Current Drug Targets - Volume 20, Issue 10, 2019

Background: Medications currently available for the management of diabetes mellitus are inconvenient and have some limitations. Thus, investigations for novel approaches are needed to deliver and target antidiabetics safely to the site of action. Objective: The present review emphasizes the limitations of conventional antidiabetics and provides the recent progresses of nanotechnology in the treatment of diabetes mellitus with a special highlight on the novel nanocarriers methodologies employed as antidiabetic drug delivery systems. Method: The potential nanocarriers employed for the treatment of diabetes comprise liposomes, niosomes, self-nanoemulsifying drug delivery systems, polymeric nanoparticles, gold nanoparticles, dendrimers and micelles. Herbal nanomedicine has also emerged to be a promising way for adequate delivery of herbal compounds. Other nanotechnology approaches involve the usage of oral insulin, inhalable insulin, artificial pancreas, and nanopump. Results: Nanocarriers have proved to lead a successful delivery of antidiabetic medications, aiming at drug targeting for enhanced efficacy and safety. Conclusion: These innovative generations of drug delivery systems have important benefits over conventionally existing ones. The future of nanotechnology in the management of diabetes is still open with several prospects and will be of pronounced significance.

Oral Cancer (OC) is a serious and growing problem which constitutes a huge burden on people in more and less economically developed countries alike. The scenario is clearly depicted from the increase in the expected number of new cases in the US diagnosed with OC from 49,670 people in 2016, to 49,750 cases in 2017. The situation is even more alarming in India, with 75,000 to 80,000 new cases being reported every year, thus making it the OC capital of the world. Leukoplakia, erythroplakia, oral lichen planus, oral submucous fibrosis, discoid lupus erythmatosus, hereditary disorders such as dyskeratosis congenital and epidermolisys bullosa are highlighted by WHO expert working group as the predisposing factors increasing the risk of OC. Consumption of tobacco and alcohol, genetic factors, and human papilloma virus are assigned as the factors contributing to the aetiology of OC. On the other hand, pathogenesis of OC involves not only apoptosis but also pain, inflammation and oxidative stress. Inspite of current treatment options (surgery, radiotherapy, and chemotherapy), OC is often associated with recurrence and formation of secondary primary tumours resulting in poor overall survival rates (∼50%). The intervention of nano technology-based drug delivery systems as therapeutics for cancers is often viewed as a cutting edge for technologists. Though ample literature on the usefulness of nano-coutured cancer therapeutics, rarely any product is in pipeline. Yet, despite all the hype about nanotechnology, there are few ongoing trials. This review discusses the current and future trends of nano-based drug delivery for the treatment of OC.

HACE1 belongs to the family of HECT domain-containing E3 ligases, which plays an important role in the occurrence, invasion and metastatic process in many human malignancies. HACE1 is a tumor suppressor gene that is reduced in most cancer tissues compared to adjacent normal tissue. The loss or knocking out of HACE1 leads to enhanced tumor growth, invasion, and metastasis; in contrast, the overexpression of HACE1 can inhibit the development of tumors. Hypermethylation reduces the expression of HACE1, thereby promoting tumor development. HACE1 can inhibit the development of inflammation or tumors via the ubiquitination pathway. Therefore, HACE1 may be a potential therapeutic target, providing new strategies for disease prevention and treatment.

Background: One of the important factors in Low-Density Lipoprotein (LDL) metabolism is the LDL receptor (LDLR) by its capacity to bind and subsequently clear cholesterol derived from LDL (LDL-C) in the circulation. Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is a newly discovered serine protease that destroys LDLR in the liver and thereby controls the levels of LDL in plasma. Inhibition of PCSK9-mediated degradation of LDLR has, therefore, become a novel target for lipid-lowering therapy. Methods: We review the current understanding of the structure and function of PCSK9 as well as its implications for the treatment of hyperlipidemia and atherosclerosis. Results: New treatments such as monoclonal antibodies against PCSK9 may be useful agents to lower plasma levels of LDL and hence prevent atherosclerosis. Conclusion: PCSK9's mechanism of action is not yet fully clarified. However, treatments that target PCSK9 have shown striking early efficacy and promise to improve the lives of countless patients with hyperlipidemia and atherosclerosis.

Background: Normal pressure hydrocephalus (NPH) is a critical brain disorder in which excess Cerebrospinal Fluid (CSF) is accumulated in the brain’s ventricles causing damage or disruption of the brain tissues. Amongst various signs and symptoms, difficulty in walking, slurred speech, impaired decision making and critical thinking, and loss of bladder and bowl control are considered the hallmark features of NPH. Objective: The current review was aimed to present a comprehensive overview and critical appraisal of majorly employed neuroimaging techniques for rational diagnosis and effective monitoring of the effectiveness of the employed therapeutic intervention for NPH. Moreover, a critical overview of recent developments and utilization of pharmacological agents for the treatment of hydrocephalus has also been appraised. Results: Considering the complications associated with the shunt-based surgical operations, consistent monitoring of shunting via neuroimaging techniques hold greater clinical significance. Despite having extensive applicability of MRI and CT scan, these conventional neuroimaging techniques are associated with misdiagnosis or several health risks to patients. Recent advances in MRI (i.e., Sagittal-MRI, coronal-MRI, Time-SLIP (time-spatial-labeling-inversion-pulse), PC-MRI and diffusion-tensor-imaging (DTI)) have shown promising applicability in the diagnosis of NPH. Having associated with several adverse effects with surgical interventions, non-invasive approaches (pharmacological agents) have earned greater interest of scientists, medical professional, and healthcare providers. Amongst pharmacological agents, diuretics, isosorbide, osmotic agents, carbonic anhydrase inhibitors, glucocorticoids, NSAIDs, digoxin, and gold-198 have been employed for the management of NPH and prevention of secondary sensory/intellectual complications. Conclusion: Employment of rational diagnostic tool and therapeutic modalities avoids misleading diagnosis and sophisticated management of hydrocephalus by efficient reduction of Cerebrospinal Fluid (CSF) production, reduction of fibrotic and inflammatory cascades secondary to meningitis and hemorrhage, and protection of brain from further deterioration.

Naltrexone is a competitive opioid receptor antagonist approved as supportive treatment in alcohol dependence and opioid addiction. At a dose of 50-100 mg daily, naltrexone is used off-label in dermatology for the treatment of trichotillomania and different types of pruritus. At a dose as low as 1- 5 mg per day, naltrexone demonstrates immunomodulatory action i.e. modulates Toll-like receptors signaling, decreases release of proinflammatory cytokines (tumor necrosis factor, interleukin-6, interleukin- 12), inhibits T lymphocyte proliferation, down-regulates the expression of chemokine receptors and adhesion molecules. The efficacy of standard and low doses of naltrexone in a variety of dermatological disorders has been reported. These include diseases such as familial benign chronic pemphigus (Hailey-Hailey disease), dermatomyositis, systemic sclerosis, psoriasis and lichen planopilaris. Optimistic preliminary findings, low cost of therapy and good tolerance make naltrexone a promising alternative therapy or adjunct drug in dermatology.

Toll-like receptors (TLR) are one among the initial responders of the immune system which participate in the activation inflammatory processes. Several different types of TLR such as TLR2, TLR4, TLR7 and TLR9 have been identified in various cell types, each having distinct ligands like lipids, lipoproteins, nucleic acids and proteins. Though its prime concern is xenobiotic defences, TLR signalling has also recognized as an activator of inflammation and associated development of chronic degenerative disorders (CDDs) including obesity, type 2 diabetes mellitus (T2DM), fatty liver disease, cardiovascular and neurodegenerative disorders as well as various types of cancers. Numerous drugs are in use to prevent these disorders, which specifically inhibit different pathways associated with the development of CDDs. Compared to these drug targets, inhibition of TLR, which specifically responsible for the inflammatory insults has proven to be a better drug target. Several natural products have emerged as inhibitors of CDDs, which specifically targets TLR signalling, among these, many are in the clinical trials. This review is intended to summarize the recent progress on TLR association with CDDs and to list possible use of natural products, their combinations and their synthetic derivative in the prevention of TLR-driven CDD development.

Human NIN1/RPN12 binding protein 1 homolog (NOB1), an RNA binding protein, is expressed ubiquitously in normal tissues such as the lung, liver, and spleen. Its core physiological function is to regulate protease activities and participate in maintaining RNA metabolism and stability. NOB1 is overexpressed in a variety of cancers, including pancreatic cancer, non-small cell lung cancer, ovarian cancer, prostate carcinoma, osteosarcoma, papillary thyroid carcinoma, colorectal cancer, and glioma. Although existing data indicate that NOB1 overexpression is associated with cancer growth, invasion, and poor prognosis, the molecular mechanisms behind these effects and its exact roles remain unclear. Several studies have confirmed that NOB1 is clinically relevant in different cancers, and further research at the molecular level will help evaluate the role of NOB1 in tumors. NOB1 has become an attractive target in anticancer therapy because it is overexpressed in many cancers and mediates different stages of tumor development. Elucidating the role of NOB1 in different signaling pathways as a potential cancer treatment will provide new ideas for existing cancer treatment methods. This review summarizes the research progress made into NOB1 in cancer in the past decade; this information provides valuable clues and theoretical guidance for future anticancer therapy by targeting NOB1.