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Dendrimer generational nomenclature: the need to harmonize

Kesharwani P, Tekade RK, Jain NK

Drug Discov Today, 2015 May;20(5):497-9.
PMID: 25578746 DOI: 10.1016/j.drudis.2014.12.015
Significance of Various Experimental Models and Assay Techniques in Cancer Diagnosis

Ghanghoria R, Kesharwani P, Jain NK

Mini Rev Med Chem, 2017;17(18):1713-1724.
PMID: 26891934 DOI: 10.2174/1389557516666160219122002

The experimental models are of vital significance to provide information regarding biological as well as genetic factors that control the phenotypic characteristics of the disease and serve as the foundation for the development of rational intervention stratagem. This review highlights the importance of experimental models in the field of cancer management. The process of pathogenesis in cancer progression, invasion and metastasis can be successfully explained by employing clinically relevant laboratory models of the disease. Cancer cell lines have been used extensively to monitor the process of cancer pathogenesis process by controlling growth regulation and chemo-sensitivity for the evaluation of novel therapeutics in both in vitro and xenograft models. The experimental models have been used for the elaboration of diagnostic or therapeutic protocols, and thus employed in preclinical studies of bioactive agents relevant for cancer prevention. The outcome of this review should provide useful information in understanding and selection of various models in accordance with the stage of cancer.
Lyophilized mucoadhesive-dendrimer enclosed matrix tablet for extended oral delivery of albendazole

Mansuri S, Kesharwani P, Tekade RK, Jain NK

Eur J Pharm Biopharm, 2016 May;102:202-13.
PMID: 26563727 DOI: 10.1016/j.ejpb.2015.10.015

Dendrimers are multifunctional carriers widely employed for delivering drugs in a variety of disease conditions including HIV/AIDS and cancer. Albendazole (ABZ) is a commonly used anthelmintic drug in human as well as veterinary medicine. In this investigation, ABZ was formulated as a "muco-dendrimer" based sustained released tablet. The mucoadhesive complex was synthesized by anchoring chitosan to fifth generation PPI dendrimer (Muco-PPI) and characterized by UV, FTIR, (1)H NMR spectroscopy and electron microscopy. ABZ was entrapped inside Muco-PPI followed by lyophilization and tableting as matrix tablet. A half-life (t1/2) of 8.06±0.15, 8.17±0.47, 11.04±0.73, 11.49±0.92, 12.52±1.04 and 16.9±1.18h was noted for ABZ (free drug), conventional ABZ tablet (F1), conventional ABZ matrix tablet (F2), PPI-ABZ complex, PPI-ABZ matrix tablet (F3) and Muco-PPI-ABZ matrix tablet (F4), respectively. Thus the novel mucoadhesive-PPI based formulation of ABZ (F4) increased the t1/2 of ABZ significantly by almost twofold as compared to the administration of free drug. The in vivo drug release data showed that the Muco-PPI based formulations have a significantly higher Cmax (2.40±0.02μg/mL) compared with orally administered free ABZ (0.19±0.07μg/mL) as well as conventional tablet (0.20±0.05μg/mL). In addition, the Muco-PPI-ABZ matrix tablet displayed increased mean residence time (MRT) and is therefore a potential candidate to appreciably improve the pharmacokinetic profile of ABZ.
Targeting luteinizing hormone-releasing hormone: A potential therapeutics to treat gynecological and other cancers

Ghanghoria R, Kesharwani P, Tekade RK, Jain NK

J Control Release, 2018 01 10;269:277-301.
PMID: 27840168 DOI: 10.1016/j.jconrel.2016.11.002

Cancer is a prime healthcare problem that is significantly responsible for universal mortality. Despite distinguished advancements in medical field, chemotherapy is still the mainstay for the treatment of cancers. During chemotherapy, approximately 90% of the administered dose goes to normal tissues, with mere 2-5% precisely reaching the cancerous tissues. Subsequently, the resultant side effects and associated complications lead to dose reduction or even discontinuance of the therapy. Tumor directed therapy therefore, represents a fascinating approach to augment the therapeutic potential of anticancer bioactives as well as overcomes its side effects. The selective overexpression of LHRH receptors on human tumors compared to normal tissues makes them a suitable marker for diagnostics, molecular probes and targeted therapeutics. These understanding enabled the rational to conjugate LHRH with various cytotoxic drugs (doxorubicin, DOX; camptothecin etc.), cytotoxic genes [small interfering RNA (siRNA), micro RNA (miRNA)], as well as therapeutic nanocarriers (nanoparticles, liposomes or dendrimers) to facilitate their tumor specific delivery. LHRH conjugation enhances their delivery via LHRH receptor mediated endocytosis. Numerous cytotoxic analogs of LHRH were developed over the past two decades to target various types of cancers. The potency of LHRH compound were reported to be as high as 5,00-10,00 folds compared to parent molecules. The objective of this review article is to discuss reports on various LHRH analogs with special emphasis on their prospective application in the medical field. The article also focuses on the attributes that must be taken into account while designing a LHRH therapeutics with special account to the biochemistry and applications of these conjugates. The record on various cytotoxic analogs of LHRH are also discussed. It is anticipated that the knowledge of therapeutic and toxicological aspects of LHRH compounds will facilitate the development of a more systematic approach to the targeted delivery of cytotoxic agents using peptides.
Luteinizing hormone-releasing hormone peptide tethered nanoparticulate system for enhanced antitumoral efficacy of paclitaxel

Ghanghoria R, Tekade RK, Mishra AK, Chuttani K, Jain NK

Nanomedicine (Lond), 2016 Apr;11(7):797-816.
PMID: 26980704 DOI: 10.2217/nnm.16.19

Paclitaxel (PTX) is an effective anticancer agent used in the therapy of a wide variety of cancers. However, the drug is difficult to formulate due to its low solubility, and therefore, it is administered under slow infusion with castor oil/ethanol solution as surfactant that causes serious side effects. This investigation investigates leutinizing hormone releasing hormone (LHRH)-tethered nanparticulate system as modality for cancer-specific delivery of PTX and therefore minimizing the adverse effects.
Reversal of Neuropsychiatric Comorbidities in an Animal Model of Temporal Lobe Epilepsy Following Systemic Administration of Dental Pulp Stem Cells and Bone Marrow Mesenchymal Stem Cells

Senthilkumar S, Maiya K, Jain NK, Mata S, Mangaonkar S, Prabhu P, et al.

Curr Gene Ther, 2023;23(3):198-214.
PMID: 36305152 DOI: 10.2174/1566523223666221027113723

INTRODUCTION: We aim to investigate whether timed systemic administration of dental pulp stem cells (DPSCs) or bone marrow mesenchymal stem cells (BM-MSCs) with status epilepticus (SE) induced blood-brain barrier (BBB) damage could facilitate the CNS homing of DPSCs/BM-MSCs and mitigate neurodegeneration, neuroinflammation and neuropsychiatric comorbidities in an animal model of Temporal Lobe epilepsy (TLE).
BACKGROUND: Cognitive impairments, altered emotional responsiveness, depression, and anxiety are the common neuropsychiatric co-morbidities observed in TLE patients. Mesenchymal stem cells (MSCs) transplantation has gained immense attention in treating TLE, as ~30% of patients do not respond to anti-epileptic drugs. While MSCs are known to cross the BBB, better CNS homing and therapeutic effects could be achieved when the systemic administration of MSC is timed with BBB damage following SE.
OBJECTIVES: The objectives of the present study are to investigate the effects of systemic administration of DPSCs/BM-MSCs timed with BBB damage on CNS homing of DPSCs/BM-MSCs, neurodegeneration, neuroinflammation and neuropsychiatric comorbidities in an animal model of TLE.
METHODOLOGY: We first assessed the BBB leakage following kainic acid-induced SE and timed the intravenous administration of DPSCs/BM-MSCs to understand the CNS homing/engraftment potential of DPSCs/BM-MSCs and their potential to mitigate neurodegeneration, neuroinflammation and neuropsychiatric comorbidities.
RESULTS: Our results revealed that systemic administration of DPSCs/BM-MSCs attenuated neurodegeneration, neuroinflammation, and ameliorated neuropsychiatric comorbidities. Three months following intravenous administration of DPSCs/BM-MSCs, we observed a negligible number of engrafted cells in the corpus callosum, sub-granular zone, and sub-ventricular zone.
CONCLUSION: Thus, it is evident that functional recovery is still achievable despite poor engraftment of MSCs into CNS following systemic administration.
Fulltext Development of substituted benzylidene derivatives as novel dual cholinesterase inhibitors for Alzheimer's treatment

Gupta SM, Behera A, Jain NK, Tripathi A, Rishipathak D, Singh S, et al.

RSC Adv, 2023 Sep 04;13(38):26344-26356.
PMID: 37671344 DOI: 10.1039/d3ra03224h

Leading pathological markers of Alzheimer's disease (AD) include Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), Amyloid beta (Aβ) and reactive oxygen species (ROS). Indole derivatives were identified and optimized to improve the potency against AChE, BuChE, Aβ and ROS. The lead molecule IND-30 was found to be selective for AChE (selectivity ratio: 22.92) in comparison to BuChE and showed maximum inhibition potential for human AChE (IC50: 4.16 ± 0.063 μM). IND-30 was found to be safe on the SH-SY5Y cell line until the dose of 30 mM. Further, molecule IND-30 was evaluated for its ability to inhibit AChE-induced Aβ aggregation at 0.5, 10 and 20 μM doses. Approximately, 50% of AChE-induced Aβ aggregation was inhibited by IND-30. Thus, IND-30 was found to be multitargeting for AD.
Machine learning for cognitive behavioral analysis: datasets, methods, paradigms, and research directions

Bhatt P, Sethi A, Tasgaonkar V, Shroff J, Pendharkar I, Desai A, et al.

Brain Inform, 2023 Jul 31;10(1):18.
PMID: 37524933 DOI: 10.1186/s40708-023-00196-6

Human behaviour reflects cognitive abilities. Human cognition is fundamentally linked to the different experiences or characteristics of consciousness/emotions, such as joy, grief, anger, etc., which assists in effective communication with others. Detection and differentiation between thoughts, feelings, and behaviours are paramount in learning to control our emotions and respond more effectively in stressful circumstances. The ability to perceive, analyse, process, interpret, remember, and retrieve information while making judgments to respond correctly is referred to as Cognitive Behavior. After making a significant mark in emotion analysis, deception detection is one of the key areas to connect human behaviour, mainly in the forensic domain. Detection of lies, deception, malicious intent, abnormal behaviour, emotions, stress, etc., have significant roles in advanced stages of behavioral science. Artificial Intelligence and Machine learning (AI/ML) has helped a great deal in pattern recognition, data extraction and analysis, and interpretations. The goal of using AI and ML in behavioral sciences is to infer human behaviour, mainly for mental health or forensic investigations. The presented work provides an extensive review of the research on cognitive behaviour analysis. A parametric study is presented based on different physical characteristics, emotional behaviours, data collection sensing mechanisms, unimodal and multimodal datasets, modelling AI/ML methods, challenges, and future research directions.
Fulltext Reactive oxygen species mediated apoptotic death of colon cancer cells: therapeutic potential of plant derived alkaloids

Nelson VK, Nuli MV, Mastanaiah J, Saleem T S M, Birudala G, Jamous YF, et al.

Front Endocrinol (Lausanne), 2023;14:1201198.
PMID: 37560308 DOI: 10.3389/fendo.2023.1201198

Colorectal cancer (CRC) is one of the most deaths causing diseases worldwide. Several risk factors including hormones like insulin and insulin like growth factors (e.g., IGF-1) have been considered responsible for growth and progression of colon cancer. Though there is a huge advancement in the available screening as well as treatment techniques for CRC. There is no significant decrease in the mortality of cancer patients. Moreover, the current treatment approaches for CRC are associated with serious challenges like drug resistance and cancer re-growth. Given the severity of the disease, there is an urgent need for novel therapeutic agents with ideal characteristics. Several pieces of evidence suggested that natural products, specifically medicinal plants, and derived phytochemicals may serve as potential sources for novel drug discovery for various diseases including cancer. On the other hand, cancer cells like colon cancer require a high basal level of reactive oxygen species (ROS) to maintain its own cellular functions. However, excess production of intracellular ROS leads to cancer cell death via disturbing cellular redox homeostasis. Therefore, medicinal plants and derived phytocompounds that can enhance the intracellular ROS and induce apoptotic cell death in cancer cells via modulating various molecular targets including IGF-1 could be potential therapeutic agents. Alkaloids form a major class of such phytoconstituents that can play a key role in cancer prevention. Moreover, several preclinical and clinical studies have also evidenced that these compounds show potent anti-colon cancer effects and exhibit negligible toxicity towards the normal cells. Hence, the present evidence-based study aimed to provide an update on various alkaloids that have been reported to induce ROS-mediated apoptosis in colon cancer cells via targeting various cellular components including hormones and growth factors, which play a role in metastasis, angiogenesis, proliferation, and invasion. This study also provides an individual account on each such alkaloid that underwent clinical trials either alone or in combination with other clinical drugs. In addition, various classes of phytochemicals that induce ROS-mediated cell death in different kinds of cancers including colon cancer are discussed.