Computational analysis of phytocompounds in Centella asiatica for its antifibrotic and drug-likeness properties - Herb to drug study.

Oral submucous fibrosis (OSMF) is a potentially malignant disorder with no permanent cure that affects the quality of life due to trismus. Computational pharmacology has accelerated the discovery of drug candidates for the treatment of incurable diseases. The present study aimed to screen the compounds of the miracle herb Centella asiatica with drug-likeness properties based on the absorption, distribution, metabolism, and excretion (ADME) properties. The pharmacological actions of these screened compounds against OSMF were identified by network pharmacology, gene ontology, pathway enrichment analysis, molecular docking, and simulation. Fifteen drug-like ligands were identified after virtual screening viz; asiatic acid, kaempferol, quercetin, luteolin, apigenin, bayogenin, gallic acid, isothankunic acid, madecassic acid, madasiatic acid, arjunolic acid, terminolic acid, catechin, epicatechin, and nobiletin. 850 potential targets were predicted for the ligands, which were analyzed against 354 proteins associated with OSMF. Compound pathway analysis and disease pathway analysis identified 53 common proteins. The GO enrichment analysis identified 472 biological process terms, 76 molecular function terms, and 44 cellular component terms. Pathway enrichment analysis predicted 142 KEGG pathways, 35 Biocarta pathways, and 236 Reactome pathways for the target proteins. The analysis revealed that the herb targets crucial events of fibrosis such as inflammation, oxidative stress, apoptosis, collagen deposition, and epithelial-mesenchymal transition. The common 53 proteins were used for protein-protein interaction (PPI) network analysis, which revealed 4 key proteins interacting with the phytocompounds viz; transforming growth factor-ß1 (TGF-ß1), mothers against decapentaplegic-3 (SMAD-3), mitogen-activated protein kinase-1 (MAPK-1) and proto-oncogene tyrosine-protein kinase (SRC). Molecular docking revealed that all ligands had a good binding affinity to the target proteins. Bayogenin had the highest binding affinity towards MAPK-1 (-9.7 kcal/mol), followed by isothankunic acid towards SRC protein (-9.3 kcal/mol). Madasiatic acid had the highest binding affinity to SMAD-3 (-7.6 kcal/mol) and TGF-ß1 (-7.1 kcal/mol). Molecular dynamics simulation demonstrated stable ligand protein interactions of bayogenin and MAPK complex, isothankunic acid and SRC complex. This in silico study is the first to identify potential phytochemicals present in Centella asiatica and their target molecules, which might be responsible for reversing OSMF.

An advanced deep learning method to detect and classify diabetic retinopathy based on color fundus images.

BACKGROUND: In this article, we present a computerized system for the analysis and assessment of diabetic retinopathy (DR) based on retinal fundus photographs. DR is a chronic ophthalmic disease and a major reason for blindness in people with diabetes. Consistent examination and prompt diagnosis are the vital approaches to control DR. METHODS: With the aim of enhancing the reliability of DR diagnosis, we utilized the deep learning model called You Only Look Once V3 (YOLO V3) to recognize and classify DR from retinal images. The DR was classified into five major stages: normal, mild, moderate, severe, and proliferative. We evaluated the performance of the YOLO V3 algorithm based on color fundus images. RESULTS: We have achieved high precision and sensitivity on the train and test data for the DR classification and mean average precision (mAP) is calculated on DR lesion detection. CONCLUSIONS: The results indicate that the suggested model distinguishes all phases of DR and performs better than existing models in terms of accuracy and implementation time.

Rescue Stenting for Refractory Large Vessel Occlusions in the Thrombectomy Era: Intracranial Use of Coronary Stents in Low-mid Economic Settings.

BACKGROUND:  Failed mechanical thrombectomy due to a refractory emergent large vessel occlusion (RELVO) in patients presenting with an acute stroke poses a major challenge to the outcomes. OBJECTIVE:  We demonstrate the use of coronary stents in the intracranial circulation as rescue stenting for an already expensive mechanical thrombectomy procedure in a mid-low socioeconomic setting. METHODS:  A retrospective, multicenter study was conducted between December 2015 and January 2021. The studied cohort were patients who required the use of a rescue stenting using a coronary stent for emergent large vessel occlusion to avoid failed recanalization. Failed recanalization was defined as failed vessel recanalization after at least two passes. Patient demographic data, procedure specifics, type of stent used, and procedural outcomes were collected. RESULTS:  A total of 26 patients with acute ischemic stroke were included from eight different centers across India. Out of 26 patients, 19 (73.0%) were male and seven were female (26.9%). The mean age was 53.6 years, the youngest patient was 23 years old and the eldest was 68 years old. Seven patients (26.9%) had posterior circulation stroke due to occlusion of the vertebral or basilar artery and 19 patients (73.0%) had anterior circulation stroke median NIHSS at presentation was 16 (range 10 to 28) in anterior circulation stroke and 24 (range 16 to 30) in posterior circulation stroke. Intravenous thrombolysis with tissue plasminogen activator (IV tPA) was given in three patients (11.5%). The hospital course of two patients was complicated by symptomatic intracranial hemorrhage (sICH), which was fatal. Favorable revascularization outcome and favorable functional outcome was achieved in 22 patients (84.6%), three patients passed away (11.5%), and one patient was lost to follow up. CONCLUSIONS:  Overall, our study finds that rescue stenting using coronary stents can potentially improve outcomes in refractory large vessel occlusions while minimizing costs in low-mid economic settings.

Antihypertensive and pleiotropic effects of Phyllanthus emblica extract as an add-on therapy in patients with essential hypertension-A randomized double-blind placebo-controlled trial.

Essential hypertension is an important cause of cardiovascular morbidity and mortality that is compounded by concomitant risk factors like diabetes mellitus and dyslipidemia. Phyllanthus emblica is a rich source of antioxidants, tannins, and vitamin C and is used in treating various ailments in traditional medicine. This study aimed to elucidate the effects of aqueous extract of Phyllanthus emblica on essential hypertension and other protective actions. This randomized controlled trial was conducted on 150 patients with essential hypertension. Participants were randomly assigned to receive Phyllanthus emblica capsule (500 mg) or placebo twice daily, added to their routine medications for 12 weeks. Blood pressure was assessed at baseline, 2, 4, 8, and 12 weeks after beginning treatment or placebo. Other investigations like lipid parameters, oxidant and antioxidant enzyme levels, hs-CRP levels, HbA1C, LFT, RFT, uric acid, and endothelial function were measured at baseline and 12 weeks. Both Phyllanthus emblica and placebo groups were comparable at baseline. Phyllanthus emblica had a good safety profile in patients with essential hypertension. However, the treatment with Phyllanthus emblica failed to produce any additional reduction in systolic and/or diastolic blood pressure levels and did not exhibit improvement in oxidant status, antioxidant capacity, lipid profile, HbA1C, arterial stiffness parameters, or hs-CRP levels.

Epidemiology and Outcomes of Hospitalizations Due to Hepatocellular Carcinoma.

Background Hepatocellular Carcinoma (HCC) is a severe complication of cirrhosis and the incidence of HCC has been increasing in the United States (US). We aim to describe the trends, characteristics, and outcomes of hospitalizations due to HCC across the last decade. Methods We derived a study cohort from the Nationwide Inpatient Sample (NIS) for the years 2008-2017. Adult hospitalizations due to HCC were identified using the International Classification of Diseases (9th/10th Editions) Clinical Modification diagnosis codes (ICD-9-CM/ICD-10-CM). Comorbidities were also identified by ICD-9/10-CM codes and Elixhauser Comorbidity Software (Agency for Healthcare Research and Quality, Rockville, Maryland, US). Our primary outcomes were in-hospital mortality and discharge to the facility. We then utilized the Cochran-Armitage trend test and multivariable survey logistic regression models to analyze the trends, outcomes, and predictors. Results A total of 155,436 adult hospitalizations occurred due to HCC from 2008-2017. The number of hospitalizations with HCC decreased from 16,754 in 2008 to 14,715 in 2017. Additionally, trends of in-hospital mortality declined over the study period but discharge to facilities remained stable. Furthermore, in multivariable regression analysis, predictors of increased mortality in HCC patients were advanced age (OR 1.1; 95%CI 1.0-1.2; p< 0.0001), African American (OR 1.3; 95%CI 1.1-1.4;p< 0.001), Rural/ non-teaching hospitals (OR 2.7; 95%CI 2.4-3.3; p< 0.001), uninsured (OR 1.9; CI 1.6-2.2; p< 0.0001) and complications like septicemia and pneumonia as well as comorbidities such as hypertension, diabetes mellitus, and renal failure. We observed similar trends in discharge to facilities. Conclusions In this nationally representative study, we observed a decrease in hospitalizations of patients with HCC along with in-hospital mortality; however, discharge to facilities remained stable over the last decade. We also identified multiple predictors significantly associated with increased mortality, some of which are potentially modifiable and can be points of interest for future studies.

Efficacy of Phyllanthus niruri on improving liver functions in patients with alcoholic hepatitis: A double-blind randomized controlled trial.

INTRODUCTION: Phyllanthus niruri, a traditional herbal medicine, was found to be hepatoprotective as evidenced by several preclinical and clinical studies. However, to the best of our knowledge, there are no clinical trials available to date to evaluate its efficacy in alcoholic hepatitis. MATERIALS AND METHODS: The present study is a block randomized, double-blind, parallel-arm placebo-controlled trial that was designed to assess the efficacy of P. niruri on the liver and renal function parameters, total oxidant and antioxidant levels in alcoholic hepatitis patients in comparison to placebo over a 4-week period. Patients were screened by CAGE questionnaire, and those with a confirmed diagnosis of mild-moderate alcoholic hepatitis based on laboratory findings and Maddrey's discriminant function score were randomly allocated to treatment and placebo arms. Clinical assessments were done at baseline, 2 weeks, and 4 weeks. A total of 454 patients were screened and 100 eligible patients were recruited for the study, and 71 were analyzed using the modified intention-to-treat approach. RESULTS: Serum levels of liver and renal function parameters failed to demonstrate significant improvement with P. niruri. However, there was a statistically significant increase in the level of total antioxidants with P. niruri (P = 0.034) with an additional appetite stimulant activity (P = 0.03) in 4 weeks. CONCLUSION: A 4-week administration of P. niruri in mild-moderate alcoholic hepatitis patients showed an improvement in the total antioxidant levels with an appetite stimulant activity compared to a placebo.

Efficacy of BCG vaccine and Mitomycin C for the treatment of ocular squamous cell carcinoma in bovines.

Bovine ocular squamous cell carcinoma (BOSCC) also called cancer eye, represents the most economically important neoplasm in large animals. Hereditary factors, environmental factors, lack of eyelid pigmentation, age and dietary habits have all been reported to play a role in the etiopathogenesis of bovine ocular squamous cell carcinoma. In group I, six animals with small, localized eye cancer where vision was not affected were included and subjected to intralesional injection of Bacillus Calmette- Guerin (BCG) vaccine at 0, 14, 35, and 56 days interval. In group II (six animals), surgical excision and Mitomycin C 0.04% topically on alternate weeks for two months as adjunctive therapy. All the animals recovered completely with no recurrence for a follow up period of one year.

Effect of Curcuma longa on vascular function in native Tamilians with type 2 diabetes mellitus: A randomized, double-blind, parallel arm, placebo-controlled trial.

Diabetes mellitus is characterized by increased central arterial stiffness and endothelial dysfunction leading to increased risk of cardiovascular complications. The aim of this study is to evaluate the effect of Curcuma longa on arterial stiffness and endothelial dysfunction in patients with type 2 diabetes mellitus. This randomized controlled trial was conducted in 136 patients of type 2 diabetes. Among them, 114 completed at least one follow-up visit and included for data analysis. Arterial stiffness parameters were measured at baseline and every month for 3 months and endothelial dysfunction markers at baseline and after 3 months of treatment with C. longa or placebo. These parameters were compared between the two groups. Both C. longa and placebo groups were comparable at baseline. After 3 months of treatment, C. longa produced significant reduction from baseline in carotid-femoral pulse wave velocity (p = .002), left brachial-ankle pulse wave velocity (p = .001), aortic augmentation pressure (p = .007), aortic augmentation index (p = .007), and aortic augmentation index at heart rate 75 (p = .018) as compared with the placebo group. Three months treatment with C. longa significantly decreases arterial stiffness as compared with placebo in type 2 diabetes mellitus patients.

Hybrid Nanoreactors: Enabling an Off-the-Shelf Strategy for Concurrently Enhanced Chemo-immunotherapy.

Immunosuppressive tumors generally exhibit poor response to immune checkpoint blockade based cancer immunotherapy. Rationally designed hybrid nanoreactors are now presented that have integrated functions as Fenton catalysts and glutathione depletion agents for amplifying the immunogenic cell death and activating immune cells. A simple physical mixture of nanoreactors and chemodrugs in combination with immune checkpoint blockades show synergistically and concurrently enhanced chemo-immunotherapy efficacy, inhibiting the growth of both treated primary immunosuppressive tumors and untreated distant tumors. The off-the-shelf strategy uses tumor antigens generated in situ and avoids cargo loading, and is thus a substantial advance in personalized nanomedicine for clinical translation.

Asymmetric mesoporous silica nanoparticles as potent and safe immunoadjuvants provoke high immune responses.

Asymmetric mesoporous silica nanoparticles with a head-tail structure are potent immunoadjuvants for delivering a peptide antigen, generating a higher antibody immune response in mice compared to their symmetric counterparts.

Adsorptive Removal of Selected Anionic and Cationic Dyes by Using Graphitic Carbon Material Prepared from Edible Sugar: A Study of Kinetics and Isotherms.

Graphitic carbon-like material (GCM) derived from edible sugar under a nitrogen environment was applied as an adsorbent for the removal of anionic and cationic dyes (methyl orange, MO) and methylene blue (MB) from wastewater. The physico-chemical characterization of GCM was analyzed by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, and X-ray photoelectron spectroscopy (XPS). The plate-like morphology with an average size of 50-100 nm was measured from the SEM images. The measured BET 'surface area and pore volume were 574 m2/g and 0.248 cm3/g, respectively with pore diameter (d), 1.8 47 (< 2 nm) indicates that the GCM classified as a microporous. The effects of dosage, pH, contact time and concentration on the adsorption of MB and MO onto GCM were studied to unveil the adsorption process. The experimental isotherm data concurred with the Langmuir isotherm model (R2 = 0.990) for MB, while the MO isotherm data concurred with Freundlich model (R2 = 0.995). The maximum adsorption capacity achieved from the Langmuir isotherm equation at 25 °C was 38.75 and 43.48 mg/g for MB and MO, respectively, which indicates that GCM is a suitable adsorbent for the adsorption of both anionic and cationic dyes. The kinetic study demonstrated that the adsorption of both dyes onto GCM was the pseudo-second-order diffusion kinetics. The thermodynamic parameters reveal the adsorption of both dyes was endothermic spontaneous through chemical interactions. The GCM was found to be a potential adsorbent for the removal of MB and MO from an aqueous solution.

Draft Genome Sequence of Entomopathogenic Brevibacillus laterosporus Strain Lak 1210, an Alkaliphilic Chitin Degrader.

We announce here the draft genome sequence of Brevibacillus laterosporus strain Lak 1210, isolated from mangrove soil. This alkaliphilic strain is an efficient chitin degrader and has the ability to control insects and inhibit phytopathogenic fungi. The assembly consists of 5,082,926 bp, with 4,321 protein-coding sequences and a GC content of 41.15%.

Multi-shelled Dendritic Mesoporous Organosilica Hollow Spheres: Roles of Composition and Architecture in Cancer Immunotherapy.

Developing potent adjuvants for the stimulation of robust immune response is central for effective cancer immunotherapy. Double-shelled dendritic mesoporous organosilica hollow spheres are an excellent adjuvant and provide superior immunity in cancer immunotherapy, and better than their counterparts either with a pure silica composition or a single-walled architecture. This study provides new insights in the rational design of effective nanostructured adjuvants for vaccine developments.

Understanding the Effect of Surface Chemistry of Mesoporous Silica Nanorods on Their Vaccine Adjuvant Potency.

Mesoporous silica nanoparticles are reported as adjuvants in nanovaccines in generating robust antigen-specific immunity. However, the effect of surface chemistry in initiating and modulating the immune response remains largely unexplored. In this study, mesoporous silica nanorods (MSNRs) are modified with NH2 and C18 groups to investigate the influence of surface functional groups (OH, NH2 , and C18 ) on their adjuvant efficacy. It is found that compared to OH and NH2 groups, the hydrophobic C18 modification significantly enhances antigen uptake by antigen presenting cells and endosomal-lysosomal escape in vitro, dendritic cells, and macrophages maturation ex vivo, and elicits secretion of interferon-γ level and antibody response in immunized mice. Moreover, bare MSNR and MSNRNH2 exhibit T-helper 2 biased immune response, while MSNRC18 shows a T-helper 1 biased immune response. These findings suggest that the surface chemistry of nanostructured adjuvants has profound impact on the immune response, which provides useful guidance for the design of effective nanomaterial based vaccines.

Core-Shell-structured Dendritic Mesoporous Silica Nanoparticles for Combined Photodynamic Therapy and Antibody Delivery.

Multifunctional core-shell-structured dendritic mesoporous silica nanoparticles with a fullerene-doped silica core, a dendritic silica shell and large pores have been prepared. The combination of photodynamic therapy and antibody therapeutics significantly inhibits the cancer cell growth by effectively reducing the level of anti-apoptotic proteins.

Asymmetric Silica Nanoparticles with Tunable Head-Tail Structures Enhance Hemocompatibility and Maturation of Immune Cells.

Asymmetric mesoporous silica nanoparticles (MSNs) with controllable head-tail structures have been successfully synthesized. The head particle type is tunable (solid or porous), and the tail has dendritic large pores. The tail length and tail coverage on head particles are adjustable. Compared to spherical silica nanoparticles with a solid structure (Stöber spheres) or large-pore symmetrical MSNs with fully covered tails, asymmetrical head-tail MSNs (HTMSNs) show superior hemocompatibility due to reduced membrane deformation of red blood cells and decreased level of reactive oxygen species. Moreover, compared to Stöber spheres, asymmetrical HTMSNs exhibit a higher level of uptake and in vitro maturation of immune cells including dendritic cells and macrophage. This study has provided a new family of nanocarriers with potential applications in vaccine development and immunotherapy.

A Vesicle Supra-Assembly Approach to Synthesize Amine-Functionalized Hollow Dendritic Mesoporous Silica Nanospheres for Protein Delivery.

Intracellular delivery of proteins is a promising strategy of intervention in disease, which relies heavily on the development of efficient delivery platforms due to the cell membrane impermeability of native proteins, particularly for negatively charged large proteins. This work reports a vesicle supra-assembly approach to synthesize novel amine-functionalized hollow dendritic mesoporous silica nanospheres (A-HDMSN). An amine silica source is introduced into a water-oil reaction solution prior to the addition of conventional silica source tetraethylorthosilicate. This strategy favors the formation of composite vesicles as the building blocks which further assemble into the final product. The obtained A-HDMSN have a cavity core of ≈170 nm, large dendritic mesopores of 20.7 nm in the shell and high pore volume of 2.67 cm3 g-1 . Compared to the calcined counterpart without amine groups (C-HDMSN), A-HDMSN possess enhanced loading capacity to large negative proteins (IgG and ß-galactosidase) and improved cellular uptake performance, contributed by the cationic groups. A-HDMSN enhance the intracellular uptake of ß-galactosidase by up to 5-fold and 40-fold compared to C-HDMSN and free ß-galactosidase, respectively. The active form of ß-galactosidase delivered by A-HDMSN retains its intracellular catalytic functions.

In silico approaches to identify the potential inhibitors of glutamate carboxypeptidase II (GCPII) for neuroprotection.

To develop a potential inhibitor for glutamate carboxypeptidase II (GCPII) effective against all the eight common genetic variants reported, PyMOL molecular visualization system was used to generate models of variants using the crystal structure of GCPII i.e. 2OOT as a template. High-throughput virtual screening of 29 compounds revealed differential efficacy across the eight genetic variants (pIC50: 4.70 to 10.22). Pharmacophore analysis and quantitative structure-activity relationship (QSAR) studies revealed a urea-based N-acetyl aspartyl glutamate (NAAG) analogue as more potent inhibitor, which was effective across all the genetic variants of GCPII as evidenced by glide scores (-4.32 to -7.08) and protein-ligand interaction plots (13 interactions in wild GCPII). This molecule satisfied Lipinski rule of five and rule of three for drug-likeliness. Being a NAAG-analogue, this molecule might confer neuroprotection by inhibiting glutamatergic neurotransmission mediated by N-acetylated alpha-linked acidic dipeptidase (NAALADase), a splice variant of GCPII.

Clinical utility of genetic variants of glutamate carboxypeptidase II in predicting breast cancer and prostate cancer risk.

In view of documented evidence showing glutamate carboxypeptidase II (GCPII) inhibitors as promising anti-cancer agents, certain variants of GCPII modulate breast and prostate cancer risk, and we developed an artificial neural network (ANN) model of GCPII variants and ascertained the risk associated with eight genetic variants of GCPII. In parallel, an in silico model was developed to substantiate the ANN simulations. The ANN model with modified sigmoid function was used for disease prediction, whereas the hyperbolic tangent function was used to predict folate hydrolase 1 (FOLH1) and prostate specific membrane antigen (PSMA) expression. PyMOL models of GCPII variants were developed, and their affinity toward the folylpolyglutamate (FPG) ligand was tested using glide score analysis. Of the eight genetic variants of GCPII, p.P160S alone conferred protection against both of the cancers. This variant exhibited higher affinity toward FPG compared with wild GCPII (-2.06 vs. -1.69); and positive correlation was observed between the P160S variant and circulating folate (r = 0.60). The ANN model for disease prediction showed significant predictability associated with GCPII variants toward breast cancer (area under the curve (AUC): 1.00) and prostate cancer (AUC: 0.97), with clear distinguishing ability of healthy controls (AUC: 0.96). The ANN models for the expression of FOLH1 and PSMA explained 60.5% and 86.7% of the variability, respectively. Thus, GCPII variants are potential contributors of risk toward breast cancer and prostate cancer. Risk modulation appeared to be mediated through changes in the expression of FOLH1 and PSMA.

Differential expression of metallothioneins in response to heavy metals and their involvement in metal tolerance in the symbiotic basidiomycete Laccaria bicolor.

Cysteine-rich peptides such as metallothioneins (MTs) are involved in metal homeostasis and detoxification in many eukaryotes. We report the characterization and expression of two MT genes, LbMT1 and LbMT2 from the ectomycorrhizal fungus Laccaria bicolor under metal stress conditions. LbMT1 and LbMT2 differ with respect to the length of the encoded peptides (58 versus 37 aa, respectively) and also by their expression patterns in response to metals. The expression levels of both LbMT1 and LbMT2 increased as a function of increased external Cu concentration, the expression levels for LbMT2 were always significantly higher compared with those of LbMT1. Only LbMT1, but not LbMT2, responded to Cd supply in the range of 25-100 µM while Zn did not affect the transcription of either LbMT1 or LbMT2. Both genes also responded to oxidative stress, but to a lesser extent compared to their responses to either Cu or Cd stress. Heterologous complementation assays in metal-sensitive yeast mutants indicated that both LbMT1 and LbMT2 encode peptides capable of conferring higher tolerance to both Cu and Cd. The present study identified LbMTs as potential determinants of the response of this mycorrhizal fungus to Cu and Cd stress.