral-domain-OCT (SD-OCT), and radial peripapillary capillary density (RPC%) using OCT-A. RESULTS: There was a statistically significant difference in MD and PSD among the three groups (p ⩽ 0.001). There was a significant difference in mean RNFL among the three groups (p ⩽ 0.001), this decrease was still present when comparing the AACC group to controls p = 0.032. There was a significant decrease in the peripapillary RPC% in all groups p ⩽ 0.001. The correlation between structure, function and flow was studied for all groups. Peripapillary RPC% in AACC was positively correlated to MD and peripapillary RNFL (p ⩽ 0.001). In PACS, RPC% was positively correlated to RNFL (p = 0.012). In controls, RPC% was positively correlated to PSD and peripapillary RNFL (p ⩽ 0.001). AUC was 0.8 for the MD, 0.56 for the RPC and 0.38 for the RNFL. CONCLUSIONS: Peripapillary vessel density was lower in AACC eyes than in suspects and control eyes. OCT-A parameters could be a more sensitive marker than OCT parameters after an AACC attack as evident on ROC analysis. PACS remains a clinical diagnosis as we could not find any significant differences in OCT or OCT-A parameters between suspects and normal healthy controls.

Antihyperglycemic and hepatoprotective properties of miracle fruit (Synsepalum dulcificum) compared to aspartame in alloxan-induced diabetic mice.

OBJECTIVE: This study was undertaken to investigate the antihyperglycemic potential of miracle fruit (MF) as well as its hepatic safety as compared to aspartame in alloxan-induced diabetic mice. METHODS: MF extracts were prepared and screened for their phytochemical composition using high-performance liquid chromatography (HPLC). Total phenolic, flavonoid and tannin contents and antioxidant potential were also determined. Additionally, MF was evaluated for its sensory attributes. For in vivo work, MF ethanol extract at high (MFH: 500 mg/kg body weight [BW]) and low (MFL: 250 mg/kg BW) doses as well as aspartame were injected intraperitoneally into alloxan-induced diabetic mice. Blood glucose levels were determined following acute and subchronic treatment. At the end of the study, animals were sacrificed, serum was collected for biochemical analysis and liver tissues were obtained for histopathological examination. RESULTS: MF ethanol extract contained more flavonoids and tannins, and had higher 1,1-diphenyl-1-picrylhydrazyl radical-scavenging activity (79.61%) compared to MF aqueous extract (P < 0.05). HPLC analysis of MF ethanol extract also revealed the presence of 10 antioxidants with quercetin comprising the major polyphenol. Additionally, sensory analysis of MF showed that its intake is effective in masking undesirable sourness. Subchronic administration of MFH proved amelioration of hyperglycemia in mice as compared to aspartame. Moreover, aspartame treatment significantly elevated (P < 0.05) the level of alanine aminotransferase and had destructive effects on the liver histopathology; however, hepatic architecture was restored by low and high doses of MF. CONCLUSION: MF is an effective antihyperglycemic with hepatoprotective properties that can be used as a healthier alternative sweetening agent in place of aspartame for sour beverages.

Gastroprotective and anti-inflammatory effects of Prunus cerasus phytochemicals and their possible mechanisms of action.

Prunus cerasus (P. cerasus) is an alternative-medicine used traditionally for amelioration of chronic-ailments marked by elevation in oxidative-stress like neuropathy. The oxidative-stress control was reported to ameliorate the inflammatory-process. This study aimed to phytochemically-investigate P. cerasus most-active phytochemicals utilizing in-vivo biological models to explore their gastroprotective, anti-inflammatory, and antinociceptive potentials and their possible mechanisms of action. Sonication with EtAc was used to extract P. cerasus fruit (Scf), and seed (Scs). The phytochemical-investigation of Scf was performed by RP-HPLC, while that of Scs was explored utilizing GC-FID. A bio-guided-fraction and isolation method was done utilizing column-chromatography, and have shown that cyanidin-3-glucoside (Cy3G) was the most-active constituent in Scf, while linoleic-acid (LA) was the most-active constituent in Scs. Scf, Scs, Cy3G, and LA significantly (p ˂ 0.05) protected the gastric-mucosa against HCl/EtOH-induced gastric-lesions. Scs (200 mg/kg) has shown the most gastroprotective-potentials, and had comparable-results to ranitidine (50 mg/kg). Scf, Scs, Cy3G, and LA have shown significant anti-inflammatory and antinociceptive potentials against carrageenan induced-edema and nociceptive-pain, respectively, where Scs (200 mg/kg) has shown the most anti-inflammatory and antinociceptive potentials, and had comparable results to ibuprofen (100 mg/kg). Scf, Scs, Cy3G, and LA have counter-acted carrageenan-induced oxidative-stress markers, with increased serum-catalase and reduced-glutathione levels, and decreased lipid-peroxidation. Histopathological-studies demonstrated gastroprotective potentials, regeneration and improvement of the spleen-structural architecture when treated with highest doses of Scs and Scf. The reduction of the pro-inflammatory TNF-alpha and IL-6, and elevation the anti-inflammatory factor IL-10 levels, spleen regenerative-capacity and oxidative-stress amelioration might be the main-mechanism responsible for P. cerasus anti-inflammatory potentials. P. cerasus appears to aid in ameliorating the inflammatory process, and reducing pain-thresholds while preserving the stomach.

Sarcophine and (7S, 8R)-dihydroxydeepoxysarcophine from the Red Sea soft coral Sarcophyton glaucum as in vitro and in vivo modulators of glycine receptors.

The inhibitory glycine receptor (GlyR) is a key mediator of synaptic signalling in spinal cord, brain stem, and higher centres of the central nervous system. We examined the glycinergic activity of sarcophine (SN), a marine terpenoid known for its various biological activities, and its trans-diol derivative (7S, 8R)-dihydroxy-deepoxysarcophine (DSN). SN was isolated from the Red Sea soft coral Sacrophyton glaucum, DSN was semisynthesized by hydrolysis of the epoxide ring. In cytotoxicity tests against HEK293 cells, SN and DSN had LD50 values of 29.3 ± 3.0 mM and 123.5 ± 13.0 mM, respectively. Both compounds were tested against recombinant human α1 glycine receptors in HEK293 cells using whole-cell recording techniques. Both, SN and DSN were shown for the first time to be inhibitors of recombinant glycine receptors, with KIvalues of 2.1 ± 0.3 µM for SN, and 109 ± 9 µM for DSN. Receptor inhibition was also studied in vivo in a mouse model of strychnine toxicity. Surprisingly, in mouse experiments strychnine inhibition was not augmented by either terpenoid. While DSN had no significant effect on strychnine toxicity, SN even delayed strychnine effects. This could be accounted for by assuming that strychnine and sarcophine derivatives compete for the same binding site on the receptor, so the less toxic sarcophine can prevent strychnine from binding. The combination of modulatory activity and low level of toxicity makes sarcophines attractive structures for novel glycinergic drugs.

Review on Recent Trials Evaluating the Effect of Intravitreal Injections of Anti-VEGF Agents on the Macular Perfusion of Diabetic Patients with Diabetic Macular Edema.

BACKGROUND: Diabetic macular edema (DME) is a major cause of vision loss in diabetics worldwide. Anti-vascular endothelial growth factor (anti-VEGF) agents have become the mainstay of treatment of vision loss due to DME. Long-term effects of these agents on the macular perfusion (MP) are a current concern. OBJECTIVE: To review recently published studies that evaluated the effect of intravitreal injection of anti-VEGF agents on the MP of diabetics with DME. METHODS: Different databases were searched including PubMed, Medline, Ovid, Science Direct, and Google Scholar for relevant studies published between 2010 and 2019. All studies found were compared regarding methodology and results and included in this review. Some studies relating to retinal perfusion in general and not strictly MP were also included for comprehensiveness. RESULTS: Several studies utilizing different anti-VEGF agents were identified. All the large randomized controlled clinical trials identified utilized primarily fluorescein angiography (FA) and human graders and found generally no worsening of MP associated with anti-VEGF agents use in diabetic patients with DME. Some of these studies, however, depended on post-hoc analysis. Several more recent, but smaller case series, have utilized the relatively new and non-invasive optical coherence tomography angiography (OCTA) in this evaluation and found more conflicting results. CONCLUSION: The large clinical trials recently performed depended mainly on FA in the analysis of MP changes following injections and generally found no worsening of MP. More recently, smaller case series have utilized OCTA in this analysis, yielding more conflicting results. Large randomized controlled trials using OCTA are thus needed.

Evaluation of Changes in Macular Perfusion Detected by Optical Coherence Tomography Angiography following 3 Intravitreal Monthly Bevacizumab Injections for Diabetic Macular Edema in the IMPACT Study.

OBJECTIVE: To evaluate macular perfusion changes following intravitreal bevacizumab injections for diabetic macular edema (DME) using spectral domain optical coherence tomography angiography (SD-OCTA). METHODS: This study was a prospective noncomparative interventional case series. Treatment naïve patients with DME underwent full ophthalmological examination and SD-OCTA scanning at baseline and after 3 intravitreal bevacizumab injections. Both the 6 × 6 and 3 × 3 mm macular scan protocols were used. Pretreatment and posttreatment OCTA images were automatically aligned using a commercially available retina alignment software (i2k Align Retina software); then the fractal dimension (FD), vascular density (VD), and skeleton VD changes were obtained at the full retinal thickness (Full) and superficial (SCP) and deep (DCP) capillary plexuses after processing images using a semiautomated program. The foveal avascular zone (FAZ) was manually measured and FD was calculated using the FracLac plugin of ImageJ. RESULTS: Forty eyes of 26 patients were included. Following injections, there were an 8.1% increase in FAZ, 1.3% decrease in FD-Full and FD-SCP, 1.9% decrease in FD-DCP, 8% decrease in VD-Full, 9.1% decrease in VD-SCP, 10.6% decrease in VD-DCP, 13.3% decrease in skeleton VD-Full, 12.5% decrease in skeleton VD-SCP, and 16.3% decrease in skeleton VD-DCP in the 6 × 6 mm macular area and a 2.6% decrease in FD-Full, 3.4% decrease in FD-SCP, 11.5% decrease in VD-Full, 14.3% decrease in VD-SCP, and 25.1% decrease in skeleton VD-SCP in the 3 × 3 mm macular area which were all statistically significant (p < 0.05). Using univariate and multivariate analysis, the pretreatment FD, VD, and skeleton VD at each capillary layer significantly negatively correlated with the change in FD, VD, and skeleton VD at the corresponding capillary layer, respectively (p < 0.05). CONCLUSION: OCTA is a useful noninvasive tool for quantitative evaluation of macular perfusion changes following DME treatment. This trial is registered with NCT03246152.

Niosomes of active Fumaria officinalis phytochemicals: antidiabetic, antineuropathic, anti-inflammatory, and possible mechanisms of action.

BACKGROUND: Fumaria officinalis (F. officinalis, FO) has been used in many inflammatory and painful-ailments. The main aim of this work is to perform an in-depth bio-guided phytochemical investigation of F. officinalis by identifying its main-active ingredients. Optimizing pharmacokinetics via niosomal-preparation will also be done to enhance their in vivo antineuropathic and anti-inflammatory potentials, and to explore their possible-mechanism of actions. METHODS: Bio-guided phytochemical-investigations including fractionation, isolation, chromatographic-standardization, and identification of the most active compound(s) were done. Optimized niosomal formulations of F. officinalis most active compound(s) were prepared and characterized. An in vivo biological-evaluation was done exploring acute, subchronic, and chronic alloxan-induced diabetes and diabetic-neuropathy, and carrageenan-induced acute inflammatory-pain and chronic-inflammatory edema. RESULTS: In-vivo bio-guided fractionation and chromatographic phytochemical-analysis showed that the alkaloid-rich fraction (ARF) is the most-active fraction. ARF contained two major alkaloids; Stylopine 48.3%, and Sanguinarine 51.6%. In-vitro optimization, analytical, and in vivo biological-investigations showed that the optimized-niosome, Nio-2, was the most optimized niosomal formulation. Nio-2 had particle size 96.56 ± 1.87 nm and worked by improving the pharmacokinetic-properties of ARF developing adequate entrapment-efficiency, rapid-degradation, and acceptable stability in simulated GI conditions. FO, ARF, and Nio 2 were the most potent antidiabetic and anti-inflammatory compounds. The reduction of the pro-inflammatory tumor necrosis factor-alpha (TNF-alpha) and Interleukin 6 (IL-6), and elevation the anti-inflammatory factor IL-10 levels and amelioration of the in vivo oxidative-stress might be the main-mechanism responsible for their antinociceptive and anti-inflammatory activities. CONCLUSIONS: Fumaria officinalis most-active fraction was identified as ARF. This study offers an efficient and novel practical oral formulation ameliorating various inflammatory conditions and diabetic complications especially neuropathic-pain.

Trabeculectomy With Extended Subscleral Tunnel Versus Conventional Trabeculectomy in the Management of POAG: A 1-Year Randomized-controlled Trial.

PRECIS: This clinical trial compares a modified trabeculectomy technique [extended subscleral tunnel (ESST)] with conventional trabeculectomy [subscleral trabeculectomy (SST)] in terms of success rate and bleb morphology. ESST showed comparable results, with lower incidence of bleb-related complications and need for postoperative antiglaucoma medications. BACKGROUND: To evaluate the outcome of modified trabeculectomy with extended subscleral tunnel "ESST" versus conventional subscleral trabeculectomy "SST" in the management of uncontrolled primary open-angle glaucoma. PARTICIPANTS AND METHODS: This is a randomized clinical trial of 40 eyes (40 patients) divided into 2 equal groups. In the first group, a conventional SST with adjuvant 0.3% mitomycin-C was performed. In the second group, the ESST group, an additional 1.00 mm wide longitudinal scleral groove was dissected and excised in the center of the deep scleral bed extending 1.00 mm beyond the posterior margin of the flap. Patients were examined on days 1, 7, 14, 30, 90, 180, and at 1 year, with a special focus on intraocular pressure and bleb morphology. Postoperative ultrasound biomicroscopy was performed to evaluate the surgical area. RESULTS: Both groups showed a significant reduction in intraocular pressure, with the ESST group showing significantly lower values on days 7, 14, 30, 90, and 180 (P=0.001, 0.004, 0.026, 0.001, and 0.048), but no significant differences on day 1 and at 1 year (P=0.06 and 0.07). The need for postoperative antiglaucoma medications was significantly lower in the ESST group (P=0.043). Visually significant cataract and bleb related complications were more in the SST group (P=0.044 and <0.001). Significantly more eyes in the ESST group showed normal bleb vascularity and wider extent. CONCLUSIONS: ESST offers a guarded posterior flow with a success rate comparable to that of conventional SST. ESST could minimize bleb-related complications and bleb-dysesthesia with better long-term bleb morphology and vascularity. It could also minimize the need for further adjuvant postoperative antiglaucoma medications.

Phytochemical and anti-neuropathic investigations of Crocus sativus via alleviating inflammation, oxidative stress and pancreatic beta-cells regeneration.

Objective: The aim of this study is to investigate the phytochemical and the long-term anti-neuropathic potentials of Crocus sativus cultivated in the University botanical garden, and explore its most bioactive compounds and their underlying mechanisms of action. Methods: Phytochemical analysis and bio-guided isolation-procedures including RP-HPLC and 1H and 13C NMR utilizing biological models of diabetes, inflammation, and diabetic-neuropathy were used. Cultivated saffron (S-RCED) and Spanish-saffron stigma (S-SP) alone or in combination with Camellia sinus (CS) were investigated. Results: The RP-HPLC analyses showed the presence of picrocrocin, crocin I, crocin II, crocin I', crocin II', and safranal (SAF) in both S-SP and S-RCED extracts with higher-concentrations. It had been shown that SAF was the most bioactive-compound in Crocus sativus. Both S-SP and S-RCED possessed significant (P < 0.05) anti-diabetic activities in acute (6 h), subchronic (8 d) and chronic (8 weeks) models. S-RCED had been proven with more hypoglycemic potentials when compared to S-SP and SAF. S-SP, S-RCED, and SAF produced significant anti-inflammatory and anti-nociceptive activities against carrageenan-induced inflammatory, hyperalgesic and tactile diabetic-neuropathy models, respectively. S-SP, S-RCED, and SAF elevated serum catalase, reduced glutathione, and insulin serum levels, ameliorated lipid peroxidation and HbA1c levels, and histopathologically regenerated the pancreatic beta-cells. Combinations with CS showed more significant efficacy than the single component. Conclusion: The oxidative stress reduction, insulin secretagogue, and pancreatic beta-cells regeneration potentials might be responsible for the mechanism underlying the anti-diabetic, anti-inflammatory and anti-diabetic neuropathy activities. Thus, the cultivated Crocus sativus might be clinically useful for protecting against many serious-disorders.

Evaluation of the Effect of Repeated Intravitreal Bevacizumab Injections on the Macular Microvasculature of a Diabetic Patient Using Optical Coherence Tomography Angiography.

A 53-year-old female patient with center-involving diabetic macular edema affecting the left eye was imaged using optical coherence tomography angiography (OCTA) in both eyes. She underwent three monthly intravitreal bevacizumab injections in the left eye only and OCTA was repeated in both eyes one month following the last injection and showed decreased vascular density (VD) in the treated left eye but not in the untreated right eye compared to baseline. No further injections were required in either eye, and OCTA was done in both eyes 4 months following the last injection which showed improved VD of the left eye with stable VD in the right. Three monthly intravitreal bevacizumab injections were then required in both eyes; then OCTA was repeated following the last injection and revealed decreased VD in both eyes compared to previous scan. OCTA could be a useful tool for detecting VD changes following bevacizumab injections in diabetics.