Antioxidant constituents from Ribes glaciale Wall.: bioassay targeted in-vitro and in-silico evaluation.

Bioassay targeted phyto-investigation of dried green walnut husk of Ribes glaciale Wall. yielded one new compound as ß-D-glucopyrano (4'→3)-ß-D-glucopyranose (1) and four known compounds namely scoparone (2), apigenin (3), ß-sitosterol (4) and ß-sitosterol-D-glucoside (5). The structure of new compound was elucidated with the help of 1D, 2D and HRESIMS analysis. The antioxidant activity of extract, fractions and pure were evaluated using 2, 2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and ferric ion reducing antioxidant power (FRAP) assays that found in the following order: butanol fr. (BF) > chloroform fr. (CF) > ethylacetate fr. (EF) > Petroleum ether fr. (PF). To search for potent antioxidant agents in extract, the isolated compounds 1, 2, 3, 4 and 5 were docked on the enzyme human NADPH oxidase, lipoxygenase, cytochrome P450 and myeloperoxidase. The compound 1 was found a potent inhibitor of target enzyme revealing its high free radical scavenging potential.

Natural product-inspired synthesis of coumarin-chalcone hybrids as potential anti-breast cancer agents.

Twelve novel neo-tanshinlactone-chalcone hybrid molecules were constructed through a versatile methodology involving the Horner-Wadsworth-Emmons (HWE) olefination of 4-formyl-2H-benzo [h]chromen-2-ones and phosphonic acid diethyl esters, as the key step, and evaluated for anticancer activity against a series of four breast cancers and their related cell lines, viz. MCF-7 (ER + ve), MDA-MB-231 (ER-ve), HeLa (cervical cancer), and Ishikawa (endometrial cancer). The title compounds showed excellent to moderate in vitro anti-cancer activity in a range of 6.8-19.2 µM (IC50). Compounds 30 (IC50 = 6.8 µM and MCF-7; IC50 = 8.5 µM and MDA-MB-231) and 31 (IC50 = 14.4 µM and MCF-7; IC50 = 15.7 µM and MDA-MB-231) exhibited the best activity with compound 30 showing more potent activity than the standard drug tamoxifen. Compound 30 demonstrated a strong binding affinity with tumor necrosis factor α (TNF-α) in molecular docking studies. This is significant because TNFα is linked to MCF-7 cancer cell lines, and it enhances luminal breast cancer cell proliferation by upregulating aromatase. Additionally, virtual ADMET studies confirmed that hybrid compounds 30 and 31 met Lipinski's rule; displayed high bioavailability, excellent oral absorption, favorable albumin interactions, and strong penetration capabilities; and improved blood-brain barrier crossing. Based on the aforementioned results, compound 30 has been identified as a potential anti-breast cancer lead molecule.

Pentafuhalol-B, a Phlorotannin from Brown Algae, Strongly Inhibits the PLK-1 Overexpression in Cancer Cells as Revealed by Computational Analysis.

Polo-like kinase-1 (PLK-1) is an essential mitotic serine/threonine (Ser/Thr) kinase that belongs to the Polo-like kinase (PLK) family and is overexpressed in non-small cell lung cancer (NSCLC) via promotion of cell division. Therefore, PLK-1 may act as a promising target for the therapeutic cure of various cancers. Although a variety of anti-cancer drugs, both synthetic and naturally occurring, such as volasertib, onvansertib, thymoquinone, and quercetin, are available either alone or in combination with other therapies, they have limited efficacy, especially in the advanced stages of cancer. To the best of our knowledge, no anticancer agent has been reported from marine algae or microorganisms to date. Thus, the aim of the present study is a high-throughput virtual screening of phlorotannins, obtained from edible brown algae, using molecular docking and molecular dynamic simulation analysis. Among these, Pentafuhalol-B (PtB) showed the lowest binding energy (best of triplicate runs) against the target protein PLK-1 as compared to the reference drug volasertib. Further, in MD simulation (best of triplicate runs), the PtB-PLK-1 complex displayed stability in an implicit water system through the formation of strong molecular interactions. Additionally, MMGBSA calculation (best of triplicate runs) was also performed to validate the PtB-PLK-1 complex binding affinities and stability. Moreover, the chemical reactivity of PtB towards the PLK-1 target was also optimised using density functional theory (DFT) calculations, which exhibited a lower HOMO-LUMO energy gap. Overall, these studies suggest that PtB binds strongly within the pocket sites of PLK-1 through the formation of a stable complex, and also shows higher chemical reactivity than the reference drug volasertib. The present study demonstrated the inhibitory nature of PtB against the PLK-1 protein, establishing its potential usefulness as a small molecule inhibitor for the treatment of different types of cancer.

Drug repositioning to discover novel ornithine decarboxylase inhibitors against visceral leishmaniasis.

Visceral leishmaniasis (VL) is caused by Leishmania donovani (Ld), and most cases occur in Brazil, East Africa, and India. The treatment for VL is limited and has many adverse effects. The development of safer and more efficacious drugs is urgently needed. Drug repurposing is one of the best processes to repurpose existing drugs. Ornithine decarboxylase (ODC) is an important target against L. donovani in the polyamine biosynthesis pathway. In this study, we have modeled the 3D structure of ODC and performed high-throughput virtual screening of 8630 ZINC database ligands against Leishmania donovani ornithine decarboxylase (Ld ODC), selecting 45 ligands based on their high binding score. It is further validated through molecular docking simulation and the selection of the top two lead molecules (ceftaroline fosamil and rimegepant) for Molecular Dynamics (MD) simulation, Density functional theory (DFT), and molecular mechanics generalized born surface area (MMGBSA) analysis. The results showed that the binding affinities of ceftaroline fosamil, and rimegepant are, respectively, -10.719 and 10.159 kcal/mol. The docking complexes of the two lead compounds, ceftaroline fosamil, and rimegepant, with the target ODC, were found stable during molecular dynamics simulations. Furthermore, the analysis of MMGBSA revealed that these compounds had a high binding free energy. The DFT analysis showed that the top lead molecules were more reactive than the standard drug (pentamidine). In-silico findings demonstrated that ceftaroline fosamil, and rimegepant might be recognized as potent antagonists against ODC for the treatment of VL.

Bioactive components of different nasal spray solutions may defeat SARS-Cov2: repurposing and in silico studies.

The recent outbreak "Coronavirus Disease 2019 (COVID-19)" is caused by fast-spreading and highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). This virus enters into the human respiratory system by binding of the viral surface spike glycoprotein (S-protein) to an angiotensin-converting enzyme2 (ACE2) receptor that is found in the nasal passage and oral cavity of a human. Both spike protein and the ACE2 receptor have been identified as promising therapeutic targets to develop anti-SARS-CoV2 drugs. No therapeutic drugs have been developed as of today except for some vaccines. Therefore, potent therapeutic agents are urgently needed to combat the COVID-19 infections. This goal would be achieved only by applying drug repurposing and computational approaches. Thus, based on drug repurposing approach, we have investigated 16 bioactive components (1-16) from different nasal spray solutions to check their efficacies against human ACE2 and SARS-CoV2 spike proteins by performing molecular docking and molecular dynamic (MD) simulation studies. In this study, three bioactive components namely ciclesonide (8), levocabastine (13), and triamcinolone acetonide (16) have been found as promising inhibitory agents against SARS-CoV2 spike and human ACE2 receptor proteins with excellent binding affinities, comparing to reference drugs such as nafamostat, arbidol, losartan, and benazepril. Furthermore, MD simulations were performed (triplicate) for 100 ns to confirm the stability of 8, 13, and 16 with said protein targets and to compute MM-PBSA-based binding-free energy calculations. Thus, bioactive components 8, 13, and 16 open the door for researchers and scientist globally to investigate them against SARS-CoV2 through in vitro and in vivo analysis.

OCT Assistance in Identifying Retinal Breaks in Symptomatic Posterior Vitreous Detachments.

BACKGROUND AND OBJECTIVE: Posterior vitreous detachment (PVD) is a separation of the posterior hyaloid from the retina that manifests as photopsias and floaters. Optical coherence tomography (OCT) has demonstrated posterior vitreous opacities (PVOs) that may correlate with Shaffer's sign, which may correlate with retinal breaks. PATIENTS AND METHODS: Patients with symptomatic PVDs were retrospectively reviewed at a single institution by a single provider. Masked qualitative review of SD-OCTs by a single reviewer determined presence of PVOs. RESULTS: Among 78 patients, PVOs were found in 32 of the patients (41%), and 19 (59%) had retinal breaks. In those without PVOs, six (13%) had a break. Sensitivity and specificity were 76.0% and 75.5%, respectively. Removing patients with vitreous hemorrhages, sensitivity, and specificity of PVOs was 82.4% and 86.4%, respectively. CONCLUSION: In symptomatic PVDs, PVOs on OCT correlated with the presence of a retinal break, especially in the absence of a vitreous hemorrhage. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:628-632.].

An International Comparison of Baseline Characteristics of Patients Undergoing Initiation of Anti-VEGF Therapy for DME.

BACKGROUND AND OBJECTIVE: Diabetic macular edema (DME) is a leading cause of vision loss worldwide. The object of this study is to compare global differences of baseline characteristics of patients undergoing initiation of anti-vascular endothelial growth factor (VEGF) therapy for DME. PATIENTS AND METHODS: This multicenter, cross-sectional study included diabetic patients with foveal-involving retinal edema secondary to DME as documented by fundus exam and optical coherence tomography who were undergoing initiation of intravitreal anti-VEGF drugs. Variables were collected to find possible risk factors and to create an epidemiological profile of DME patients undergoing initiation of anti-VEGF agents. RESULTS: Nine hundred two patients were selected. Mean age was 62.4 (±11) years, 49.7% were Caucasians, 57.6% were male, and 96% had type two diabetes with an average disease duration of 181.7 months ± 113 months. Of the patients included, 74.7% suffered from hypertension, 26.6% from cardiovascular disease, 12.1% from cerebrovascular disease, 12.8% from peripheral vascular disease, and 12.8% from renal insufficiency. Best-corrected visual acuity (BCVA) was 65 (±20) Early Treatment Diabetic Retinopathy Study letters, central subfield thickness was 364 (±162) µm, cube volume 11.1 ± 3.1 mm3, cube average thickness 328.8 µm ± 61 µm, and 63.9% had nonproliferative diabetic retinopathy. Comparison between U.S. versus international patients, and patients with BCVA 70 letters or less versus more than 70 letters were performed, significant differences were acknowledged, and risk factors were recognized. CONCLUSION: There were key differences in the epidemiologic profile between patients presenting with DME in the U.S. and internationally. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e300-e310.].

Baseline Ocular Characteristics of Patients Undergoing Initiation of Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema.

BACKGROUND AND OBJECTIVES: Patients with diabetic macular edema (DME) have variable anatomic and visual responses to anti-vascular endothelial growth (VEGF) treatments based on their presenting visual acuity (VA). The aim of study is to report the baseline ocular and imaging characteristics of patients presenting with DME who were treatment-naïve and who initiated anti-VEGF in routine clinical practice. PATIENTS AND METHODS: Single-center, cross-sectional study of 638 patients. Subjects were divided into two VA groups: Early Treatment Diabetic Retinopathy Study (ETDRS) less than 70 and ETDRS greater than 70 and ocular variables were compared between groups. RESULTS: Average central subfield thickness (CST) was 363.5 µm, cube volume was 11.7 mm3, and cube average thickness (CAT) was 326.1 µm. Additionally, 21.5% had subretinal fluid (SRF), and 50.5% had hard exudates on presentation. Eyes with ETDRS less than 70 had greater CAT (338.5 µm3 vs. 313.2 µm3; P < .001), greater cube volume (12.2 mm3 vs. 11.3 mm3; P < .001), greater CST (383.5 µm vs. 350.0 µm; P < .001), and SRF (25.5% vs. 17.3%; P = .012). Furthermore, 7.64% had glaucoma, 1.3% had dry age-related macular degeneration, 4.5% of patients were vitrectomized, and 28.7% were pseudophakic. Regarding diabetic stage, 37% had proliferative diabetic retinopathy (PDR) and 63% presented with nonproliferative diabetic retinopathy. Patients presenting with ETDRS less than 70 were more likely to have a history of vitrectomy (7.1% vs. 1.9%, P = .002) and presence of PDR (42.3% vs. 31.4%, P = .004). CONCLUSION: The results describe a population of patients from a routine clinical practice not entirely represented in clinical trials, with key differences in ocular characteristics seen between VA groups. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:69-75.].

Characterization of the Systemic Findings of Patients Undergoing Initiation of Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema in Routine Clinical Practice.

BACKGROUND AND OBJECTIVES: Previous studies have validated that baseline visual acuity (VA) can predict a variance response to anti-vascular endothelial growth factor (VEGF) treatment. However, little is known about the initial systemic presentation of diabetic macular edema (DME) in clinical practice. The aim of this study is to report the baseline systemic findings of patients presenting with DME who received anti-VEGF in clinical practice. PATIENTS AND METHODS: A retrospective chart review of patients with DME presenting between April 2012 and December 2016 was performed. RESULTS: Data from 638 patients were retrieved. The average patient age was 63.1 years (±11.6 years), and 53% were male. There were 95.6% type II diabetics with an average HgA1c of 8.1% (range: 5.1% to 14.5%). Insulin use was present in 67%, biguanides in 43%, sulfonylureas in 32.8%, DDP4 inhibitors in 11.8%, thiazolidinediones in 3.9%, and D-phenylalanine derivatives in 0.94%. Hypertension was present in 78.4% of patients, cardiac comorbidities in 29.3%, peripheral vascular disease in 16.5%, and renal insufficiency in 22.6%. Patients were then split into two different cohorts based on VA (ETDRS < 70 and ETDRS ≥ 70), and variables were compared between groups. CONCLUSION: It was shown that older age, hypertension, elevated creatinine, elevated high-density lipoprotein cholesterol, and decreased biguanide use were positively associated with worse presenting VA. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:16-24.].

Cautery selection for oculofacial plastic surgery in patients with implantable electronic devices.

PURPOSE: To discover oculofacial plastic surgeon practice patterns for cautery selection in the setting of implantable electronic devices and present guidelines based on a review of current literature. METHODS: A 10-Question web-based survey was sent to the email list serve of the American Society of Ophthalmic Plastic and Reconstructive Surgery to determine surgeon cautery preference in the setting of various implantable electronic devices and comfort level with the guidelines for cautery selection in their practice or institution. The relationship between survey questions was assessed for statistical significance using Pearson's Chi-square tests. RESULTS: Two hundred ninety-three (41% response rate) surveys were completed and included for analysis. Greater than half of respondents either had no policy (36%) or were unaware of a policy (19%) in their practice or institution regarding cautery selection in patients with a cardiac implantable electronic device. Bipolar cautery was favored for use in patients with a cardiac implantable electronic device (79%-80%) and this number dropped in patients with implantable neurostimulators (30%). Overall, one-third of respondents did not feel comfortable with their practice/institution policy. CONCLUSION: Choices and comfort level among oculofacial plastic surgeons for cautery selection in patients with implantable electronic devices vary considerably, and some choices may increase the risk for interference-related complications. Practice patterns vary significantly in the setting of a neurostimulator or cochlear implant, where interference can cause thermal injury to the brain and implant damage, respectively. Guidelines are proposed for cautery selection in patients with implantable electronic devices undergoing oculofacial plastic surgery.

Deoxycholic Acid and the Marginal Mandibular Nerve: A Cadaver Study.

BACKGROUND: One of the rare but serious complications observed with deoxycholic acid administration is damage to the marginal mandibular nerve. In this study, we evaluated if deoxycholic acid directly induces histologic damage to fresh cadaveric marginal mandibular nerve. METHODS: A segment of marginal mandibular nerve was harvested from 12 hemifaces of 6 fresh cadavers. The nerve specimen was exposed to either 0.9% sterile saline for 24 h, deoxycholic acid (10 mg/ml) for 20 min, or deoxycholic acid (10 mg/ml) for 24 h. The nerve specimens were then fixed in glutaraldehyde for a minimum of 24 h. Toluidine blue stained sections were evaluated for stain intensity using light microscopy and color deconvolution image analysis. Supraplatysmal fat was harvested as a positive control and exposed to the same treatments as the marginal mandibular nerve specimens, then evaluated using transmission electron microscopy. RESULTS: Toluidine blue staining was less in the marginal mandibular nerve exposed to deoxycholic acid when compared to saline. The specimen exposed to deoxycholic acid for 24 h showed less toluidine blue staining than that of the nerve exposed to deoxycholic acid for 20 min. Transmission electron microscopy of submental fat exposed to deoxycholic acid revealed disruption of adipocyte cell membrane integrity and loss of cellular organelles when compared to specimens only exposed to saline. CONCLUSIONS: Deoxycholic acid (10 mg/ml) damages the marginal mandibular nerve myelin sheath in fresh human cadaver specimens. Direct deoxycholic acid neurotoxicity may cause marginal mandibular nerve injury clinically. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Herpes zoster keratitis development after acute retinal necrosis.

PURPOSE: To report a case of herpes zoster keratitis in a patient undergoing treatment for herpetic acute retinal necrosis. METHODS: Case report. RESULTS: A 71 year old male presented with acute retinal necrosis of the left eye due to herpes zoster and was treated with intravitreal foscarnet and oral valcyclovir. He developed a retinal detachment and underwent surgical repair. After four weeks, he developed an ipsilateral herpetic zoster keratitis demonstrated by Rose-Bengal staining that was responsive to topical ganciclovir gel. CONCLUSIONS: This case report describes the unusual development of herpes zoster keratitis after the development of unilateral acute retinal necrosis (ARN) in a patient on antiviral treatment.

Juvenile X-linked retinoschisis responsive to intravitreal corticosteroids.

PURPOSE: To report the case of an adult male with X-linked retinoschisis (XLRS) who presented with cystoid macular edema (CME) that responded consistently to treatment with intravitreal steroids. OBSERVATIONS: A 39 year old male with unilateral presentation of CME after repair of a retinal detachment secondary to XLRS responded initially to an injection of intravitreal triamcinolone acetonide (IVTA). Central subfield thickness on OCT was reduced. Three months later, the CME recurred and he was unresponsive to topical treatment so repeat IVTA was given, and the CME once again was reduced dramatically. After the next recurrence, intravitreal dexamethasone implant treatment was initiated and successful at treating recurrences in 3 month intervals for 5 additional injections. Finally, an intravitreal fluocinolone acetonide implant was surgically placed with control of CME. CONCLUSIONS AND IMPORTANCE: Corticosteroids have never been reported to be effective in CME related to XLRS. Here, we document a case of a man who successfully had decrease of intraretinal fluid and schisis with treatment of intravitreal corticosteroids as demonstrated by spectral domain optical coherence tomography.

Optical Coherence Tomography Angiography Reveals Choriocapillaris Flow Reduction in Placoid Chorioretinitis.

PURPOSE: To elucidate the origin of disease in acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and related placoid disorders, and to determine the principle tissue level of involvement: retinal pigment epithelium (RPE) versus choriocapillaris (CC). To determine the prevalence, extent, and persistence of choroidal flow reduction in placoid chorioretinitis using en face optical coherence tomography (OCT) and OCT angiography (OCTA). DESIGN: Multicenter, prospective case series. PARTICIPANTS: Patients with a clinical diagnosis of APMPPE, persistent placoid maculopathy (PPM), or relentless placoid chorioretinitis (RPC). METHODS: Morphologic evaluation of en face structural OCT and OCTA images with customized segmentation through the deep capillary plexus, outer nuclear layer, inner segment ellipsoid band, choriocapillaris, and outer choroid. MAIN OUTCOME MEASURES: Segmented images were graded by 3 masked readers with regard to reduction of flow and signal attenuation, and intergrader agreement was determined by mean unweighted kappa analysis. RESULTS: In this study, 24 eyes of 15 patients with APMPPE, PPM, or RPC were recruited and 60% of patients were male (N = 9) and the mean age was 33.6 years (range, 19-73 years). Of the 24 eyes, 96% (23/24) were graded as definite (18/24, 75%) or questionable (5/24, 21%) flow reduction within the choriocapillaris on OCTA, and 58% (14/24) were graded as definite decreased flow within the outer choroid. Mean weighted kappa analysis among readers was 0.655 for OCTA of the choriocapillaris and 0.684 for OCTA of the outer choroid. Areas of choriocapillaris flow deficit correlated closely with ischemic lesions seen with fluorescein angiography and indocyanine green angiography but were more extensive with OCTA and significantly improved with treatment or nontreatment follow-up. Corresponding zones of outer retinal disruption also were identified and colocalized with the areas of choriocapillaris flow reduction seen with OCTA. CONCLUSIONS: Optical coherence tomography angiography indicates that the inner choroid is the primary site of disease pathogenesis in APMPPE and related placoid disorders with secondary photoreceptor disruption. Optical coherence tomography angiography may be used to enhance diagnosis of placoid disorders and to monitor the progression of choriocapillaris ischemia and its response to therapy.