A review on metal complexes and its anti-cancer activities: Recent updates from in vivo studies.

Research into cancer therapeutics has uncovered various potential medications based on metal-containing scaffolds after the discovery and clinical applications of cisplatin as an anti-cancer agent. This has resulted in many metallodrugs that can be put into medical applications. These metallodrugs have a wider variety of functions and mechanisms of action than pure organic molecules. Although platinum-based medicines are very efficient anti-cancer agents, they are often accompanied by significant side effects and toxicity and are limited by resistance. Some of the most studied and developed alternatives to platinum-based anti-cancer medications include metallodrugs based on ruthenium, gold, copper, iridium, and osmium, which showed effectiveness against many cancer cell lines. These metal-based medicines represent an exciting new category of potential cancer treatments and sparked a renewed interest in the search for effective anti-cancer therapies. Despite the widespread development of metal complexes touted as powerful and promising in vitro anti-cancer therapeutics, only a small percentage of these compounds have shown their worth in vivo models. Metallodrugs, which are more effective and less toxic than platinum-based drugs and can treat drug-resistant cancer cells, are the focus of this review. Here, we highlighted some of the most recently developed Pt, Ru, Au, Cu, Ir, and Os complexes that have shown significant in vivo antitumor properties between 2017 and 2023.

Employing virtual screening and molecular dynamics simulations for identifying hits against the active cholera toxin.

Cholera is a major global threat, affecting millions each year. The ADP ribosyltransferase activity of the active cholera toxin catalyses the massive loss of water and electrolytes during cholera infections. The active toxin heterodimer comprises the A1 subunit from Vibrio cholerae and ARF (ADP Ribosylation Factor) from the human host. Although the active toxin is a potential target for drug discovery against cholera, it has been scarcely targeted to date. The A1-ARF interface contains a potential druggable site for small molecule inhibitors. By combining a sequential docking and scoring strategy with molecular dynamics (MD) simulations, this study identified hits against the protein-protein interface (PPI) of the active cholera toxin from an in-house library of 9,175 ADMET-screened alkaloids. The docking algorithms and scoring functions of Glide SP, Glide XP, and AutoDock were employed for initial library screening. Three alkaloids were initially selected by docking-based virtual screening. The stability of the hit-toxin complexes was validated by MD simulations. Two of the three hits, namely, A6225 (7-formyldehydrothalicsimidine) and A16503 (1,2,7,8-tetrahydroxy dibenz[cd,f]indol-4(5H)-one), formed stable complexes with the toxin. Analyses of the hydrogen bond occupancies revealed that the hits formed stable hydrogen bonds with the toxin PPI. The hits identified herein can serve as reference compounds for drug discovery against cholera in the future.

Prediction and characterisation of lantibiotic structures with molecular modelling and molecular dynamics simulations.

Lantibiotics are lanthionine-containing bactericidal peptides produced by gram-positive bacteria as a defence mechanism against other bacterial species. Lantipeptides disrupt the integrity of target cells by forming pores in their cell membranes, or by preventing cell wall biosynthesis, which subsequently results in cell death. Lantibiotics are of immense importance to the food preservation and pharmaceutical industries. The rise in multidrug resistance demands the discovery of novel antimicrobials, and several authors advocate that lantibiotics hold the future of antimicrobial drug discovery. Owing to their amenability to structural modifications, novel lantibiotics with higher efficacy and antimicrobial activity can be constructed by bioengineering and nanoengineering strategies, and is opined to have immense therapeutic success in combating the rise in multidrug resistance. Understanding the structure and dynamics of lantibiotics is therefore crucial for the development of novel lantipeptides, and this study aimed to study the structural properties and dynamics of 37 lantibiotics using computational strategies. The structures of these 37 lantibiotics were constructed from homology, and their structural stability and compactness were analysed by molecular dynamics simulations. The phylogenetic relationships, physicochemical properties, disordered regions, pockets, intramolecular bonds and interactions, and structural diversity of the 37 lantipeptides were studied. The structures of the 37 lantipeptides constructed herein remained stable throughout simulation. The study revealed that the structural diversity of lantibiotics is not significantly correlated to sequence diversity, and this property could be exploited for designing novel lantipeptides with higher efficacy.

Targeting the dengue ß-OG with serotype-specific alkaloid virtual leads.

The dengue envelope ß-OG pocket is a crucial hinge for mediating virus-host fusion via conformational changes in the envelope to the fusion-competent form. The ß-OG pocket is a small molecule target site for inhibition of virus-host fusion. As of date, the only structure of the ß-OG pocket known is of serotype 2. Studies of ß-OG inhibition by small molecules primarily target viral serotype 2. Envelope and ß-OG sequence alignments, reveal dissimilarities across serotypes. In light of protein sequence-structure-function correlation, sequence variations suggest serotypic variations in ß-OG druggability. This, together with the fact that dengue viral proteins do have serotype-specific variations of structure and function, lead to the study of the serotype-specificity of the dengue ß-OG ligand binding behaviour. ß-OG druggability was compared using comparative models of envelope proteins containing the ß-OG pocket in four serotypes of the dengue virus. ß-OG ligand binding was found to vary with respect to hydrophobicity, hydrophilicity, hydrogen bonding, van der Waals interactions with ligands and tightness of the binding site. The study also reports serotype-specific virtual leads identified from a library of 9175 alkaloids, using a consensus docking and scoring approach. The docking algorithms of Glide SP and XP, together with the Lamarckian genetic algorithm were employed for consensus docking. For consensus scoring, the Glide empirical score was employed along with the scoring function of AutoDock. A multi-dimensional lead optimisation approach was performed for optimising affinity, ligand efficiency, lipophilic ligand efficiency, ADMET and molecular torsional strains. The study proposes the serotype-specific inhibition of the ß-OG for an effective inhibition of virus-host fusion, in contrast to a pan inhibitor.

Identification of inhibitors against the potential ligandable sites in the active cholera toxin.

The active cholera toxin responsible for the massive loss of water and ions in cholera patients via its ADP ribosylation activity is a heterodimer of the A1 subunit of the bacterial holotoxin and the human cytosolic ARF6 (ADP Ribosylation Factor 6). The active toxin is a potential target for the design of inhibitors against cholera. In this study we identified the potential ligandable sites of the active cholera toxin which can serve as binding sites for drug-like molecules. By employing an energy-based approach to identify ligand binding sites, and comparison with the results of computational solvent mapping, we identified two potential ligandable sites in the active toxin which can be targeted during structure-based drug design against cholera. Based on the probe affinities of the identified ligandable regions, docking-based virtual screening was employed to identify probable inhibitors against these sites. Several indole-based alkaloids and phosphates showed strong interactions to the important residues of the ligandable region at the A1 active site. On the other hand, 26 top scoring hits were identified against the ligandable region at the A1 ARF6 interface which showed strong hydrogen bonding interactions, including guanidines, phosphates, Leucopterin and Aristolochic acid VIa. This study has important implications in the application of hybrid structure-based and ligand-based methods against the identified ligandable sites using the identified inhibitors as reference ligands, for drug design against the active cholera toxin.

Isolation and characterisation of methanol-soluble fraction of Alternanthera philoxeroides (Mart.) - evaluation of their antioxidant, α-glucosidase inhibitory and antimicrobial activity in in vitro systems.

Alternanthera philoxeroides (Mart.) is a tropical weed commonly known as alligator weed. It grows rapidly within a small span of time and easily available all over the world. The objective of this work was to isolate and characterise the major phenolic components present in the methanol-soluble fraction (fraction X) of A. philoxeroides leaves and to explore the biological activity (antioxidant, α-glucosidase inhibition and antimicrobial) of the fraction in in vitro system. Chromatographic (HPLC) and spectroscopic (MALDI-TOF, ¹H NMR) techniques were used to purify and characterise the phenolics present in fraction X. Five major phenolics (kaempferol, ferulic acid, salicylic acid, syringic acid and chlorogenic acid) were found in fraction X. The fraction showed anti-oxidant property, dose-dependent inhibition of α-glucosidase activity and anti-microbial activity. Hence fraction X from the weed has therapeutic potential in pathophysiological condition.

Huge congenital teratoma containing tooth in a three-day-old neonate.

Congenital teratoma is a rare cause of congenital proptosis. A full term three-day-old male child was presented with massive unilateral swelling in the left orbit, which was noted since birth. Diagnosis of orbital teratoma without intracranial extension was made based on clinical examination and imaging. Lid-sparing exenteration of the left orbit was done. Histopathological examination confirmed the diagnosis of cystic teratoma. Congenital orbital teratoma with a tooth and mature elements of all the three germ cell layers is reported due to its extreme rarity.

A case of atypical cleft hand - reported with ontogenetic review.

An asymptomatic atypical U shaped cleft hand has been found in a 21-year-old lady attending OPD. On digital skiagram it was found that central digits were absent with remnants of bases of the metacarpals, which have fused with the carpal bones. Moreover, the scaphoid and trapezium had fused to form a single mass. There was no other anomaly in other limbs, so far searched for. An endeavor has been made to explain the anomaly with ontogenetic review.

Antagomirbase- a putative antagomir database.

UNLABELLED: The accurate prediction of a comprehensive set of messenger putative antagomirs against microRNAs (miRNAs) remains an open problem. In particular, a set of putative antagomirs against human miRNA is predicted in this current version of database. We have developed Antagomir database, based on putative antagomirs-miRNA heterodimers. In this work, the human miRNA dataset was used as template to design putative antagomirs, using GC content and secondary structures as parameters. The algorithm used predicted the free energy of unbound antagomirs. Although in its infancy the development of antagomirs, that can target cell specific genes or families of genes, may pave the way forward for the generation of a new class of therapeutics, to treat complex inflammatory diseases. Future versions need to incorporate further sequences from other mammalian homologues for designing of antagomirs for aid in research. AVAILABILITY: The database is available for free at http://bioinfopresidencycollegekolkata.edu.in/antagomirs.html.

Rhinosporidiosis of lacrimal sac: a rare case report from North East India.

Rhinosporidiosis usually affects the mucous membrane of nose and conjunctiva, less frequently lacrimal sac, urethra, and skin. This is a case presentation of rare lacrimal sac rhinosporidiosis for the first time reported from the state of Tripura in North East India. Diagnosis of rhinosporidiosis is usually made by routine histological examination and treatment is surgical excision. It needs follow up as recurrence is common.

Hydatid cyst of liver: a case with an unusual clinical presentation.

Hydatid cyst caused by the parasite Echinococcus most commonly involve liver and usually presented with right hypochondrial pain which may be associated with jaundice, urticarial skin rashes, pruritus etc., We report here a case of 32 years old young lady who clinically presented with acute exacerbation of bronchial asthma of recent onset. Her chest x-ray was unremarkable except slightly pushed up diaphragm on right side. Ultrasonography of abdomen revealed a cyst in the right lobe of liver, suggestive of hydatid cyst. Following confirmation of diagnosis by computed tomography (CT)-guided Fine Needle Aspiration Cytology (FNAC) surgical resection of the cystic lesion was done. On subsequent follow up for one year she was found to be cured of bronchial asthma. This case of hepatic hydatid cyst is reported here for its unique clinical presentation exclusively with bronchial asthma which completely subsided with resection of the cyst.

Lysine richness in human snurps - possible sites for electrophilic attacks.

Gene-expression strategies are remodeled following exposure to stress. The reactive oxidants and electrophiles generated after stress actually affects the structural and functional properties of different cellular proteins. It is also seen that lysine rich motifs of proteins play crucial role in electrophilic attack and modification. Therefore, this study revealing lysine richness in 5 main human snrups (Small Nuclear Ribonucleoproteins) indicates a possible mechanism of gene regulation under stress. This possibility is highly supported by the findings that surface residues of the molecules were full of lysine rich clusters. Lysine richness is also found to be a highly conserved pattern across the various domains of life indicative of stress adaptation in the prebiotic to biotic world transition. Moreover the modeled structures showed good all atom contacts and minimal outliers.

In silico screening of herbal and nanoparticle lead compounds for effectivity against H5N1, H1N1 neuraminidase and telomerase.

BACKGROUND: Traditionally, drugs were discovered by testing compounds synthesized in time consuming multi-step processes against a battery of in vivo biological screens. Promising compounds were then further studied in development, where their pharmacokinetic properties, metabolism and potential toxicity were investigated. METHODS: Here we present a study on the most talked about herbal lead compounds and their potential binding affinity to the effector molecules of major disease causing agents, H5N1 and H1N1(Neuraminidase). The work also encompasses the screening of the nanoparticle compound - fullerene which have been reported to have anti HIV activity. Further studies were also performed with telomerase which has been the target of numerous anti cancer experiments. RESULTS: The results revealed that most herbal lead compounds were effective targets against H5N1 neuraminidase, namely baicalein was found to be an effective target for inhibiting the neuraminidase of H1N1 virus. Telomerase was found to be effectively bound by curcumin at the RNA binding interface. The study with nanoparticle fullerene also showed that it has the potential of serving as an effective ligand for inhibiting H1N1 neuraminidase and telomerase. CONCLUSION: Our data demonstrate that the new in silico screening method is highly efficient for identifying potential lead compounds against major infectious disease.

Targeting pseudoknots in H5N1 hemagglutinin using designed aptamers.

Influenza A virus subtype H5N1 is highly contagious among birds, causing high mortality among domestic poultry. The viral genome is contained on eight single RNA strands of which HA encode the antigenic glycoprotein called hemagglutinin. Hemagglutinin found on the surface of the influenza viruses and is responsible for binding the virus to the cell that is being infected. Among the most prevalent RNA structures the pseudoknot motif represents an important piece of RNA architecture, as it provides a means for a single RNA strand to fold upon itself to produce a globular structure capable of performing important biological functions. In this analysis we have identified the pseudoknot motifs in the hemagglutinin gene of HPAI A (H5N1) Asian strains. Specific aptamers have been designed against these pseudoknots. These in-silico aptamers can be used to hinder the ability of pseudoknots to facilitate ribosomal frameshifting. This may ultimately lead to reduce the coding efficiency of the HA that encodes hemagglutinin and might be used as molecular medicine for H5N1.

Direct enzymatic assay for %HbA1c in human whole blood samples.

OBJECTIVES: Development and validation of a direct enzymatic HbA1c assay that utilizes a single channel on chemistry auto-analyzers without the need to run separate glycated hemoglobin and total hemoglobin assays. DESIGN AND METHODS: An enzyme based single channel assay was developed to measure %HbA1c in human whole blood samples. The performance characteristics of the Diazyme Direct Enzymatic HbA1c Assay were evaluated on the Hitachi 917 auto-analyzer using whole blood samples, appropriate controls and a reference lot of manufactured reagents. Accuracy studies were completed by comparing the Direct Enzymatic Assay to existing HPLC and immunoassay methods. Interference testing was performed to determine the effect of total hemoglobin, glycated serum proteins, chemical substances and hemoglobin variants in patient samples. RESULTS: The Direct Enzymatic HbA1c Assay showed within run precision and total precision results of < or = 2% CV for both normal and abnormal level samples. Method comparison studies showed that there was a good correlation between the Direct Enzymatic HbA1c and the HPLC (R(2)=0.98) or the immunoassay (R(2)=0.97) methods. The assay measured within the range of 4-16% HbA1c and showed excellent performance with variant hemoglobin in samples. CONCLUSIONS: Diazyme Direct Enzymatic HbA1c Assay is accurate and precise when compared to currently marketed medical devices. The assay is designed to report %HbA1c values directly without need for a separate measurement of total hemoglobin and is not adversely affected by interferences from common hemoglobin variants in samples. It is a cost effective, user-friendly method and is adaptable to most general chemistry analyzers.

Recurrent intracranial hemorrhage in brain tumor.

There are only a few causes of recurrent intracranial hemorrhage among which a brain tumor like glioblastoma multiforme is one. Glioblastoma multiforme in children under 14 years of age is relatively uncommon than adults. We report a case of unusual presentation of glioblastoma multiforme with recurrent intratumoral bleed with hemiparesis with symptoms free period in between.

Unilateral loss of vision following snakebite.

A 14- year-old boy presented at the outpatients' department with the complaint of visual loss in the right eye of 1 1/2 months duration. He had the history of snakebite for which he was admitted to hospital. The diminution of vision started next day after snakebite. On examination, he had no perception of light in his right eye. USG B scan showed vitreous haemorrhage in his right eye. He was given IV methylpredinisolone. At follow-up after one month he still had no perception of light in his right eye with the haemorrhage in the vitreous subsided.