Regulatory safety pharmacology and toxicity assessments of a standardized stem extract of Cassia occidentalis Linn. in rodents.

Cassia occidentalis Linn (CO) is an annual/perennial plant having traditional uses in the treatments of ringworm, gastrointestinal ailments and piles, bone fracture, and wound healing. Previously, we confirmed the medicinal use of the stem extract (ethanolic) of CO (henceforth CSE) in fracture healing at 250 mg/kg dose in rats and described an osteogenic mode of action of four phytochemicals present in CSE. Here we studied CSE's preclinical safety and toxicity. CSE prepared as per regulations of Current Good Manufacturing Practice for human pharmaceuticals/phytopharmaceuticals and all studies were performed in rodents in a GLP-accredited facility. In acute dose toxicity as per New Drug and Clinical Trial Rules, 2019 (prior name schedule Y), in rats and mice and ten-day dose range-finding study in rats, CSE showed no mortality and no gross abnormality at 2500 mg/kg dose. Safety Pharmacology showed no adverse effect on central nervous system, cardiovascular system, and respiratory system at 2500 mg/kg dose. CSE was not mutagenic in the Ames test and did not cause clastogenicity assessed by in vivo bone marrow genotoxicity assay. By a sub chronic (90 days) repeated dose (as per OECD, 408 guideline) study in rats, the no-observed-adverse-effect-level was found to be 2500 mg/kg assessed by clinico-biochemistry and all organs histopathology. We conclude that CSE is safe up to 10X the dose required for its osteogenic effect.

Withania somnifera shows a protective effect in monocrotaline-induced pulmonary hypertension.

CONTEXT: Withania somnifera (Linn.) Dunal (Solanaceae), a clinically used herbal drug in Ayurveda, shows potent antioxidant, anti-inflammatory, pro-apoptotic, and cardioprotective effects. However, the efficacy of W. somnifera in pulmonary hypertension (PH), a cardiopulmonary disorder, remains unexplored. OBJECTIVE: The present study investigates the effect of W. somnifera root powder on monocrotaline (MCT)-induced PH in rats. MATERIALS AND METHODS: In preventive studies, W. somnifera root powder (50 and 100 mg/kg/d, p.o.) was administered from day 1 following single administration of MCT (60 mg/kg, s.c.) in Sprague-Dawley (SD) rats. After 35 d, right ventricular pressure (RVP) was measured in anesthetized rats. Various physical markers of right ventricular hypertrophy (RVH) were measured in isolated hearts. Markers of endothelial function, inflammation, and oxidative stress were estimated in lung homogenate. Vasoreactivity of pulmonary arteries was also studied. In therapeutic treatment, W. somnifera (50 and 100 mg/kg/d, p.o.) was administered from day 21 to 35 post-MCT administration. RESULTS: Preventive treatment with 50 and 100 mg/kg W. somnifera significantly reduced the RVP (32.18 ± 1.273 mm Hg and 29.98 ± 1.119 mm Hg, respectively, versus 42.96 ± 1.789 mm Hg of MCT) and all markers of RVH in MCT-challenged rats. There was an improvement in inflammation, oxidative stress and endothelial dysfunction, and attenuation of proliferative marker and apoptotic resistance in lungs. Therapeutic treatment with W. somnifera (100 mg/kg) also reduced RVP and RVH. DISCUSSION: This study demonstrated that W. somnifera significantly protected against MCT-induced PH due to its antioxidant, anti-inflammatory, pro-apoptotic, and cardioprotective properties.

Computational reproducibility of Jupyter notebooks from biomedical publications.

BACKGROUND: Jupyter notebooks facilitate the bundling of executable code with its documentation and output in one interactive environment, and they represent a popular mechanism to document and share computational workflows, including for research publications. The reproducibility of computational aspects of research is a key component of scientific reproducibility but has not yet been assessed at scale for Jupyter notebooks associated with biomedical publications. APPROACH: We address computational reproducibility at 2 levels: (i) using fully automated workflows, we analyzed the computational reproducibility of Jupyter notebooks associated with publications indexed in the biomedical literature repository PubMed Central. We identified such notebooks by mining the article's full text, trying to locate them on GitHub, and attempting to rerun them in an environment as close to the original as possible. We documented reproduction success and exceptions and explored relationships between notebook reproducibility and variables related to the notebooks or publications. (ii) This study represents a reproducibility attempt in and of itself, using essentially the same methodology twice on PubMed Central over the course of 2 years, during which the corpus of Jupyter notebooks from articles indexed in PubMed Central has grown in a highly dynamic fashion. RESULTS: Out of 27,271 Jupyter notebooks from 2,660 GitHub repositories associated with 3,467 publications, 22,578 notebooks were written in Python, including 15,817 that had their dependencies declared in standard requirement files and that we attempted to rerun automatically. For 10,388 of these, all declared dependencies could be installed successfully, and we reran them to assess reproducibility. Of these, 1,203 notebooks ran through without any errors, including 879 that produced results identical to those reported in the original notebook and 324 for which our results differed from the originally reported ones. Running the other notebooks resulted in exceptions. CONCLUSIONS: We zoom in on common problems and practices, highlight trends, and discuss potential improvements to Jupyter-related workflows associated with biomedical publications.

A collaborative semantic-based provenance management platform for reproducibility.

Scientific data management plays a key role in the reproducibility of scientific results. To reproduce results, not only the results but also the data and steps of scientific experiments must be made findable, accessible, interoperable, and reusable. Tracking, managing, describing, and visualizing provenance helps in the understandability, reproducibility, and reuse of experiments for the scientific community. Current systems lack a link between the data, steps, and results from the computational and non-computational processes of an experiment. Such a link, however, is vital for the reproducibility of results. We present a novel solution for the end-to-end provenance management of scientific experiments. We provide a framework, CAESAR (CollAborative Environment for Scientific Analysis with Reproducibility), which allows scientists to capture, manage, query and visualize the complete path of a scientific experiment consisting of computational and non-computational data and steps in an interoperable way. CAESAR integrates the REPRODUCE-ME provenance model, extended from existing semantic web standards, to represent the whole picture of an experiment describing the path it took from its design to its result. ProvBook, an extension for Jupyter Notebooks, is developed and integrated into CAESAR to support computational reproducibility. We have applied and evaluated our contributions to a set of scientific experiments in microscopy research projects.

End-to-End provenance representation for the understandability and reproducibility of scientific experiments using a semantic approach.

BACKGROUND: The advancement of science and technologies play an immense role in the way scientific experiments are being conducted. Understanding how experiments are performed and how results are derived has become significantly more complex with the recent explosive growth of heterogeneous research data and methods. Therefore, it is important that the provenance of results is tracked, described, and managed throughout the research lifecycle starting from the beginning of an experiment to its end to ensure reproducibility of results described in publications. However, there is a lack of interoperable representation of end-to-end provenance of scientific experiments that interlinks data, processing steps, and results from an experiment's computational and non-computational processes. RESULTS: We present the "REPRODUCE-ME" data model and ontology to describe the end-to-end provenance of scientific experiments by extending existing standards in the semantic web. The ontology brings together different aspects of the provenance of scientific studies by interlinking non-computational data and steps with computational data and steps to achieve understandability and reproducibility. We explain the important classes and properties of the ontology and how they are mapped to existing ontologies like PROV-O and P-Plan. The ontology is evaluated by answering competency questions over the knowledge base of scientific experiments consisting of computational and non-computational data and steps. CONCLUSION: We have designed and developed an interoperable way to represent the complete path of a scientific experiment consisting of computational and non-computational steps. We have applied and evaluated our approach to a set of scientific experiments in different subject domains like computational science, biological imaging, and microscopy.

BiodivNERE: Gold standard corpora for named entity recognition and relation extraction in the biodiversity domain.

Background: Biodiversity is the assortment of life on earth covering evolutionary, ecological, biological, and social forms. To preserve life in all its variety and richness, it is imperative to monitor the current state of biodiversity and its change over time and to understand the forces driving it. This need has resulted in numerous works being published in this field. With this, a large amount of textual data (publications) and metadata (e.g. dataset description) has been generated. To support the management and analysis of these data, two techniques from computer science are of interest, namely Named Entity Recognition (NER) and Relation Extraction (RE). While the former enables better content discovery and understanding, the latter fosters the analysis by detecting connections between entities and, thus, allows us to draw conclusions and answer relevant domain-specific questions. To automatically predict entities and their relations, machine/deep learning techniques could be used. The training and evaluation of those techniques require labelled corpora. New information: In this paper, we present two gold-standard corpora for Named Entity Recognition (NER) and Relation Extraction (RE) generated from biodiversity datasets metadata and abstracts that can be used as evaluation benchmarks for the development of new computer-supported tools that require machine learning or deep learning techniques. These corpora are manually labelled and verified by biodiversity experts. In addition, we explain the detailed steps of constructing these datasets. Moreover, we demonstrate the underlying ontology for the classes and relations used to annotate such corpora.

Understanding experiments and research practices for reproducibility: an exploratory study.

Scientific experiments and research practices vary across disciplines. The research practices followed by scientists in each domain play an essential role in the understandability and reproducibility of results. The "Reproducibility Crisis", where researchers find difficulty in reproducing published results, is currently faced by several disciplines. To understand the underlying problem in the context of the reproducibility crisis, it is important to first know the different research practices followed in their domain and the factors that hinder reproducibility. We performed an exploratory study by conducting a survey addressed to researchers representing a range of disciplines to understand scientific experiments and research practices for reproducibility. The survey findings identify a reproducibility crisis and a strong need for sharing data, code, methods, steps, and negative and positive results. Insufficient metadata, lack of publicly available data, and incomplete information in study methods are considered to be the main reasons for poor reproducibility. The survey results also address a wide number of research questions on the reproducibility of scientific results. Based on the results of our explorative study and supported by the existing published literature, we offer general recommendations that could help the scientific community to understand, reproduce, and reuse experimental data and results in the research data lifecycle.

Neuro-protective potential of a vesicular system of a standardized extract of a new chemotype of Withania somnifera Dunal (NMITLI118RT+) against cerebral stroke in rats.

Withania somnifera Dunal is an Indian medicinal plant with significant pharmacological properties, such as adaptogenic, anti-inflammatory, anti-oxidant, anti-platelet, anti-hypertensive, hypoglycemic and hypolipidemic effects. Several chemotypes of W. somnifera include NMITLI-101, NMITLI-118 and NMITLI-128. The present work elaborates the optimization and development of a liposomal delivery system for efficient delivery of NMITLI118RT+ [a standardized ethanolic extract of a new chemotype of W. somnifera Dunal (NMITLI-118) roots] against cerebral stroke in rats. Liposomal systems were prepared using thin-film hydration method and characterized on the basis of size, zeta potential, physical stability, FT-IR, DSC-TGA analysis and surface morphological studies by TEM. NMITLI118RT+ and its formulations (NMITLI118RT+LF) were evaluated for biological activity utilizing middle cerebral artery occlusion model in rats. The Z average of the developed liposomal formulation was about 142.6 ± 0.09 nm with a zeta potential of -31.20 ± 1.0 mV. Results of TEM revealed spherical particles in the range of 200 nm. The entrapment efficiency was found to be 94.603 ± 2%. The formulation was found to be physically stable over a 3-week period. Results were suggestive of the fact that both NMITLI118RT+ and its delivery system possess significant neuroprotective activity in cerebral ischemia. The liposomal system largely exhibits better performance over NMITLI118RT+ precisely in the post-treatment group. The present studies could elucidate the successful development of a delivery system for NMITLI118RT+ and demonstrate their beneficial neuro-protective potential in overcoming and reversing the consequences of I/R injury following stroke.

Phospholipid complexation of NMITLI118RT+: way to a prudent therapeutic approach for beneficial outcomes in ischemic stroke in rats.

Withania somnifera Dunal (Solanaceae) known as Ashwagandha, a popular plant of Indian origin is known to possess tremedous medicinal potential, often used as anti-inflammatory, anti-platelet, antihypertensive, hypoglycemic, hypolipidemic and adaptogenic candidate. Some of its chemotypes developed by CSIR, India includes NMITLI-101, NMITLI-118, NMITLI-128. In this study the investigators have attempted development of a phytosomal complex of NMITLI118RT + (standardized ethanolic extract of a new chemotype of W. somnifera Dunal.), its pharmaceutical characterization and evaluation of its neuro-protective potential against experimenal stroke in rats in continuation with their previous work in this area. The phytosomal complex (NIMPLC) was prepared by following a cohesive optimization design and was characterized on the basis of solubility, dissolution profile, FT-IR, DSC-TGA analysis, zeta potential, physical stability, forced degradation and photolytic degradation. Results were suggestive of a pharmaceutically acceptable formulation. NIMPLC was taken up further for biological evaluation using the middle cerebral artery occlusion (MCAO) model in rats. It could be demonstrated that the beneficial effects of NMITLI118RT + could be augmented by NIMPLC in 1 h pre and 6 h post treatment as was evident from reduction in MDA levels, increment in GSH levels, reduction in neurological deficit (ND) scores and reduction in infarct size. The study could successfully demonstrate the beneficial effects of NIMPLC in brain function restoration following stroke.

Tiotropium bromide: a new long-acting bronchodilator for the treatment of chronic obstructive pulmonary disease.

BACKGROUND: Tiotropium bromide is a new inhaled anticholinergic agent approved for once-daily, long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). OBJECTIVE: This article reviews the pharmacology, pharmacokinetic and pharmacodynamic properties, clinical efficacy, tolerability, and cost of tiotropium therapy in patients with COPD. METHODS: The MEDLINE (1966-October 2004), Iowa Drug Information Service (1966-October 2004), and International Pharmaceutical Abstracts (1970-November 2004) databases were searched for original research and review articles published in English. The search terms were tiotropium, Ba 679 BR, and HandiHaler. Reference lists from these articles were also consulted, as was selected information provided by the manufacturer of tiotropium. All relevant identified studies were included in the review, with preference given to Phase II/III trials. Pharmacoeconomic studies were limited to those conducted in the United States. RESULTS: Tiotropium is a nonselective anticholinergic agent that exhibits kinetic receptor selectivity for the muscarinic M1 and M3 receptors. After inhalation, tiotropium has an onset of action within 30 minutes, a peak effect within 3 to 4 hours, and a > or = 24-hour duration of action that allows once-daily dosing. In clinical trials, patients receiving tiotropium 18 microg QD had significant improvements in trough, peak, and mean forced expiratory volume in 1 second (FEV1), dyspnea, and health-related quality of life, as well as fewer COPD exacerbations and hospitalizations, compared with patients receiving placebo and ipratropium (all, P < 0.05). Improvement in FEV1 was also significantly greater in patients who received tiotropium compared with those who received salmeterol (P < 0.05), although the number of exacerbations and extent of health resource use were comparable between groups. Dry mouth was the most commonly reported adverse effect. One analysis found tiotropium to be cost-effective compared with ipratropium. CONCLUSIONS: Tiotropium offers several advantages over ipratropium in the management of COPD. Long-term (> 1 year) studies are necessary to determine the impact of tiotropium on disease progression and life expectancy.

Anti-stroke profile of thiazolidin-4-one derivatives in focal cerebral ischemia model in rat.

Recently, some PPARγ agonists like pioglitazone, rosiglitazone, and other newer thiazolidine-2, 4-dione (TZD) derivatives have been shown to be neuroprotective in experimental model of cerebral ischemia/reperfusion (I/R) injury. Replacement of active pharmacophore viz: thiazolidine-2,4-dione of these PPARγ agonists with biologically privileged scaffold thiazolidin-4-one derivatives have been synthesized and bioevaluated in focal cerebral ischemia model in rats with an aim to ameliorate cerebral ischemic damage. Of 20 synthesized molecules, three of the substituted compounds (2, 6 and 18) have shown significant (p < 0.001) neuroprotection even much better than rosiglitazone at same dose, when administered 1 h prior to 2/24hrI/R cerebral injury in rats, whereas compounds 10, 15, and 17 also showed significant but moderate effect on most of the parameters used in the study. Moreover, compound 2 and 6 also showed curative potential after 6 h post I/R treatment. The compound 2 has also shown significant effect on glutamate uptake by perhaps enhancing the GLT-1 activity. Thus, the present study indicates that some of the synthesized thiazolidin-4-one substituted PPARγ agonists exhibit better neuroprotection and have potential to ameliorate the ischemic damage. Therefore, this novel class of compounds could be further suitably modified to obtain potent anti-ischemic agents, warranting clinical exploitation.