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Nucleic Acid Aptamers as a Potential Nucleus Targeted Drug Delivery System

Shrivastava G, Bakshi HA, Aljabali AA, Mishra V, Hakkim FL, Charbe NB, et al.

Curr Drug Deliv, 2020;17(2):101-111.
PMID: 31906837 DOI: 10.2174/1567201817666200106104332

BACKGROUND: Nucleus targeted drug delivery provides several opportunities for the treatment of fatal diseases such as cancer. However, the complex nucleocytoplasmic barriers pose significant challenges for delivering a drug directly and efficiently into the nucleus. Aptamers representing singlestranded DNA and RNA qualify as next-generation highly advanced and personalized medicinal agents that successfully inhibit the expression of certain proteins; possess extraordinary gene-expression for manoeuvring the diseased cell's fate with negligible toxicity. In addition, the precisely directed aptamers to the site of action present a tremendous potential to reach the nucleus by escaping the ensuing barriers to exhibit a better drug activity and gene expression.
OBJECTIVE: This review epigrammatically highlights the significance of targeted drug delivery and presents a comprehensive description of the principal barriers faced by the nucleus targeted drug delivery paradigm and ensuing complexities thereof. Eventually, the progress of nucleus targeting with nucleic acid aptamers and success achieved so far have also been reviewed.
METHODS: Systematic literature search was conducted of research published to date in the field of nucleic acid aptamers.
CONCLUSION: The review specifically points out the contribution of individual aptamers as the nucleustargeting agent rather than aptamers in conjugated form.
A new era in oxygen therapeutics? From perfluorocarbon systems to haemoglobin-based oxygen carriers

Charbe NB, Castillo F, Tambuwala MM, Prasher P, Chellappan DK, Carreño A, et al.

Blood Rev, 2022 Jan 21.
PMID: 35094845 DOI: 10.1016/j.blre.2022.100927

Blood transfusion is the key to life in case of traumatic emergencies, surgeries and in several pathological conditions. An important goal of whole blood or red blood cell transfusion is the fast delivery of oxygen to vital organs and restoration of circulation volume. Whole blood or red blood cell transfusion has several limitations. Free haemoglobin not only loses its tetrameric configuration and extracts via the kidney leading to nephrotoxicity but also scavenges nitric oxide (NO), leading to vasoconstriction and hypertension. PFC based formulations transport oxygen in vivo, the contribution in terms of clinical outcome is challenging. The oxygen-carrying capacity is not the only criterion for the successful development of haemoglobin-based oxygen carriers (HBOCs). This review is a bird's eye view on the present state of the PFCs and HBOCs in which we analyzed the current modifications made or which are underway in development, their promises, and hurdles in clinical implementation.
Fulltext Dynamics of Prolyl Hydroxylases Levels During Disease Progression in Experimental Colitis

Bakshi HA, Mishra V, Satija S, Mehta M, Hakkim FL, Kesharwani P, et al.

Inflammation, 2019 Dec;42(6):2032-2036.
PMID: 31377947 DOI: 10.1007/s10753-019-01065-3

Hypoxia inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitors are shown to be protective in several models of inflammatory bowel disease (IBD). However, these non-selective inhibitors are known to inhibit all the three isoforms of PHD, i.e. PHD-1, PHD-2 and PHD-3. In the present report, we investigated the associated changes in levels of PHDs during the development and recovery of chemically induced colitis in mice. The results indicated that in the experimental model of murine colitis, levels of both, PHD-1 and PHD-2 were found to be increased with the progression of the disease; however, the level of PHD-3 remained the same in group of healthy controls and mice with colitis. Thus, the findings advocated that inhibitors, which inhibited all three isoforms of PHD could not be ideal therapeutics for IBD since PHD-3 is required for normal gut function. Hence, this necessitates the development of new compounds capable of selectively inhibiting PHD-1 and PHD-2 for effective treatment of IBD.
Small interfering RNA for cancer treatment: overcoming hurdles in delivery

Charbe NB, Amnerkar ND, Ramesh B, Tambuwala MM, Bakshi HA, Aljabali AAA, et al.

Acta Pharm Sin B, 2020 Nov;10(11):2075-2109.
PMID: 33304780 DOI: 10.1016/j.apsb.2020.10.005

In many ways, cancer cells are different from healthy cells. A lot of tactical nano-based drug delivery systems are based on the difference between cancer and healthy cells. Currently, nanotechnology-based delivery systems are the most promising tool to deliver DNA-based products to cancer cells. This review aims to highlight the latest development in the lipids and polymeric nanocarrier for siRNA delivery to the cancer cells. It also provides the necessary information about siRNA development and its mechanism of action. Overall, this review gives us a clear picture of lipid and polymer-based drug delivery systems, which in the future could form the base to translate the basic siRNA biology into siRNA-based cancer therapies.
Cellular signalling pathways mediating the pathogenesis of chronic inflammatory respiratory diseases: an update

Mehta M, Dhanjal DS, Paudel KR, Singh B, Gupta G, Rajeshkumar S, et al.

Inflammopharmacology, 2020 Aug;28(4):795-817.
PMID: 32189104 DOI: 10.1007/s10787-020-00698-3

Respiratory disorders, especially non-communicable, chronic inflammatory diseases, are amongst the leading causes of mortality and morbidity worldwide. Respiratory diseases involve multiple pulmonary components, including airways and lungs that lead to their abnormal physiological functioning. Several signaling pathways have been reported to play an important role in the pathophysiology of respiratory diseases. These pathways, in addition, become the compounding factors contributing to the clinical outcomes in respiratory diseases. A range of signaling components such as Notch, Hedgehog, Wingless/Wnt, bone morphogenetic proteins, epidermal growth factor and fibroblast growth factor is primarily employed by these pathways in the eventual cascade of events. The different aberrations in such cell-signaling processes trigger the onset of respiratory diseases making the conventional therapeutic modalities ineffective. These challenges have prompted us to explore novel and effective approaches for the prevention and/or treatment of respiratory diseases. In this review, we have attempted to deliberate on the current literature describing the role of major cell signaling pathways in the pathogenesis of pulmonary diseases and discuss promising advances in the field of therapeutics that could lead to novel clinical therapies capable of preventing or reversing pulmonary vascular pathology in such patients.
Hypoxia-Inducible Factor (HIF): Fuel for Cancer Progression

Satija S, Kaur H, Tambuwala MM, Sharma P, Vyas M, Khurana N, et al.

Curr Mol Pharmacol, 2021;14(3):321-332.
PMID: 33494692 DOI: 10.2174/1874467214666210120154929

Hypoxia is an integral part of the tumor microenvironment, caused primarily due to rapidly multiplying tumor cells and a lack of proper blood supply. Among the major hypoxic pathways, HIF-1 transcription factor activation is one of the widely investigated pathways in the hypoxic tumor microenvironment (TME). HIF-1 is known to activate several adaptive reactions in response to oxygen deficiency in tumor cells. HIF-1 has two subunits, HIF-1β (constitutive) and HIF-1α (inducible). The HIF-1α expression is largely regulated via various cytokines (through PI3K-ACT-mTOR signals), which involves the cascading of several growth factors and oncogenic cascades. These events lead to the loss of cellular tumor suppressant activity through changes in the level of oxygen via oxygen-dependent and oxygen-independent pathways. The significant and crucial role of HIF in cancer progression and its underlying mechanisms have gained much attention lately among the translational researchers in the fields of cancer and biological sciences, which have enabled them to correlate these mechanisms with various other disease modalities. In the present review, we have summarized the key findings related to the role of HIF in the progression of tumors.
Perfluorocarbons Therapeutics in Modern Cancer Nanotechnology for Hypoxiainduced Anti-tumor Therapy

Satija S, Sharma P, Kaur H, Dhanjal DS, Chopra RS, Khurana N, et al.

Curr Pharm Des, 2021;27(43):4376-4387.
PMID: 34459378 DOI: 10.2174/1381612827666210830100907

With an estimated failure rate of about 90%, immunotherapies that are intended for the treatment of solid tumors have caused an anomalous rise in the mortality rate over the past decades. It is apparent that resistance towards such therapies primarily occurs due to elevated levels of HIF-1 (Hypoxia-induced factor) in tumor cells, which are caused by disrupted microcirculation and diffusion mechanisms. With the advent of nanotechnology, several innovative advances were brought to the fore; and, one such promising direction is the use of perfluorocarbon nanoparticles in the management of solid tumors. Perfluorocarbon nanoparticles enhance the response of hypoxia-based agents (HBAs) within the tumor cells and have been found to augment the entry of HBAs into the tumor micro-environment. The heightened penetration of HBAs causes chronic hypoxia, thus aiding in the process of cell quiescence. In addition, this technology has also been applied in photodynamic therapy, where oxygen self-enriched photosensitizers loaded perfluorocarbon nanoparticles are employed. The resulting processes initiate a cascade, depleting tumour oxygen and turning it into a reactive oxygen species eventually to destroy the tumour cell. This review elaborates on the multiple applications of nanotechnology based perfluorocarbon formulations that are being currently employed in the treatment of tumour hypoxia.
Fulltext Correction: Aljabali, A.A.A.; et al. Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer via down Regulation of Nuclear p65 and HIF-1α. Cancers 2020, 12, 113

Aljabali AAA, Bakshi HA, Hakkim FL, Haggag YA, Al-Batanyeh KM, Zoubi MSA, et al.

Cancers (Basel), 2020 Nov 30;12(12).
PMID: 33266353 DOI: 10.3390/cancers12123587

The authors wish to make the following corrections to this paper [...].
Fulltext Dietary Crocin is Protective in Pancreatic Cancer while Reducing Radiation-Induced Hepatic Oxidative Damage

Bakshi HA, Zoubi MSA, Hakkim FL, Aljabali AAA, Rabi FA, Hafiz AA, et al.

Nutrients, 2020 06 26;12(6).
PMID: 32604971 DOI: 10.3390/nu12061901

Pancreatic cancer is one of the fatal causes of global cancer-related deaths. Although surgery and chemotherapy are standard treatment options, post-treatment outcomes often end in a poor prognosis. In the present study, we investigated anti-pancreatic cancer and amelioration of radiation-induced oxidative damage by crocin. Crocin is a carotenoid isolated from the dietary herb saffron, a prospect for novel leads as an anti-cancer agent. Crocin significantly reduced cell viability of BXPC3 and Capan-2 by triggering caspase signaling via the downregulation of Bcl-2. It modulated the expression of cell cycle signaling proteins P53, P21, P27, CDK2, c-MYC, Cyt-c and P38. Concomitantly, crocin treatment-induced apoptosis by inducing the release of cytochrome c from mitochondria to cytosol. Microarray analysis of the expression signature of genes induced by crocin showed a substantial number of genes involved in cell signaling pathways and checkpoints (723) are significantly affected by crocin. In mice bearing pancreatic tumors, crocin significantly reduced tumor burden without a change in body weight. Additionally, it showed significant protection against radiation-induced hepatic oxidative damage, reduced the levels of hepatic toxicity and preserved liver morphology. These findings indicate that crocin has a potential role in the treatment, prevention and management of pancreatic cancer.
Overview of key molecular and pharmacological targets for diabetes and associated diseases

Shahcheraghi SH, Aljabali AAA, Al Zoubi MS, Mishra V, Charbe NB, Haggag YA, et al.

Life Sci, 2021 Aug 01;278:119632.
PMID: 34019900 DOI: 10.1016/j.lfs.2021.119632

Diabetes epidemiological quantities are demonstrating one of the most important communities' health worries. The essential diabetic difficulties are including cardiomyopathy, nephropathy, inflammation, and retinopathy. Despite developments in glucose decreasing treatments and drugs, these diabetic complications are still ineffectively reversed or prohibited. Several signaling and molecular pathways are vital targets in the new therapies of diabetes. This review assesses the newest researches about the key molecules and signaling pathways as targets of molecular pharmacology in diabetes and diseases related to it for better treatment based on molecular sciences. The disease is not cured by current pharmacological strategies for type 2 diabetes. While several drug combinations are accessible that can efficiently modulate glycemia and mitigate long-term complications, these agents do not reverse pathogenesis, and in practice, they are not established to modify the patient's specific molecular profiling. Therapeutic companies have benefited from human genetics. Genome exploration, which is agnostic to the information that exists, has revealed tens of loci that impact glycemic modulation. The physiological report has begun to examine subtypes of diseases, illustrate heterogeneity and propose biochemical therapeutic pathways.
Fulltext The viral capsid as novel nanomaterials for drug delivery

Aljabali AA, Hassan SS, Pabari RM, Shahcheraghi SH, Mishra V, Charbe NB, et al.

Future Sci OA, 2021 Oct;7(9):FSO744.
PMID: 34737885 DOI: 10.2144/fsoa-2021-0031

The purpose of this review is to highlight recent scientific developments and provide an overview of virus self-assembly and viral particle dynamics. Viruses are organized supramolecular structures with distinct yet related features and functions. Plant viruses are extensively used in biotechnology, and virus-like particulate matter is generated by genetic modification. Both provide a material-based means for selective distribution and delivery of drug molecules. Through surface engineering of their capsids, virus-derived nanomaterials facilitate various potential applications for selective drug delivery. Viruses have significant implications in chemotherapy, gene transfer, vaccine production, immunotherapy and molecular imaging.