Mitochondrial targeting theranostic nanomedicine and molecular biomarkers for efficient cancer diagnosis and therapy.

Mitochondria play a crucial part in the cell's ability to adapt to the changing microenvironments and their dysfunction is associated with an extensive array of illnesses, including cancer. Mitochondrial dysfunction has been identified as a potential therapeutic target for cancer therapy. The objective of this article is to give an in-depth analysis of cancer treatment that targets the mitochondrial genome at the molecular level. Recent studies provide insights into nanomedicine techniques and theranostic nanomedicine for mitochondrial targeting. It also provides conceptual information on mitochondrial biomarkers for cancer treatment. Major drawbacks and challenges involved in mitochondrial targeting for advanced cancer therapy have also been discussed. There is a lot of evidence and reason to support using nanomedicine to focus on mitochondrial function. The development of a delivery system with increased selectivity and effectiveness is a prerequisite for a theranostic approach to cancer treatment. If given in large amounts, several new cancer-fighting medicines have been created that are toxic to healthy cells as well. For effective therapy, a new drug must be developed rather than an old one. When it comes to mitochondrial targeting therapy, theranostic techniques offer valuable insight

Integrating network pharmacology with molecular docking to rationalize the ethnomedicinal use of Alchornea laxiflora (Benth.) Pax & K. Hoffm. for efficient treatment of depression

Background: Alchornea laxiflora (Benth.) Pax & K. Hoffm. (A. laxiflora) has been indicated in traditional medicine to treat depression. However, scientific rationalization is still lacking. Hence, this study aimed to investigate the antidepressant potential of A. laxiflora using network pharmacology and molecular docking analysis.Materials and methods: The active compounds and potential targets of A. laxiflora and depression-related targets were retrieved from public databases, such as PubMed, PubChem, DisGeNET, GeneCards, OMIM, SwissTargetprediction, BindingDB, STRING, and DAVID. Essential bioactive compounds, potential targets, and signaling pathways were predicted using in silico analysis, including BA-TAR, PPI, BA-TAR-PATH network construction, and GO and KEGG pathway enrichment analysis. Later on, with molecular docking analysis, the interaction of essential bioactive compounds of A. laxiflora and predicted core targets of depression were verified.Results: The network pharmacology approach identified 15 active compounds, a total of 219 compound-related targets, and 14,574 depression-related targets with 200 intersecting targets between them. SRC, EGFR, PIK3R1, AKT1, and MAPK1 were the core targets, whereas 3-acetyloleanolic acid and 3-acetylursolic acid were the most active compounds of A. laxiflora with anti-depressant potential. GO functional enrichment analysis revealed 129 GO terms, including 82 biological processes, 14 cellular components, and 34 molecular function terms. KEGG pathway enrichment analysis yielded significantly enriched 108 signaling pathways. Out of them, PI3K-Akt and MAPK signaling pathways might have a key role in treating depression. Molecular docking analysis results exhibited that core targets of depression, such as SRC, EGFR, PIK3R1, AKT1, and MAPK1, bind stably with the analyzed bioactive compounds of A. laxiflora.Conclusion: The present study elucidates the bioactive compounds, potential targets, and pertinent mechanism of action of A. laxiflora in treating depression. A. laxiflora might exert an antidepressant effect by regulating PI3K-Akt and MAPK signaling pathways. However, further investigations are required to validate

Modern Approaches in the Discovery and Development of Plant-Based Natural Products and Their Analogues as Potential Therapeutic Agents

Natural products represents an important source of new lead compounds in drug discovery research. Several drugs currently used as therapeutic agents have been developed from natural sources; plant sources are specifically important. In the past few decades, pharmaceutical companies demonstrated insignificant attention towards natural product drug discovery, mainly due to its intrinsic complexity. Recently, technological advancements greatly helped to address the challenges and resulted in the revived scientific interest in drug discovery from natural sources. This review provides a comprehensive overview of various approaches used in the selection, authentication, extraction/isolation, biological screening, and analogue development through the application of modern drug-development principles of plant-based natural products. Main focus is given to the bioactivity-guided fractionation approach along with associated challenges and major advancements. A brief outline of historical development in natural product drug discovery and a snapshot of the prominent natural drugs developed in the last few decades are also presented. The researcher’s opinions indicated that an integrated interdisciplinary approach utilizing technological advances is necessary for the successful development of natural products. These involve the application of efficient selection method, well-designed extraction/isolation procedure, advanced structure elucidation techniques, and bioassays with a high-throughput capacity to establish druggability and patentability of phyto-compounds. A number of modern approaches including molecular modeling, virtual screening, natural product library, and database mining are being used for improving natural product drug discovery research. Renewed scientific interest and recent research trends in natural product drug discovery clearly indicated that natural products will play important role in the future development of new therapeutic drugs and it is also anticipated that efficient application of new approaches will further improve the drug discovery campaign

Design, Synthesis, and Evaluation of GUNW-3 as a Brain Targeting Agent

The blood brain barrier (BBB) is a barrier in the brain that separates the peripheral blood circulation system from the central nerve system (CNS). The barrier effectively protects the brain from xenobiotics. The BBB serves as a physical barrier through the tight junction of endothelial cells that were found to be 50-100 times tighter than that of normal endothelial cells. Different drug efflux pumps such as P-glycoproteins and multidrug-resistance proteins are found to be overdistributed on the BBB. These drug efflux pumps help pump xenobiotics out if they enter the cells and serv as an additional mechanism to prevent xenobiotics from entering the CNS. The tight junction, drug efflux pumps, and other features of the BBB prevent almost 98% of small molecules, such as most therapeutics, and almost all large molecules such as biologics, recombinant genes and proteins from entering the brain. The inability to reach the therapeutic concentration caused by the barrier is often the major cause of treatment failure for brain diseases. Although the BBB blocks foreign compounds from entering the CNS, endogenous compounds, such as glucose, amino acids, peptides, neurotransmitters, and glutathione (GSH), enter the CNS readily through their corresponding receptors or transporters present in the BBB. Some of these receptors or transporters have been targeted for facilitating therapeutics, diagnostics, and other compounds to cross the BBB to reach the CNS. GSH is an endogenous three amino acid peptide. It plays various roles in the body: as a major antioxidant, a compound that removes toxic compounds, and a compound involved in other cellular functions. GSH crosses the BBB through a Nadependent GSH transporter. Recently, GSH transporters have been found effective in facilitating crossing of compounds through the BBB to reach the CNS. To achieve GSH transporter-mediated BBB crossing, GSH has been linked to a therapeutic agent (GSHDrug) to form a prodrug. The prodrug crosses the BBB by binding the GSH part to a GSH transporter followed by internalization of the prodrug. GSH has also been linked to polyethylene glycol (PEG) which is connected to a phospholipid (P) to form GSH-PEG-P or polyethylene glycol connected to vitamin E to form GSH-PEG-E. GSH-PEG-P and GSH-PEG-E have been coated on the surface of liposomes (GSH-PEGylated liposomes) to facilitate crossing of the liposomes through the BBB using the mechanism of binding the GSH moiety to a GSH transporter followed by internalization of the liposomes through endocytosis or transcytosis. The GSH-PEGylated liposomes have been shown to safely enhance the delivery to the brain by approximately 3-folds. We have developed GUNW-3 as a GSH-transporter dependent brain targeting agent. GUNW-3 was designed by connecting a hydrophilic GSH molecule to a hydrophobic cholesterol molecule through a two ehthylene glycol unit linker with a hope that the GSH part can serve as a brain-targeting structure through binding to the GSH transporter and facilitate the entry into the brain. This dissertation describes the design, synthesis, and fully characterization of GUNW-3. The dissertation also describes the ability of GUNW-3 to form micelles by itself (GUNW-3 micelles), the ability of GUNW- 3 micelles to cross the BBB to reach the brain, and the ability of GUNW-3 micelles to carry a dye (DiR) to the brain. Further, the dissertation shows the ability of GUNW-3 helps guide liposomes to the brain by forming GUNW-3 liposomes and the ability of GUNW-3 liposomes to deliver a dye (DiR) to the brain. Below is a brief description of the findings in this dissertation. GUNW-3 was synthesized in 4 steps from cholesterol and other commercially available reagents. GUNW-3 was found to be relatively stable. A cytotoxicity study of GUNW-3 revealed IC50 values of 0.65 mM and 0.47 mM for CV-1 cells (monkey kidney cells) and NCI-H226 cells (human lung cancer cells) respectively. GUNW-3 was found to form micelles by itself with a CMC value of 3.9 μM. CMC is a critical micelle parameter to reflect the stability of micelles and is also a parameter to determine if the micelles are stable enough to be used for a clinical application. The CMC of micelles need to be in μM concentration so that the micelles are stable enough to remain as micelles once being diluted in the blood stream. The CMC in low μM (3.9 μM) of GUNW-3 suggests that GUNW-3 micelles can be used for a therapeutic application. Further, the CMC of GUNW-3 is much lower than the IC50 values of the molecule indicating that GUNW-3 is not cytotoxic. For brain targeting, our data with ex-vivo imaging of the brains shows that the brain uptake of DiR, a dye, delivered by GUNW-3 micelles were 5 times higher than that of the control liposome and 12 times higher than that of free DiR at the first hour. After 48 h, the brain uptake of DiR delivered by GUNW-3 micelles was 6.5 times higher than that of the control liposome and 14 times higher than that of free DiR. GUNW-3 was also found to help deliver liposomes to the brain most likely by embedding the hydrophobic cholesterol part into the liposome double lipid layer and the hydrophilic GSH part floating on the surface of the liposomes for brain targeting. Our data from ex-vivo imaging of the brains demonstrate that GUNW-3 liposomes were able to significantly (\u3e3 folds) improve the delivery of DiR to the brain and retain in the brain well when compared with the control liposomes. Liposomes and micelles are known effective drug carriers that can be used to deliver various drugs or compounds such as small molecule therapeutics, DNA, RNA, and proteins (e.g., antibodies). Liposomes and micelles can encapsulate drugs and protect them from in vivo/in vitro degradation. They can also help reduce drug clearance, increase in vivo drug half-life, enhance the drug payload, control drug release, and improve drug solubility. The abilities to deliver DiR to the brain by GUNW-3 micelles and GUNW-3 liposomes warrantee further investigation of these two brain targeting delivery systems for delivering compounds to the brain for brain disease treatment or prevention. In summary, we have synthesized and characterized the rationally designed GUNW-3 as a brain targeting agent. GUNW-3 micelles and GUNW-3 liposomes showed promising brain targeting abilities. GUNW-3 micelles and GUNW-3 liposomes will be promising delivery systems for therapeutic and diagnostic molecules

Modern Approaches in the Discovery and Development of Plant-Based Natural Products and Their Analogues as Potential Therapeutic Agents

Natural products represents an important source of new lead compounds in drug discovery research. Several drugs currently used as therapeutic agents have been developed from natural sources; plant sources are specifically important. In the past few decades, pharmaceutical companies demonstrated insignificant attention towards natural product drug discovery, mainly due to its intrinsic complexity. Recently, technological advancements greatly helped to address the challenges and resulted in the revived scientific interest in drug discovery from natural sources. This review provides a comprehensive overview of various approaches used in the selection, authentication, extraction/isolation, biological screening, and analogue development through the application of modern drug-development principles of plant-based natural products. Main focus is given to the bioactivity-guided fractionation approach along with associated challenges and major advancements. A brief outline of historical development in natural product drug discovery and a snapshot of the prominent natural drugs developed in the last few decades are also presented. The researcher’s opinions indicated that an integrated interdisciplinary approach utilizing technological advances is necessary for the successful development of natural products. These involve the application of efficient selection method, well-designed extraction/isolation procedure, advanced structure elucidation techniques, and bioassays with a high-throughput capacity to establish druggability and patentability of phyto-compounds. A number of modern approaches including molecular modeling, virtual screening, natural product library, and database mining are being used for improving natural product drug discovery research. Renewed scientific interest and recent research trends in natural product drug discovery clearly indicated that natural products will play important role in the future development of new therapeutic drugs and it is also anticipated that efficient application of new approaches will further improve the drug discovery campaign

Synthesis, characterization and biological activity of a Schiff base derived from o-amino benzoic acid and its Co(II), Cd(II) and Ni(II) complexes

Equimolar amounts of imidazoleacetophenone and 2-aminobenzoic acid were combined together and the Schiff base 4(1H-imidazole-yl)acetophenoneanthranilic acid was prepared as a new bidentate complexing agent. The synthesized ligand was reacted with cobalt(II), cadmium(II), and nickel(II) ions yielding air stable complexes. For quantification and characterization purposes, elemental analysis, infrared spectra, electronic spectra, proton nuclear magnetic resonance spectra and mass spectra studies were carried out on the obtained complexes and ligand. Thermogravimetric analysis and magnetic susceptibility measurements were also used for characterization. The ligand IR spectrum showed that the ligand acts as a bidentate coordinates to the metal ions through the nitrogen and oxygen atoms.Measurements of magnetic susceptibility for Ni(II) and Co(II) complexes were found to be 3.4 and 3.8 B.M., respectively, in the range normal for the octahedral geometry. The conductivity measurements revealed that the chelates are non-electrolytes. An in vitro antimicrobial investigation was also carried out for the free ligand and its metal complexes against a number of bacterial and fungal strains, to assess their antimicrobial properties by diffusion technique. Antimicrobial activity of the prepared complexes showed higher activity than the free ligand

Optimization of Chromatographic Conditions with QbD for Method Development and Validation of Bosutinib by HPLC: Applications in Dosage Forms and Rat Plasma Analysis

Aim: Bosutinib (BST) is an anti-cancer medicine that is used to treat a variety of different types of cancer. Using the HPLC method of analysis and the Quality by Design (QbD) strategy, the study aimed to precisely quantify the drug in tablet form and in rat plasma. Methodology: For the developed method’s validation, the chromatographic settings were fine-tuned by making use of the Box–Behnken Design (BBD). In the BBD, two dependent variables and three independent variables were selected. Isocratically, samples were eluted, having eluent phase composition of ammonium acetate (CH3COONH4) buffer pH 3.0 and acetonitrile (CH3CN) (60:40% v/v), in Raptor C-18 column at temperature 25 ∘C with a flow rate of 1 mL/min for 5 min. The wavelength of detection was set at 260 nm. In this study, encorafenib (ENC) was employed as an internal standard. Result: A sharp and resolved peak of BST and ENC at a retention time of 1.92 min and 4.01 min, respectively, was observed by the developed method. The limits of quantification and detection of the newly established method were found to be 1.503 μg/mL−1 and 0.496 μg/mL−1. The calibration curve’s observed linearity range was between 2 and 20 μg/mL−1, with an r2 of 0.999. The developed and optimized method was verified in compliance with the ICH guidelines. The results of all validation parameters were within the acceptable range, for example, % RSD of system suitability (0.63–4.46), % RSD of linear regression (1.659), interday and intraday precision % RSD value (1.723–1.892), and (1.762–1.923), respectively, and accuracy (1.476–1.982). Conclusion: The quantity of BST in tablet dosage form and in rat plasma samples was determined using a simple, quick, and robust method that was devised and validated

Expatiating the Pharmacological and Nanotechnological Aspects of the Alkaloidal Drug Berberine: Current and Future Trends

Traditionally, herbal compounds have been the focus of scientific interest for the last several centuries, and continuous research into their medicinal potential is underway. Berberine (BBR) is an isoquinoline alkaloid extracted from plants that possess a broad array of medicinal properties, including anti-diarrheal, anti-fibrotic, antidiabetic, anti-inflammatory, anti-obesity, antihyperlipidemic, antihypertensive, antiarrhythmic, antidepressant, and anxiolytic effects, and is frequently utilized as a traditional Chinese medicine. BBR promotes metabolisms of glucose and lipids by activating adenosine monophosphate-activated protein kinase, stimulating glycolysis and inhibiting functions of mitochondria; all of these ameliorate type 2 diabetes mellitus. BBR has also been shown to have benefits in congestive heart failure, hypercholesterolemia, atherosclerosis, non-alcoholic fatty liver disease, Alzheimer’s disease, and polycystic ovary syndrome. BBR has been investigated as an interesting pharmacophore with the potential to contribute significantly to the research and development of novel therapeutic medicines for a variety of disorders. Despite its enormous therapeutic promise, the clinical application of this alkaloid was severely limited because of its unpleasant pharmacokinetic characteristics. Poor bioavailability, limited absorption, and poor water solubility are some of the obstacles that restricted its use. Nanotechnology has been suggested as a possible solution to these problems. The present review aims at recent updates on important therapeutic activities of BBR and different types of nanocarriers used for the delivery of BBR in different diseases

Development of screen- printed carbon electrode-based immunosensors for the electrochemical detection of dengue virus antigen

Objective: This study describes the development of a cost-effective and sensitive immunosensor for rapid detection of the dengue virus (DENV) antigen in human plasma. Methods: Screen-printed carbon electrodes (SPCEs) were used to fabricate the immunosensor by immobilizing the DENV antibodies to its surface using 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride/N-hydroxysulfosuccinimide (EDC/s-NHS) as linker. The detection of the antigen–antibody interaction was achieved by linear sweep voltammetry (LSV) using potentiostat instrument and a sensor connector. The developed method was validated as per the ICH guidelines for linearity, sensitivity and accuracy. Results: The developed immunosensors showed excellent sensitivities in detecting the DENV antigens in both phosphate buffer saline (PBS) maintained at pH 7.4 as well as diluted human plasma. The limit of detection (LOD) values obtained in PBS was 0.11 nM; whereas in human plasma, it was calculated to be 0.16 nM. Good linearity was obtained for both PBS and human plasma over a wide range of concentrations showing promising applications of the immunosensor in both qualitative and quantitative detection of dengue virus antigen. Also, the developed immunosensor was able to detect the dengue antigen in 5 min showing rapid detection. Conclusion: A sensitive, reliable and cost-effective biosensor was developed which was able to detect the dengue virus antigen selectively and rapidly

Insights into the Explicit Protective Activity of Herbals in Management of Neurodegenerative and Cerebrovascular Disorders

The longstanding progressive neurodegenerative conditions of the central nervous system arise mainly due to deterioration, degradation and eventual neuronal cell loss. As an individual ages, the irreversible neurodegenerative disorders associated with aging also begin to develop, and these have become exceedingly prominent and pose a significant burden mentally, socially and economically on both the individual and their family. These disorders express several symptoms, such as tremors, dystonia, loss of cognitive functions, impairment of motor activity leading to immobility, loss of memory and many more which worsen with time. The treatment employed in management of these debilitating neurodegenerative disorders, such as Parkinson’s disease (which mainly involves the loss of dopaminergic neurons in the nigrostriatal region), Alzheimer’s disease (which arises due to accumulation of Tau proteins causing diffusive atrophy in the brain), Huntington’s disease (which involves damage of striatal and spinal neurons, etc.), have several adverse effects, leading to exploration of several lead targets and molecules existing in herbal drugs. The current review highlights the mechanistic role of natural products in the treatment of several neurodegenerative and cerebrovascular diseases such as Parkinson’s disease, Alzheimer’s disease, ischemic stroke and depression