Design, synthesis, and histone deacetylase inhibition study of novel 4-(2-aminoethyl) phenol derivatives.

Histone deacetylases (HDACs) have been identified as promising targets for anticancer treatment. The study demonstrates virtual screening, molecular docking, and synthesis of 4-(2-aminoethyl) phenol derivatives as HDAC inhibitors. The virtual screening and molecular docking analysis led to the identification of 10 representative compounds, which were evaluated based on their drug-like properties. The results demonstrated that these compounds effectively interacted with the active site pocket of HDAC 3 through π-stacking, Zn2+ coordination, hydrogen bonding, and hydrophobic interactions with catalytic residues. Furthermore, a series of 4-(2-aminoethyl) phenol derivatives were synthesized, and their HDAC inhibitory activity was evaluated. Compounds 18 and 20 showed significant HDAC inhibitory activity of 64.94 ± 1.17% and 52.45 ± 1.45%, respectively, compared to the solvent control. The promising results of this study encourage further research on 4-(2-aminoethyl) phenol derivatives and may provide significant insight into the design of novel small molecule HDAC inhibitors to fight against target-specific malignancies of chronic obstructive pulmonary disease and nonsmall cell lung cancer in the future.

An extensive review on antifungal approaches in the treatment of mucormycosis.

During the period of COVID-19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and rapidly progressing fungal infection associated with high mortality and morbidity in India as well as globally. The causative agents for this infection are collectively called mucoromycetes which are the members of the order Mucorales. The diagnosis of the infection needs to be performed as soon as the occurrence of clinical symptoms which differs with types of Mucorales infection. Imaging techniques magnetic resonance imaging or computed tomography scan, culture testing, and microscopy are the approaches for the diagnosis. After the diagnosis of the infection is confirmed, rapid action is needed for the treatment in the form of antifungal therapy or surgery depending upon the severity of the infection. Delaying in treatment declines the chances of survival. In antifungal therapy, there are two approaches first-line therapy (monotherapy) and combination therapy. Amphotericin B (1) and isavuconazole (2) are the drugs of choice for first-line therapy in the treatment of mucormycosis. Salvage therapy with posaconazole (3) and deferasirox (4) is another approach for patients who are not responsible for any other therapy. Adjunctive therapy is also used in the treatment of mucormycosis along with first-line therapy, which involves hyperbaric oxygen and cytokine therapy. There are some drugs like VT-1161 (5) and APX001A (6), Colistin, SCH 42427, and PC1244 that are under clinical trials. Despite all these approaches, none can be 100% successful in giving results. Therefore, new medications with favorable or little side effects are required for the treatment of mucormycosis.

Ocular proton therapy, pencil beam scanning high energy proton therapy or stereotactic radiotherapy for uveal melanoma; an in silico study.

PURPOSE: In radiotherapy, the dose and volumes of the irradiated normal tissues is correlated to the complication rate. We assessed the performances of low-energy proton therapy (ocular PT) with eye-dedicated equipment, high energy PT with pencil-beam scanning (PBS) or CyberKnifeR  -based stereotactic irradiation (SBRT). MATERIAL AND METHODS: CT-based comparative dose distribution between external beam radiotherapy techniques was assessed using an anthropomorphic head phantom. The prescribed dose was 60Gy_RBE in 4 fractions to a typical posterior pole uveal melanoma. Clinically relevant structures were delineated, and doses were calculated using radiotherapy treatment planning softwares and measured using Gafchromic dosimetry films inserted at the ocular level. RESULTS: Precision was significantly better with ocular PT than both PBS or SBRT in terms of beam penumbra (80%-20%: laterally 1.4 vs. ≥10mm, distally 0.8 vs. ≥2.5mm). Ocular PT duration was shorter, allowing eye gating and lid sparing more easily. Tumor was excellent with all modalities, but ocular PT resulted in more homogenous and conformal dose compared to PBS or SBRT. The maximal dose to ocular/orbital structures at risk was smaller and often null with ocular PT compared to other modalities. Mean dose to ocular/orbital structures was also lower with ocular PT. Structures like the lids and lacrimal punctum could be preserved with ocular PT using gaze orientation and lid retractors, which is easier to implement clinically than with the other modalities. The dose to distant organs was null with ocular PT and PBS, in contrast to SBRT. CONCLUSIONS: ocular PT showed significantly improved beam penumbra, shorter treatment delivery time, better dose homogeneity, and reduced maximal/mean doses to critical ocular structures compared with other current external beam radiation modalities. Similar comparisons may be warranted for other tumor presentations.

Non-destructive insights into photosynthetic and photoprotective mechanisms in Arabidopsis thaliana grown under two light regimes.

Probing insights into understanding photosynthetic processes via non-invasive means has an added advantage when used in phenotyping or precision agriculture. We employed Raman spectroscopy and fluorescence-based methods to investigate both the changes in the photosynthetic processes and the underlying protective mechanisms on Arabidopsis thaliana wild-type (WT), and ros1, which is a mutant of a repressor of transcriptional gene silencing, both grown under low light (LL: 100 µmol m-2s-1) and high light (HL: 400 µmol m-2s-1) regimes. Raman imaging detected a lower carotenoid intensity after two weeks in those plants grown under HL, compared to those grown under the LL regime; we interpret this as the result of oxidative damage of ß-carotene molecules. Further, the data revealed a significant depletion in carotenoids with enhanced phenolics around the midrib and tip of the WT leaves, but not in the ros1. On the contrary, small necrotic zones appeared after two weeks of HL in the ros1 mutant, pointing to the starting oxidative damage. The lower maximum quantum yield of the photochemistry (Fv/Fm) in the WT as well as in the ros1 mutant grown in HL (compared to those in the LL two weeks post-exposure), indicates the HL partially inactivated photosystems. Chlorophyll a fluorescence imaging further showed high non-photochemical quenching (NPQ) in the plants grown under the HL regime for both the WT and the ros1 mutant, but the spatial heterogeneity of NPQ images was much higher in the HL-grown ros1 mutant. Fluorescence screening methods revealed significantly high values of chlorophyll proxies in the WT as well as in the ros1 mutant two weeks after in the HL compared to those under LL. The data generally revealed an increased accumulation of phenolics under HL in both the WT and ros1 mutant plants, but the proxies of anthocyanin and flavonols were significantly lower in the ros1 mutant than in the WT. The comparatively low accumulation of anthocyanin in the ros1 mutant compared to the WT supports the Raman data. We conclude that integrated use of these techniques can be efficiently applied for a better understanding of insights into photosynthetic mechanisms.

Continuing perioperative estrogen therapy does not increase venous thromboembolic events in transgender patients: a systematic review and meta-analysis.

OBJECTIVE: The aim of this study is to compare the risk of venous thromboembolic events (VTE) between patients suspending and continuing estrogen therapy perioperatively, in male to female gender-affirming surgery (vaginoplasty). MATERIALS AND METHODS: The authors conducted a systematic review and meta-analysis of existing research on male to female gender-affirming study, which compared the risk of VTE among the usage of estrogen perioperatively. RESULTS: A total of 209 studies were identified as potentially eligible among PubMed, Embase, and Cochrane library databases. Among the studies, 191 studies were excluded due to their abstract inappropriateness. Out of the remaining 18 studies, only 3 articles were eligible and were finally included. Meta-analysis was performed and showed odds ratio of 0.77 (95% CI: 0.04, 14.01). CONCLUSIONS: Perioperative estrogen therapy does not increase VTE risk on male to female gender-affirming surgery. Therefore, estrogen therapy may be continued perioperatively in vaginoplasty. More prospective studies are needed.

Dysfunctional State of T Cells or Exhaustion During Chronic Viral Infections and COVID-19: A Review.

Coronavirus disease 2019 (COVID-19) continuously affecting the lives of millions of people. The virus is spread through the respiratory route to an uninfected person, causing mild-to-moderate respiratory disease-like symptoms that sometimes progress to severe form and can be fatal. When the host is infected with the virus, both innate and adaptive immunity comes into play. The effector T cells act as the master player of adaptive immune response in eradicating the virus from the system. But during cancer and chronic viral infections, the fate of an effector T cell is altered, and the T cell may enters a state of exhaustion, which is marked by loss of effector function, depleted proliferative capacity and cytotoxic effect accomplished by an increased expression of numerous inhibitory receptors such as programmed cell death protein 1 (PD-1), lymphocyte-activation protein 3 (LAG-3), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on their surface. Various other transcriptional and epigenetic changes take place inside the T cell when it enters into an exhausted state. Latest studies point toward the induction of an abnormal immune response such as lymphopenia, cytokine storm, and T cell exhaustion during SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. This review sheds light on the dysfunctional state of T cells during chronic viral infection and COVID-19. Understanding the cause and the effect of T cell exhaustion observed during COVID-19 may help resolve new therapeutic potentials for treating chronic infections and other diseases.

Andrographolide: Regulating the Master Regulator NF-κB.

Natural product based medicines are being used in India since 12th century BC and their efficacies are well established in Indian traditional medicine system. However, the mechanism of action as per the modern medicinal system was not well reported. Plant-derived natural compounds are very useful for inflammatory disorders and other diseases such as cancer. Various medicines like artemisinin, vincristine, vinblastine, taxol, and so forth, are invaluable contributions of nature to modern medicine. The role of transcription factor NF-κB was well delineated in inflammatory processes. Binding of NF-κB to the promoter site of several inflammatory genes activate them to secrete proinflammatory cytokines and chemokines. Plant derived natural compounds like andrographolide could be useful in inflammatory disorders as it directly inhibit the binding of NF-κB with DNA at promoter site. Transcription factor NF-κB is a master regulator of the proinflammatory gene expression program and since it was suppressed by andrographolide, hence andrographolide is rightly termed as regulator of master regulator.

Optical coherence tomography angiography-based analysis of intrinsic vasculature in juxtapapillary melanoma after ruthenium-106 plaque brachytherapy.

In this case report, we demonstrate the use of optical coherence tomography angiography (OCTA) as a tool to evaluate intrinsic vasculature in a case of juxtapapillary melanoma which underwent ruthinium.106 plaque brachytherapy. In this case, OCTA could demonstrate a decrease in caliber and density of the intrinsic vasculature of the tumor post brachytherapy.

Comparison of 30-day postoperative outcomes of open and minimally invasive pyeloplasty utilizing the prospective National Surgical Quality Improvement Program-Pediatric database.

INTRODUCTION: Open pyeloplasty (OP) has traditionally been the standard for the operative management of ureteropelvic junction obstruction in children. With advances in minimally invasive pyeloplasty (MIP) techniques, it is quickly becoming a popular alternative in both adult and pediatric population. OBJECTIVE: To evaluate the differences in outcomes between MIP and OP for the surgical correction of ureteropelvic junction obstruction in children. STUDY DESIGN: Data were obtained from the pediatric National Surgical Quality Improvement Program 2012-2017. We identified 1280 patients who underwent MIP and 1190 patients who underwent OP between 2012 and 2017. Propensity score matching was utilized to adjust for baseline differences. Univariate and multivariable regression were performed to assess odds of complications and procedure-related readmission. RESULTS: Patients who underwent OP had a significantly decreased operative time (192.42 vs 142.00 min, p < 0.001) compared to MIP. There was no significant difference in the rates of overall peri-operative complications (3.7% [MIP] vs 2.4% [OP] p = 0.397). On multivariable analysis, patients undergoing OP had a lower risk of procedure-related readmission (odds ratio [OR] 0.404, 95% confidence interval [CI] 0.157-0.951, p = 0.046) than MIP. In a multivariable linear regression model, the risk of having any postoperative complication, regardless of surgical approach, decreased with increasing patient age (OR 0.945, 95% CI 0.893-0.996, p = 0.037). DISCUSSION: Although recent small, retrospective institutional studies have found decreased hospitalization time of MIP as compared to OP, in our large prospective database, we found no such association. While some studies suggest a higher rate of wound complications in the OP group, this was not reproduced in our study as well. MIP was, in fact, associated with higher rate of readmissions as compared to the OP group, which may act as a surrogate of long-term complications in these patients. CONCLUSION: MIP offers an alternative to OP in the pediatric population with similar rates of peri-operative complications. However, our study shows decreased odds of procedure-related readmission in OP, which may serve as a surrogate for less postoperative complications in these patients.

Optical coherence tomography angiography in assessment of response to therapy in retinal capillary hemangioblastoma and diffuse choroidal hemangioma.

In this series, we discuss the role of optical coherence tomography angiography (OCTA) in assessing response to treatment in intraocular vascular tumors. This is a series of two cases: Multiple retinal capillary hemangioblastoma (RCH) treated with laser photocoagulation and diffuse choroidal hemangioma (DCH) with radiotherapy. In large RCH and DCH, optical coherence tomography (OCT) showed significant reduction of subretinal and intraretinal fluid. But post-treatment mean tumor vascular density (MTVD) was slightly reduced. In one small RCH, vascular loop was seen suggesting minimal residual disease. So, OCTA helps in identifying treatment inadequacy and understanding alternate mechanism involved in treatment response in vascular tumors.

Optical coherence tomography angiography of fleeting macroaneurysm in retinal racemose angioma.

We present a rare case of retinal racemose angioma complicated with fleeting macroaneurysm (MA). A 50-year-old female presented with diminution of vision in her right eye for 6 years. Fundus examination showed a racemose angioma with hemorrhagic MA temporal to the fovea in the right eye. On subsequent follow-ups, spontaneous thrombosis of MA was noted with the development of new MA inferior to the fovea, with intraretinal hemorrhage extending into the fovea. Focal laser to MA resulted in resolution of MA with improvement in vision. We report optical coherence tomography angiographic features of the fleeting MA in a case of racemose angioma.

Optical coherence tomography angiography features of choroidal hemangioma.

This is an observational case series of four cases of choroidal hemangioma. All cases underwent OCT angiography with swept source OCTA (Topcon DRI OCT Triton plus) 6 mm * 6 mm protocol. OCTA at the level of large choroidal vessels demonstrated peculiar vascular pattern in all four eyes. Patterns observed were bag of worms, spaghetti like and vessels with terminal bulbs. In eye with diffuse choroidal hemangioma comparison of choroidal vascular pattern with the contralateral eyes showed significant difference in the vascular architecture. OCTA is an excellent non invasive tool in assessing the choroidal vascular pattern in eyes with choroidal hemangioma.

Effect of dehulling, germination and cooking on nutrients, anti-nutrients, fatty acid composition and antioxidant properties in lentil (Lens culinaris).

The changes in chemical composition, antioxidant activity and fatty acid composition of lentil flour after dehulling, germination and cooking of seeds were investigated. Dehulling showed no significant effect on protein content, however, protein content decreased in most of the varieties after germination and cooking. Total soluble sugars (TSS) content increased significantly after dehulling (2.0-41.64 %) and cooking (2.08-31.07 %) whereas, germination had no significant effect on TSS content. Total lipids increased significantly after dehulling (21.56-42.86 %) whereas, it decreased significantly after germination (2.97-26.52 %) and cooking (23.05-58.63 %). Cooking was more effective than other methods in reducing trypsin inhibitors (80.51-85.41 %). Dehulling was most effective in reducing tannins (89.46-92.99 %) and phytic acid (52.63-60.00 %) content over raw seed. Myristic, palmitic, stearic, oleic and linoleic acid content decreased while linolenic acid content increased after dehulling. Dehulling, germination and cooking decreased the content of antioxidant metabolite (gallic acid, catechin and quercetin) and also antioxidant activities. Raw samples followed by germinated samples showed the highest concentrations of phytochemicals responsible for antioxidant activity and also the antioxidant capacities. Present study showed germination and cooking would be useful in formulation and development of lentil based functional foods for human health benefits.

Augmentation of humoral and cellular immunity in response to Tetanus and Diphtheria toxoids by supercritical carbon dioxide extracts of Hippophae rhamnoides L. leaves.

Hippophae rhamnoides L. commonly known as Seabuckthorn (SBT), a wild shrub of family Elaegnacea, has extensively used for treating various ailments like skin diseases, jaundice, asthma, lung troubles. SBT leaves have been reported to possess several pharmacological properties including immunomodulatory, antioxidant, anti-inflammatory, antimicrobial and tissue regeneration etc. The present study was undertaken to evaluate the adjuvant property of supercritical carbon dioxide extracts (SCEs 300ET and 350ET) of SBT leaves in balb/c mice immunized with Tetanus and Diphtheria toxoids. The dynamic changes in the immune response were measured in terms of humoral and cell-mediated immune responses. We have seen the effect of SCEs on immunoglobulin subtypes and secondary immune response generation. In addition, the effect of SCEs on antigen specific cellular immunity was evaluated. Our results show that SCEs 300ET and 350ET significantly enhanced antibody titers in response to both TT and DT antigens. The secondary immune response generated was significantly increased in case of TT immunized animals. SCEs also enhanced cytokine levels (IFN-γ, IL-4, TNF-α and IL-1ß) and increased lymphoproliferation. Besides, both SCEs did not show any toxic effects. Therefore, the study suggests that SCEs are safe and have potent immunostimulatory activity and hence, seems to be a promising balanced Th1 and Th2 directing immunological adjuvant for various veterinary as well as human vaccines.