Exploration of tumor penetrating peptide iRGD as a potential strategy to enhance tumor penetration of cancer nanotherapeutics.

Cancer therapy continues to be a huge challenge as most chemotherapeutic agents exert serious adverse effects on healthy organs. Chemotherapeutic agents lack selective targeting and even the existing target specific therapies are failing due to poor distribution into the tumor microenvironment. Nanotechnology offers multiple advantages to address the limitations encountered by conventional therapy. However, the delivery of nanotherapeutics to tumor tissue has not improved over the years partly due to the poor and inadequate distribution of nanotherapeutics into deeper tumor regions resulting in resistance and relapse. To curb the penetration concerns, iRGD was explored and found to be highly effective in improving the delivery of cancer nanomedicine. The preclinical observations are highly encouraging; however, the clinical translation is at a nascent stage. Based on this, we have made an elaborative effort to give a detailed account of various promising applications of iRGD to increase anticancer and tumor imaging potential. Importantly, we have comprehensively discussed the shortcomings and uncertainties associated with the clinical translation of iRGD-based therapeutic approaches and future directions.

Nanoceria Ameliorates Fibrosis, Inflammation, and Cellular Stress in Experimental Chronic Pancreatitis.

Chronic pancreatitis (CP) is an inflammatory, irreversible disorder of the pancreas which leads to organ atrophy and poses high risk for the development of pancreatic cancer. Given the lack of clinically approved therapy, we explored the pharmacological potential of the nanoparticles of cerium oxide (nanoceria, NC) against animal models of CP. Nanoceria ameliorated the features of CP as evident from biochemical parameters. It inhibited the inflammatory cytokines and chemokines by abrogation of macrophage signaling. Further, NC attenuated the fibrogenesis by inhibition of TGF-ß signaling, endoplasmic reticulum stress, and epithelial-to-mesenchymal transition. Our findings reveal the anti-CP potential of the novel redox regenerative nanoceria against two models of CP.

Acetaminophen induced hepatotoxicity: An overview of the promising protective effects of natural products and herbal formulations.

BACKGROUND: The liver plays an important role in regulating the metabolic processes and is the most frequently targeted organ by toxic chemicals. Acetaminophen (APAP) is a well-known anti-allergic, anti-pyretic, non-steroidal anti-inflammatory drug (NSAID), which upon overdose leads to hepatotoxicity, the major adverse event of this over-the-counter drug. PURPOSE: APAP overdose induced acute liver injury is the second most common cause that often requires liver transplantation worldwide, for which N-acetyl cysteine is the only synthetic drug clinically approved as an antidote. So, it was felt that there is a need for the novel therapeutic approach for the treatment of liver diseases with less adverse effects. This review provides detailed analysis of the different plant extracts; phytochemicals and herbal formulations for the amelioration of APAP-induced liver injury. METHOD: The data was collected using different online resources including PubMed, ScienceDirect, Google Scholar, Springer, and Web of Science using keywords given below. RESULTS: Over the past decades various reports have revealed that plant-based approaches may be a better treatment choice for the APAP-induced hepatotoxicity in pre-clinical experimental conditions. Moreover, herbal compounds provide several advantages over the synthetic drugs with fewer side effects, easy availability and less cost for the treatment of life-threatening diseases. CONCLUSION: The current review summarizes the hepatoprotective effects and therapeutic mechanisms of various plant extracts, active phytoconstituents and herbal formulations with potential application against APAP induced hepatotoxicity as the numbers of hepatoprotective natural products are more without clinical relativity. Further, pre-clinical pharmacological research will contribute to the designing of natural products as medicines with encouraging prospects for clinical application.

Nanoceria, the versatile nanoparticles: Promising biomedical applications.

Nanotechnology has been a boon for the biomedical field due to the freedom it provides for tailoring of pharmacokinetic properties of different drug molecules. Nanomedicine is the medical application of nanotechnology for the diagnosis, treatment and/or management of the diseases. Cerium oxide nanoparticles (CNPs) are metal oxide-based nanoparticles (NPs) which possess outstanding reactive oxygen species (ROS) scavenging activities primarily due to the availability of "oxidation switch" on their surface. These NP have been found to protect from a number of disorders with a background of oxidative stress such as cancer, diabetes etc. In fact, the CNPs have been found to possess the environment-dependent ROS modulating properties. In addition, the inherent catalase, SOD, oxidase, peroxidase and phosphatase mimetic properties of CNPs provide them superiority over a number of NPs. Further, chemical reactivity of CNPs seems to be a function of their surface chemistry which can be precisely tuned by defect engineering. However, the contradictory reports make it necessary to critically evaluate the potential of CNPs, in the light of available literature. The review is aimed at probing the feasibility of CNPs to push towards the clinical studies. Further, we have also covered and censoriously discussed the suspected negative impacts of CNPs before making our way to a consensus. This review aims to be a comprehensive, authoritative, critical, and accessible review of general interest to the scientific community.

Inhibition of discoidin domain receptors by imatinib prevented pancreatic fibrosis demonstrated in experimental chronic pancreatitis model.

Discoidin domain receptors (DDR1 and DDR2) are the collagen receptors of the family tyrosine kinases, which play significant role in the diseases like inflammation, fibrosis and cancer. Chronic pancreatitis (CP) is a fibro-inflammatory disease in which recurrent pancreatic inflammation leads to pancreatic fibrosis. In the present study, we have investigated the role of DDR1 and DDR2 in CP. The induced expression of DDR1 and DDR2 was observed in primary pancreatic stellate cells (PSCs) and cerulein-induced CP. Subsequently, the protective effects of DDR1/DDR2 inhibitor, imatinib (IMT) were investigated. Pharmacological intervention with IMT effectively downregulated DDR1 and DDR2 expression. Further, IMT treatment reduced pancreatic injury, inflammation, extracellular matrix deposition and PSCs activation along with inhibition of TGF-ß1/Smad signaling pathway. Taken together, these results suggest that inhibition of DDR1 and DDR2 controls pancreatic inflammation and fibrosis, which could represent an attractive and promising therapeutic strategy for the treatment of CP.

Targeting inflammatory cytokine storm to fight against COVID-19 associated severe complications.

Such testing and trying time probably never seen before in the human history. The novel coronavirus disease abbreviated as COVID-19 is the ongoing health crisis which entered into human life in late December 2019. The ease of transmission between humans and the undetectability in early stage makes COVID-19 frightening and unprecedented. The disease is characterised by pneumonia progressing to breathing difficulty, acute respiratory distress syndrome (ARDS) and multi-organ failure. Clinical studies suggest excessive release of inflammatory mediators leads to cytokine storm, a phenomenon which appears to be potentially life-threatening in COVID-19. Across the globe, when the world authorities are grappling to contain the virus, our review provides a glimpse on structure, pathophysiology of the virus and further sheds light on various clinical complications associated with the disease in order to open up/raise new horizons to explore various possible theoretical targets for COVID-19. The review also portrays a question and debates: Can targeting cytokine storm can be a feasible approach to combat COVID-19?

Therapeutic applications of selenium nanoparticles.

Nanoparticles (NPs) serve to reduce the toxicity, enhance bioactivity, improve targeting, and provide versatile means to control the release profile of the encapsulated moiety. Among different NPs, inorganic NPs of metals like Ag, Au, Ce, Fe, Se, Ti and Zn possess a significant place owing to their unique bioactivities in nanoforms. Selenium (Se) is an essential trace element. It is incorporated into selenoproteins as selenocysteine (Sec) representing the most important part of the active center of their enzymatic activities. Many selenoproteins have oxidoreductase activity and, thus, regulate the physiological redox balance. Se has a narrow therapeutic window and the toxicity margins are very delicate whereas the nanoparticles of Se (SeNPs) possess remarkably reduced toxicity. SeNPs have been explored in various oxidative stress and inflammation mediated disorders like arthritis, cancer, diabetes and nephropathy with potential therapeutic benefits. SeNPs constitute an attractive carrier platform to ferry various drugs to the site of action. Herein we have discussed the significance of nanosizing on the pharmacological activity of Se. The role of SeNPs in pharmacological protection against various inflammatory and oxidative stress mediated conditions is presented. However, it is largely unknown how SeNPs may affect the pharmacokinetics and pharmacodynamics of selenoproteins. Most of the available studies were poorly designed without any comparison to the other Se sources. In the future, detailed studies with inclusion of an appropriate source of Se should be carried out with emphasis on understanding the role of selenoproteins in the observed pharmacological activity.

Protective Effect of Nanoceria on Cisplatin-Induced Nephrotoxicity by Amelioration of Oxidative Stress and Pro-inflammatory Mechanisms.

Cisplatin (CP) is one of the most important anticancer compounds with its therapeutic usefulness in diverse types of solid cancer. However, its use is limited due to nephrotoxicity induced by it. Oxidative stress is an effective participant which contributes actively to pathogenesis of CP-induced nephrotoxicity. Nanoparticle form of a rare earth metal cerium, also known as nanoceria (NC), has come up as a potential antioxidant and anti-inflammatory agent. In the present study, administration of CP in Swiss mice resulted in reduction of body weight, increased oxidative stress and pro-inflammatory cytokine levels including IL-6 and TNF-α along with alteration in normal histological architecture of kidney. On the contrary, NC (0.2 and 2 mg/kg i.p.) ameliorated nephrotoxicity of CP which was evident by reduction in levels of renal injury markers in plasma, i.e., creatinine and blood urea nitrogen. NC ameliorated oxidative stress by showing a reduction in levels of malondialdehyde and increased levels of endogenous antioxidants reduced glutathione and catalase. Further, NC treatment also reduced the levels of pro-inflammatory cytokines. Furthermore, protective effect of NC was also corroborated by histopathological studies wherein, kidneys from CP group showed altered tissue structure after acute as well as chronic exposure of CP while the tissues from treated groups showed absence of alterations in kidney histology. The results from present study suggested that oxidative stress and pro-inflammatory cytokines play a central role in pathogenesis of CP-induced nephrotoxicity and NC provides protection from CP-induced nephrotoxicity due to its antioxidant and anti-inflammatory properties.

Cardioprotective effects of nanoceria in a murine model of cardiac remodeling.

Isoproterenol (ISO), a synthetic ß1 adrenergic agonist is a well-known agent to be associated with severe cardiotoxicity manifested as marked myocardial necrosis and fibrosis. Oxidative stress plays a crucial role in mediating ISO induced cardiotoxicity. In present study, we have investigated the possible protective effect of nanoceria (NC) in ISO induced cardiac injury. We have given long duration exposure (a total of 10 days) of low dose ISO (20 mg/kg/day) to investigate the protective effects of NC in chronic cardiac injury model. ISO (20 mg/kg/day for 10 days) produced cardiac injury as evident by increased plasma LDH and CK-MB, AST, ALT, cardiac hypertrophy, severe myocardial fibrosis (MF) and significantly higher levels of cytokines, IL-6, TGF-ß and TNF-α. Interestingly, the treatment with NC (0.2 and 2 mg/kg) abrogated cardiotoxicity symptoms and provided protection from ISO induced cardiac injury. The results from present study demonstrated strong evidences of cardioprotective effects of NC as shown by reduction in the levels of LDH (p < 0.05 at 2 mg/kg) and CK-MB (p < 0.05 at 2 mg/kg). In addition, NC reduced oxidative stress parameters MDA (p < 0.05 at 2 mg/kg) and enhanced GSH levels which is physiological antioxidant (p < 0.01 at both doses). Further, NC exhibited promising anti-inflammatory activity and curbed the levels of cytokines (p < 0.05 at 0.2 mg/kg and p < 0.001 for IL-1ß and p < 0.001 at both doses for IL-6). In addition, NC also reduced the levels of pro-fibrotic cytokine, TGF-ß (p < 0.05 at 2 mg/kg) and helped in reduction of collagen deposition in heart thereby, preventing the myocardial remodeling. Our results strongly suggested that NC might be of potential use as a cardioprotective agent.

Nanoceria ameliorates doxorubicin induced cardiotoxicity: Possible mitigation via reduction of oxidative stress and inflammation.

Doxorubicin (DOX) is one of the most commonly used anticancer drugs but its use has been limited due to constraints of cardiotoxic side effects. The precise mechanism underlying cardiotoxicity is not yet fully understood but oxidative stress has been found to be a primary mechanism behind this. In addition, DOX induced cardiotoxicity also shows involvement of proinflammatory cytokines such as IL-6 and TNF-α. Since oxidative stress plays major role in DOX induced cardiotoxicity, different antioxidants have been tried to prevent cardiotoxicity of DOX. Nanoparticles have risen up as a promising material with a wide variety of actions, and cerium oxide nanoparticles or nanoceria (NC) is one of such kind with great antioxidant potential. NC has emerged as a promising antioxidant in different pathological conditions. The present study was aimed to investigate possible protective effects of NC in DOX induced cardiotoxicity. Cardiotoxicity was induced in Swiss mice by DOX administration through i.p. route at a dose level of 15 mg/kg in two divided doses on alternate days. In our study, NC was found to mitigate cardiotoxic potential of DOX and prevented weight loss. NC restored the levels of cardiac injury markers lactate dehydrogenase (LDH) and creatinine kinase MB (CK-MB). Moreover, NC reduced malondialdehyde (MDA) levels and increased endogenous antioxidants such as reduced glutathione (GSH) and catalase levels. In addition, NC decreased proinflammatory cytokine levels and also prevented the alteration in normal structure of heart samples. Our study showed protective effects of NC in DOX induced cardiotoxicity which can become a potential therapeutic intervention against DOX induced cardiotoxicity.