Nanotheranostics: A Cutting-Edge Technology for Cancer Management.

Cancer is the second-leading cause of death in the 21st century, where early detection and appropriate therapeutic interventions are two components essential for effective cancer management. Despite the availability of several conventional diagnostics and therapeutic agents, cancer mortality rates are rising due to an increase in the frequency of recurrence and metastasis in cancer patients. Therefore, tremendous efforts have been expended to address this significant clinical issue and improve therapeutic efficacy. In this regard, nanotheranostic is a multipotential single platform for both cancer diagnosis and treatment through enhanced aqueous solubility and bioavailability of the encapsulated agent, stimulus responsiveness, tumor-specific targeting ability, precise tumor imaging, and real-time drug delivery. Nonetheless, the translational success of nanotheranostic platforms is still in its infancy and requires more extensive research in the context of tumor heterogeneity, safety profile, and regulatory issues, which pose one of the largest technological limitations. The present review summarizes different nanotheranostic platforms and nanotheranostic candidates in clinical trials (AGuIX® , NBTXR3, Ferumoxtran, MM-398, EndoTAG-1, etc.), along with disadvantages and challenges to improving cancer diagnosis and treatment. Overall, the concept, platform, and technical knowledge of nanotheranostics are really helpful to academic and pharmaceutical researchers.

Synthesis, spectroscopic analysis, and computational-based investigations on 'azo-coumarin-Co(II)-galangin' hybrids exhibit multipotential activities.

The present study synthesized a series of cobalt (II) metal ion frame hybrid candidates (6a-6f) bearing phyto-flavonol galangin with substituted aryl diazenyl coumarins, and further structural confirmation was validated by various spectral techniques, including NMR, ATR-FTIR, UV-vis, HPLC, XRD, etc. Therapeutic potency was investigated via PASS (prediction of activity spectra for substances), molecular docking, molecular dynamics simulation, prediction of toxicity, pharmacokinetics, and drug-likeness scores, along with the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), with their energy gaps (ΔEH-L) to locate the most potential therapeutic candidates. The PASS prediction (Pa > Pi score) showed that proposed metal complexes have kinase inhibitors, antioxidative, and antischistosomal activities with potential molecular docking scores (> -7 kcal/mol) against selected targeted enzymes. Further, the MD-simulation (RMSD, RMSF, Rg, and H-bonds) of the most potential docking complex, 'HER2-6d', showed a minimum deviation similar to the standard drug (lapatinib) at 100 ns, indicating that 6d could be a potential noncovalent anticancer inhibitor. In addition, metal complexes possess a non-toxic and ideal drug-ability profiles, and positive electron space in an excited state increases the binding affinity towards target enzymes. Among all six ligands, 6c and 6d were the two most multipotent therapeutic agents from the above analyses. In summary, this could be a feasible approach towards the utilization of phytochemicals in mainstream therapeutic applications, where bioinformatics tools help to select a lead drug candidate at an early stage and guide for higher experimental success by proceeding with potential candidates.Communicated by Ramaswamy H. Sarma.

Phytochemical-Based Nanomedicine for Targeting Tumor Microenvironment and Inhibiting Cancer Chemoresistance: Recent Advances and Pharmacological Insights.

Cancer remains the leading cause of death and rapidly evolving disease worldwide. The understanding of disease pathophysiology has improved through advanced research investigation, and several therapeutic strategies are being used for better cancer treatment. However, the increase in cancer relapse and metastatic-related deaths indicate that available therapies and clinically approved chemotherapy drugs are not sufficient to combat cancer. Further, the constant crosstalk between tumor cells and the tumor microenvironment (TME) is crucial for the development, progression, metastasis, and therapeutic response to tumors. In this regard, phytochemicals with multimodal targeting abilities can be used as an alternative to current cancer therapy by inhibiting cancer survival pathways or modulating TME. However, due to their poor pharmacokinetics and low bioavailability, the success of phytochemicals in clinical trials is limited. Therefore, developing phytochemical-based nanomedicine or phytonanomedicine can improve the pharmacokinetic profile of these phytochemicals. Herein, the molecular characteristics and pharmacological insights of the proposed phytonanomedicine in cancer therapy targeting tumor tissue and altering the characteristics of cancer stem cells, chemoresistance, TME, and cancer immunity are well discussed. Further, we have highlighted the clinical perspective and challenges of phytonanomedicine in filling the gap in potential cancer therapeutics using various nanoplatforms. Overall, we have discussed how clinical success and pharmacological insights could make it more beneficial to boost the concept of nanomedicine in the academic and pharmaceutical fields to counter cancer metastases and drug resistance.

Bentonite-in hypromellose-poloxamer sol-gel for corneal application of trimetazidine: Study of rheology and ocular anti inflammatory potential.

Bentonite is reported to be used for extending ocular drug delivery safely in a controlled manner. Bentonite combined hydroxypropyl methylcellulose (HPMC)-poloxamer based sol-to-gel formulation has been developed for the prophylactic ocular anti-inflammatory effect of trimetazidine after corneal application. HPMC-poloxamer sol formulation was prepared incorporating trimetazidine to bentonite at 1: 2*10-5 to 1:5*10-6 ratios using cold method, and investigations were carried out in carrageenan-induced rabbit eye model. Pseudoplastic shear thinning behavior without any yield value and high viscosity at low shear rate were the positive attribute of the tolerability of the sol formulation after ocular instillation. Presence of bentonite nanoplatelets revealed more sustained in vitro release (~79-97 %) and corneal permeation (~79-83 %) over a period of 6 h in comparison to its absence. Prominent acute inflammation has been produced in the carrageenan-induced untreated eye, whereas the absence of ocular inflammation has been noticed in the previously sol-treated eye even after carrageenan injection. HPMC-poloxamer-based formulation exhibited stronger binding affinity (5.13 kcal/mol) in the presence of bentonite rather than its absence (3.99 kcal/mol), resulting in a stable and sustained effect. HPMC-poloxamer in-situ gel of trimetazidine containing bentonite could be utilized for sustained ocular delivery and the control of ophthalmic inflammation prophylactically.

Recent advances to combat ESKAPE pathogens with special reference to essential oils.

Biofilm-associated bacteria, especially ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), are a serious challenge worldwide. Due to the lack of discovery of novel antibiotics, in the past two decades, it has become necessary to search for new antibiotics or to study synergy with the existing antibiotics so as to counter life-threatening infections. Nature-derived compounds/based products are more efficient than the chemically synthesized ones with less resistance and lower side effects. In this descriptive review, we discuss the most promising therapeutics for the treatment of ESKAPE-related biofilms. The first aspect includes different types of natural agents [botanical drugs, essential oils (EOs), antimicrobial peptides, bacteriophages, and endolysins] effective against ESKAPE pathogens. The second part of the review deals with special references to EOs/essential oil components (EOCs) (with some exclusive examples), mode of action (via interfering in the quorum-sensing pathways, disruption of biofilm and their inhibitory concentrations, expression of genes that are involved, other virulence factors), existing in literature so far. Moreover, different essential oils and their major constituents were critically discussed using in vivo models to target ESKAPE pathogens along with the studies involving existing antibiotics.

Andrographolide induces anti-SARS-CoV-2 response through host-directed mechanism: an in silico study.

Aim: Considering the present alarming situation of COVID-19 pandemic, we concentrated on evaluating the efficacy of a novel natural antiviral drug-candidate andrographolide against SARS-CoV-2 through an in silico model of study. Materials & methods: Interaction of andrographolide against the major host molecules that are responsible for SARS-CoV-2 pathogenesis were determined using bio-computational tools, in other words, molecular docking, molecular dynamics simulation and pharmacodynamics-pharmacokinetics analysis. Result: Computational findings represent that andrographolide efficiently interacts with the major human-host-associated putative drug-targets of viral-entry points like furin (-10.54 kcal/mol), TMPRSS-2 (-9.50 kcal/mol), ACE2 (-8.99 kcal/mol) and Cathepsin L (-8.98 kcal/mol). Moreover, it also blocks the inflammatory regulators including TLR4-MD2 and IL-6, which promote virus-induced inflammation leading to cytokine storm in the host body. Conclusion: This work elucidates that, the candidature of andrographolide can be utilized as a potent natural agent for the therapeutic intervention of SARS-CoV-2 through host-directed treatment.

Disease Burden and Current Therapeutical Status of Leprosy with Special Emphasis on Phytochemicals.

BACKGROUND: Leprosy (Hansen's disease) is a neglected tropical disease affecting millions of people globally. The combined formulations of dapsone, rifampicin and clofazimine (multidrug therapy, MDT) is only supportive in the early stage of detection, while "reemergence" is a significant problem. Thus, there is still a need to develop newer antileprosy molecules either of natural or semi-synthetic origin. OBJECTIVES: The review intends to present the latest developments in the disease prevalence, available therapeutic interventions and the possibility of identifying new molecules from phytoextracts. METHODS: Literature on the use of plant extracts and their active components to treat leprosy was searched. Selected phytoconstituents were subjected to molecular docking study on both wild and mutant types of the Mycobacterium leprae. Since the M. leprae dihydropteroate synthase (DHPS) is not available in the protein data bank (PDB), it was modelled by the homology model method and validated with the Ramachandran plot along with other bioinformatics approaches. Two mutations were introduced at codons 53 (Thr to Ile) and 55 (Pro to Leu) for docking against twenty-five selected phytoconstituents reported from eight plants that recorded effective anti-leprosy activity. The chemical structure of phytochemicals and the standard dapsone structure were retrieved from the PubChem database and prepared accordingly for docking study with the virtual-screening platform of PyRx-AutoDock 4.1. RESULTS: Based on the docking score (kcal/mol), most of the phytochemicals exhibited a higher docking score than dapsone. Asiaticoside, an active saponin (-11.3, -11.2 and -11.2 kcal/mol), was proved to be the lead phytochemical against both wild and mutant types DHPS. Some other useful phytoconstituents include echinocystic acid (-9.6, -9.5 and -9.5 kcal/mol), neobavaisoflavone (-9.2, -9.0 and -9.0 kcal/mol), boswellic acid (-8.90, -8.90 and -8.90 kcal/mol), asiatic acid (-8.9, -8.8 and -8.9 kcal/mol), corylifol A (-8.8, 8.0, and -8.0), etc. Overall, the computational predictions support the previously reported active phytoextracts of Centella asiatica (L.) Urban, Albizia amara (Roxb.) Boivin, Boswellia serrata Roxb. and Psoralea corylifolia L. to be effective against leprosy. CONCLUSION: A very small percentage of well-known plants have been evaluated scientifically for antileprosy activity. Further in vivo experiments are essential to confirm anti-leprosy properties of such useful phytochemicals.

Antimicrobial Peptides Derived From Insects Offer a Novel Therapeutic Option to Combat Biofilm: A Review.

Biofilms form a complex layer with defined structures, that attach on biotic or abiotic surfaces, are tough to eradicate and tend to cause some resistance against most antibiotics. Several studies confirmed that biofilm-producing bacteria exhibit higher resistance compared to the planktonic form of the same species. Antibiotic resistance factors are well understood in planktonic bacteria which is not so in case of biofilm producing forms. This may be due to the lack of available drugs with known resistance mechanisms for biofilms. Existing antibiotics cannot eradicate most biofilms, especially of ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). Insects produce complex and diverse set of chemicals for survival and defense. Antimicrobial peptides (AMPs), produced by most insects, generally have a broad spectrum of activity and the potential to bypass the resistance mechanisms of classical antibiotics. Besides, AMPs may well act synergistically with classical antibiotics for a double-pronged attack on infections. Thus, AMPs could be promising alternatives to overcome medically important biofilms, decrease the possibility of acquired resistance and treatment of multidrug-resistant pathogens including ESKAPE. The present review focuses on insect-derived AMPs with special reference to anti-biofilm-based strategies. It covers the AMP composition, pathways and mechanisms of action, the formation of biofilms, impact of biofilms on human diseases, current strategies as well as therapeutic options to combat biofilm with antimicrobial peptides from insects. In addition, the review also illustrates the importance of bioinformatics tools and molecular docking studies to boost the importance of select bioactive peptides those can be developed as drugs, as well as suggestions for further basic and clinical research.

Phytochemicals against SARS-CoV as potential drug leads.

The newly emerged SARS-CoV-2 strains from the coronavirus (CoV) family is causing one of the most disruptive pandemics of the past century. Developing antiviral drugs is a challenge for the scientific community and pharmaceutical industry. Given the health emergency, repurposing of existing antiviral, antiinflammatory or antimalarial drugs is an attractive option for controlling SARS-CoV-2 with drugs. However, phytochemicals selected based on ethnomedicinal information as well as in vitro antiviral studies could be promising as well. Here, we summarise the phytochemicals with reported anti-CoV activity, and further analyzed them computationally to accelerate validation for drug development against SARS-CoV-2. This systematic review started from the most potent phytocompounds (IC50 in µM) against SARS-CoV, followed by a cluster analysis to locate the most suitable lead(s). The advanced molecular docking used the crystallography structure of SARS-CoV-2-cysteine-like protease (SARS-CoV-2-3CLpro) as a target. In total, seventy-eight phytochemicals with anti-CoV activity against different strains in cellular assays, were selected for this computational study, and compared with two existing repurposed FDA-approved drugs: lopinavir and ritonavir. This review brings insights in the potential application of phytochemicals and their derivatives, which could guide researchers to develop safe drugs against SARS-CoV-2.

Eosinophil: a central player in modulating pathological complexity in asthma

Eosinophils are the major inflammatory cells which play a crucial role in the development of allergic and non-allergic asthma phenotypes. Eosinophilic asthma is the most heterogeneous phenotype where activated eosinophils are reported to be significantly associated with asthma severity. Activated eosinophils display an array of cell adhesion molecules that not only act as an activation marker, suitable for assessing severity, but also secrete several tissue factors, cytokines and chemokines which modulate the clinical severity. Eosinophil activations are also strictly associated with activation of other hetero cellular populations like neutrophils, macrophages, mast cells, and platelets which culminate in the onset and progression of abnormal phenotypes such as bronchoconstriction, allergic response, fibrosis instigated by tissue inflammation, epithelial injury, and oxidative stress. During the activated state, eosinophils release several potent toxic signaling molecules such as major basic proteins, eosinophil peroxidase, eosinophil cationic protein (ECP), and lipid mediators, rendering tissue damage and subsequently leading to allergic manifestation. The tissue mediators render a more complex manifestation of a severe phenotype by activating prominent signaling cross-talk. Here, in the current review with the help of search engines of PubMed, Medline, etc, we have tried to shed light and explore some of the potent determinants regulating eosinophil activation leading to asthma phenotype (AU)

Eosinophil: a central player in modulating pathological complexity in asthma.

Eosinophils are the major inflammatory cells which play a crucial role in the development of allergic and non-allergic asthma phenotypes. Eosinophilic asthma is the most heterogeneous phenotype where activated eosinophils are reported to be significantly associated with asthma severity. Activated eosinophils display an array of cell adhesion molecules that not only act as an activation marker, suitable for assessing severity, but also secrete several tissue factors, cytokines and chemokines which modulate the clinical severity. Eosinophil activations are also strictly associated with activation of other hetero cellular populations like neutrophils, macrophages, mast cells, and platelets which culminate in the onset and progression of abnormal phenotypes such as bronchoconstriction, allergic response, fibrosis instigated by tissue inflammation, epithelial injury, and oxidative stress. During the activated state, eosinophils release several potent toxic signaling molecules such as major basic proteins, eosinophil peroxidase, eosinophil cationic protein (ECP), and lipid mediators, rendering tissue damage and subsequently leading to allergic manifestation. The tissue mediators render a more complex manifestation of a severe phenotype by activating prominent signaling cross-talk. Here, in the current review with the help of search engines of PubMed, Medline, etc, we have tried to shed light and explore some of the potent determinants regulating eosinophil activation leading to asthma phenotype.

Metabolic Diversity and Therapeutic Potential of Holarrhena pubescens: An Important Ethnomedicinal Plant.

Holarrhena pubescens is an important medicinal plant of the Apocynaceae family that is widely distributed over the Indian subcontinent. The plant is extensively used in Ayurveda and other traditional medicinal systems without obvious adverse effects. Beside notable progress in the biological and phytochemical evaluation of this plant over the past few years, comprehensive reviews of H. pubescens are limited in scope. It has economic importance due to the extensive use of seeds as an antidiabetic. Furthermore, the plant is extensively reported in traditional uses among the natives of Asia and Africa, while scientifical validation for various ailments has not been studied either in vitro or in vivo. This review aims to summarize information on the pharmacology, traditional uses, active constituents, safety and toxicity of H. pubescens. Chemical analysis of H. pubescens extracts revealed the presence of several bioactive compounds, such as conessine, isoconnessine, conessimine, conimine, conessidine, conkurchicine, holarrhimine, conarrhimine, mokluangin A-D and antidysentericine. Overall, this review covers the ethnopharmacology, phytochemical composition, and pharmacological potential of H. pubescens, with a critical discussion of its toxicity, biological activities (in vitro and in vivo), the mechanism of action, as well as suggestions for further basic and clinical research.