Chemometric guided isolation of new triterpenoid saponins as acetylcholinesterase inhibitors from seeds of Achyranthes bidentata Blume.

Achyranthes bidentata Blume (Amaranthaceae) is an annual or perennial herb widely used as ethnomedicine in Traditional Chinese Medicine for treating fever, cold, ulcers, mensural pain, dementia, and osteoporosis. In the current study, UPLC-IM-Q-TOF-MS/MS-based chemometric approach was adopted for the tentative identification of fifty-six compounds in the extract and fractions of A.bidentata seeds. Further, the chemometric-guided isolation led to the isolation of two previously undescribed oleanane-type triterpenoid saponins, named achyranosides A-B (27 and 30), along with three known compounds (31, 44, and 23) from water fraction of A. bidentata seeds. The structures of new compounds were elucidated based on the detailed analysis of NMR, HR-ESI-MS, FT-IR spectral data, and GC-FID techniques. The isolated compounds in vitro acetylcholinesterase inhibitory activity revealed the promising activity of chikusetsusaponin IVa (23) (IC50 = 63.7 µM) with mixed type of AChE inhibition in enzyme kinetic studies. Additionally, in silico binding free energy of isolated compounds disclosed the greater stability of enzyme-ligand complex owing to underlying multiple H-bond interactions. Overall, the study demonstrates the effectiveness of a chemometric-guided approach for the phytochemical exploration and isolation of new oleanane-type triterpenoid saponins from A. bidentata seeds.

Antiplasmodial activity of the bulbs of Fritillaria cirrhosa D.Don (Syn: Fritillaria roylei Hook.): UPLC-IM-Q-TOF-MS/MS-based biochemometric approach for the identification of marker compounds.

ETHNOPHARMACOLOGICAL RELEVANCE: Fritillaria cirrhosa D.Don (Syn: Fritillaria roylei Hook.) (Hindi name: Kshirakakoli) is a critically endangered Himalayan medicinal plant, well documented in Ayurveda for its therapeutic uses against various disorders such as jvara (fever), kasa (respiratory tract disease) etc. Its bulbs are also used as Szechuan-Pei-Mu for their antipyretic properties in the traditional Chinese medicine. However, despite its ethnomedicinal usage, the therapeutic use of F. cirrhosa bulbs for jvara (fever) related conditions such as malaria has remained unexplored. Hence in the context of increasing global concerns about drug-resistant malaria, it is important to investigate the antiplasmodial activity of F. cirrhosa bulbs for novel antimalarial agents. AIM OF THE STUDY: To investigate the antiplasmodial effects of the extracts/fractions of F. cirrhosa bulbs by the biochemometric approach and to rationalize its ethnopharmacological usage for jvara (fever) related conditions such as malaria. MATERIAL AND METHODS: This study involves the UHPLC-MS-based plant material selection, preparation, quantification, and assessment of F. cirrhosa bulb extracts against CQ-sensitive Pf 3D7 & CQ-resistant Pf INDO strains. Further, UPLC-IM-Q-TOF-MS-based biochemometric approach has been applied for the identification of marker compounds responsible for the observed antiplasmodial effects. The identified marker compounds were also assessed for their in silico ADMET properties and binding efficacy with the drug transporter Pf CRT. RESULTS: Different F. cirrhosa bulb extracts/fractions showed promising antiplasmodial activity with IC50 values 2.71-19.77 µg/mL for CQ-resistant Pf INDO strain and 1.76-21.52 µg/mL for CQ-sensitive Pf 3D7 strain. UPLC-IM-Q-TOF-MS/MS-based biochemometric analysis revealed four marker compounds i.e., peimine (m/z 432.3448), peimisine (m/z 428.3504), puqiedinone (m/z 414.3379), and puqiedine (m/z 416.3509) responsible for the observed antiplasmodial activity. The identified marker compounds showed excellent binding efficacy with Pf CRT and suitable drug-like properties in silico. CONCLUSIONS: The study demonstrated promising antiplasmodial activity of the chloroform and alkaloid enriched fractions of F. cirrhosa bulbs and further identified the four marker compounds responsible for the promising antiplasmodial activity. These marker compounds i.e., peimine, peimisine, puqiedinone and puqiedine were identified by the biochemometric analysis as the putative antiplasmodial constituents of the F. cirrhosa bulbs. Further, in silico studies indicated the good binding affinity of the marker compounds with Pf CRT along with suitable ADMET properties. Overall, the study elucidates the antiplasmodial activity of F. cirrhosa bulbs from the western Himalayan region and provides nascent scientific evidence for their ethnopharmacological usage in jvara (fever) related conditions such as malaria.

Technology-enhanced learning interventions on skin of colour dermatology for dermatology trainees and fellows: are they effective or sustainable?

Recent shifts towards synchronous online learning and raised awareness of ethnic inequalities in health have resulted in the establishment of frequent 'one-off' technology-enhanced learning (TEL) initiatives on diversity issues. There is little established evidence regarding the efficacy or sustainability of such interventions. We designed a prospective cohort pilot study including 14 dermatology registrars and fellows and delivered a TEL programme focusing on central centrifugal cicatricial alopecia and keloid scarring. Information was collected on the existing competence and confidence of our cohort about managing these conditions, as well as the short-term and long-term impact of our intervention. Following our programme, participant knowledge improved transiently, but was not sustainable 6 weeks later. Over half of participants were not confident in adopting newly acquired knowledge on skin of colour into practice. Results demonstrate a disparity between how effective one-off education initiatives are perceived vs. actual benefit. More systemic solutions may be warranted.

A conversation between hyphenated spectroscopic techniques and phytometabolites from medicinal plants.

Medicinal plant metabolomics has emerged as a goldmine for the natural product chemists. It provides a pool of bioactive phytoconstituents leading to accelerated novel discoveries and the elucidation of a variety of biosynthetic pathways. Further, it also acts as an innovative tool for herbal medicine's scientific validation and quality assurance. This review highlights different strategies and analytical techniques employed in the practice of metabolomics. Further, it also discusses several other applications and advantages of metabolomics in the area of natural product chemistry. Additional examples of integrating metabolomics with multivariate data analysis techniques for some Indian medicinal plants are also reviewed. Recent technical advances in mass spectrometry-based hyphenated techniques, nuclear magnetic resonance-based techniques, and comprehensive hyphenated technologies for phytometabolite profiling studies have also been reviewed. Mass Spectral Imaging (MSI) has been presented as a highly promising method for high precision in situ spatiotemporal monitoring of phytometabolites. We conclude by introducing GNPS (Global Natural Products Social Molecular Networking) as an emerging platform to make social networks of related molecules, to explore data and to annotate more metabolites, and expand the networks to novel "predictive" metabolites that can be validated.

Histopathological Spectrum and Immunohistochemical Profile of Lung Carcinomas: A 9-Year Study from a Tertiary Hospital in North India.

BACKGROUND: Lung cancer is the most common cancer worldwide and the leading cause of cancer-related death. Diagnostic bronchoscopic or percutaneous biopsies are usually small. However, judicious use of immunohistochemistry (IHC) helps in accurate subtyping, which forms the basis for molecular tests and treatment. AIM: The aim was to study the role of IHC in the diagnosis of various histological subtypes of lung cancer. METHODS: This 9-year study from 2009 to 2017 included all cases diagnosed as lung carcinoma on tissue biopsies. IHC markers were selected based on histopathology, from a panel comprising CK7, CK20, CK5/6, p63, thyroid transcription factor 1 (TTF-1), napsin A, synaptophysin, chromogranin A, neuron-specific enolase, CD56, and CDX2. Metastatic cancers to the lung were excluded from the study. RESULTS: There were 199 cases of lung carcinoma comprising squamous cell carcinoma (37.7% [n = 75]), adenocarcinoma (26.1% [n = 52]), small cell carcinoma (20.6% [n = 41]), non-small cell lung carcinoma-unclassified (10.1% [n = 20]), adenosquamous carcinoma (2.5% [n = 5]), and others (3% [n = 6]). IHC was done on 47.7% (95/199) of cases. Squamous cell carcinomas showed CK5/6 and p63 positivity in 13/13 (100%) and 12/13 (92.3%) cases, respectively. Adenocarcinomas were positive for napsin A in 12/13 (92.3%) and TTF-1 in 35/41 (85.4%) cases. Neuroendocrine markers were positive in all small cell carcinomas. CONCLUSION: Squamous cell carcinoma was the most common primary lung malignancy in the North Indian population, followed by adenocarcinoma and small cell carcinoma. IHC panel of TTF-1, napsin A, CK5/6, and p63 is very helpful to classify most non-small cell lung carcinomas.

Exploiting the potential of large databases of electronic health records for research using rapid search algorithms and an intuitive query interface.

OBJECTIVE: UK primary care databases, which contain diagnostic, demographic and prescribing information for millions of patients geographically representative of the UK, represent a significant resource for health services and clinical research. They can be used to identify patients with a specified disease or condition (phenotyping) and to investigate patterns of diagnosis and symptoms. Currently, extracting such information manually is time-consuming and requires considerable expertise. In order to exploit more fully the potential of these large and complex databases, our interdisciplinary team developed generic methods allowing access to different types of user. MATERIALS AND METHODS: Using the Clinical Practice Research Datalink database, we have developed an online user-focused system (TrialViz), which enables users interactively to select suitable medical general practices based on two criteria: suitability of the patient base for the intended study (phenotyping) and measures of data quality. RESULTS: An end-to-end system, underpinned by an innovative search algorithm, allows the user to extract information in near real-time via an intuitive query interface and to explore this information using interactive visualization tools. A usability evaluation of this system produced positive results. DISCUSSION: We present the challenges and results in the development of TrialViz and our plans for its extension for wider applications of clinical research. CONCLUSIONS: Our fast search algorithms and simple query algorithms represent a significant advance for users of clinical research databases.

Recent advances in the utility and use of the General Practice Research Database as an example of a UK Primary Care Data resource.

Since its inception in the mid-1980s, the General Practice Research Database (GPRD) has undergone many changes but remains the largest validated and most utilised primary care database in the UK. Its use in pharmacoepidemiology stretches back many years with now over 800 original research papers. Administered by the Medicines and Healthcare products Regulatory Agency since 2001, the last 5 years have seen a rebuild of the database processing system enhancing access to the data, and a concomitant push towards broadening the applications of the database. New methodologies including real-world harm-benefit assessment, pharmacogenetic studies and pragmatic randomised controlled trials within the database are being implemented. A substantive and unique linkage program (using a trusted third party) has enabled access to secondary care data and disease-specific registry data as well as socio-economic data and death registration data. The utility of anonymised free text accessed in a safe and appropriate manner is being explored using simple and more complex techniques such as natural language processing.