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.

Rare earth cerium oxide nanoparticles attenuated liver fibrosis in bile duct ligation mice model.

Liver fibrosis is one of the major liver complications which eventually progresses to liver cirrhosis and liver failure. Cerium oxide nanoparticles, also known as nanoceria (NC) are nanoparticles with potential antioxidant and anti-inflammatory activities. Herein, we evaluated the hepatoprotective and anti-fibrotic effects of nanoceria (NC) against bile duct ligation (BDL) induced liver injury. NC were administered i.p. for 12 days (0.5 and 2 mg/kg) to C57BL/6J mice. The biochemical markers of liver injury, oxidative and nitrosative stress markers, inflammatory cytokines were evaluated. Fibrosis assessment and mechanistic studies were conducted to assess the hepatoprotective effects of NC. Administration of NC proved to significantly ameliorate liver injury as evident by reduction in SGOT, SGPT, ALP and bilirubin levels in the treated animals. NC treatment significantly reduced the hydroxyproline levels and expression of fibrotic markers. In summary, our findings establish the hepatoprotective and anti-fibrotic effects of NC against BDL induced liver injury and liver fibrosis. These protective effects were majorly ascribed to their potential ROS inhibition and antioxidant activities through catalase, superoxide dismutase (SOD)-mimetic properties and auto-regenerating capabilities.

Yttrium Oxide Nanoparticles Attenuate L-Arginine Induced Chronic Pancreatitis.

In this work, we tested the efficacy of yttrium oxide nanoparticles (NY), a promising antioxidant and anti-inflammatory agent, in L-arginine (L-Arg) induced chronic pancreatitis (CP) model. The nanoparticles were characterized using multiple techniques including transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (pXRD), and Energy dispersive X-ray analysis (EDX). The rats were divided into three groups: normal control, L-Arg control, L-Arg + NY (1 mg/kg). We probed the mechanistic effects of the NY by ELISA, multiplex analysis of TGF-ß pathway and inflammatory cytokines and immunoblotting. NY treatment significantly reduced pancreatic oxidative-nitrosative stress. In addition, NY intervention also reduced inflammatory cytokines and chemokines resulting in the inhibition of fibrosis signaling. Further, NY treatment suppressed the TGF-ß signaling and epithelial-mesenchymal transition (EMT). We conclude that NY shows potential antioxidant, anti-inflammatory, and anti-fibrotic effects against CP and associated fibrosis.

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.

COVID-19 and fibrosis: Mechanisms, clinical relevance, and future perspectives.

Coronavirus 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has had significant impacts worldwide since its emergence in December, 2019. Despite a high recovery rate, there is a growing concern over its residual, long-term effects. However, because of a lack of long-term data, we are still far from establishing a consensus on post-COVID-19 complications. The deposition of excessive extracellular matrix (ECM), known as fibrosis, has been observed in numerous survivors of COVID-19. Given the exceptionally high number of individuals affected, there is an urgent need to address the emergence of fibrosis post-COVID-19. In this review, we discuss the clinical relevance of COVID-19-associated fibrosis, the current status of antifibrotic agents, novel antifibrotic targets, and challenges to its management.

Disulfiram prevents collagen crosslinking and inhibits renal fibrosis by inhibiting lysyl oxidase enzymes.

Chronic kidney disease is one of the major health burdens affecting a considerable number of people worldwide. The aberrant regulation of lysyl oxidase (LOX) family of enzymes results in establishment of dense extracellular matrix (ECM). Since, LOX enzymes need copper (Cu) for their proper catalytic activity; the present study investigated the efficacy of a copper chelator, disulfiram (DSF) in renal fibrosis. Antifibrotic activity of DSF was investigated in kidney epithelial cells stimulated by transforming growth factor-ß1 (5 ng/ml) as well as in two animal models. The renal injury was induced in animals by unilateral ureteral obstruction and folic acid administration (250 mg/kg). The DSF (3 and 10 mg/kg, every 3rd day) and standard LOX inhibitor, ß-aminopropionitrile (BAPN, 100 mg/kg, daily) administration was started on day 0 and continued till the day of sacrifice. DSF was found to be a potent LOX/LOXL2 inhibitor to reduce crosslinking of collagen fibrils leading to reduction in the collagen deposition. In addition, the DSF was demonstrated to inhibit epithelial-mesenchymal transition in the tubular cells and fibrotic kidneys. Our results suggested that DSF, being a clinically available drug could be translated to clinics for its potent antifibrotic activity due to its inhibitory effect on LOX proteins.

Copper chelation therapy inhibits renal fibrosis by modulating copper transport proteins.

The copper (Cu) transporter proteins play an important role in the maintenance of the Cu homeostasis in the body. Lysyl oxidase (LOX) proteins are involved in crosslinking of collagens and elastin molecules resulting in the establishment of extracellular matrix (ECM) and require Cu for their functional activity. Although there are few reports showing the protective effects of Cu chelators, the mechanism behind protection remains unknown. The present study investigated the role of Cu transporter proteins in renal fibrosis. We used tubular epithelial cells and three different animal models of renal injury to investigate the induction of Cu transporter proteins in renal injury with different etiology. We used disulfiram, clioquinol as two Cu chelators and ammonium tetrathiomolybdate as a standard Cu chelator. In addition, ß-aminopropionitrile (BAPN) was used as a standard LOX inhibitor. We demonstrated that renal fibrosis is associated with the induction of Cu transporter proteins such as ATP7A and Copper Transporter 1 (CTR1) but the Cu overload did not induce renal fibrosis. In addition, the Cu chelators inhibited renal fibrosis by inhibiting the Cu transporter proteins.

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.

Silibinin alleviates silica-induced pulmonary fibrosis: Potential role in modulating inflammation and epithelial-mesenchymal transition.

Pulmonary fibrosis (PF) is a devastating interstitial lung disease resulting from indefinite causes with very few limited, those too ineffective therapeutic options. Earlier evidence reported inflammation and epithelial-mesenchymal transition (EMT) are the major threats in PF. The present study was aimed to examine the anti-fibrotic activity of silibinin (SB) in PF. PF was induced by administering oropharyngeal 1.5 mg/mice silica on day 1, followed by treatment with and without oral SB for 14 days. Lung injury was assessed by x-ray analysis on day 14 and all the animals were sacrificed on day 15. The results showed that silica remarkably altered the histoarchitecture and induced the expression of inflammatory components in BALF and pulmonary tissue. Immunoblotting investigation quantified the expression of TGF-ß, p-smad2/3, collagen-I, fibronectin, and α-SMA in the pulmonary tissue. To this end, treatment with SB alleviated inflammatory components, including IL-1ß, IL-6, and TNF-α in the fibrotic tissue. Moreover, SB harnessed the tissue architecture, improved diffusive scattering of x-ray signals, and modulated epithelial-mesenchymal phenotypic alterations, including TGF-ß, p-smad2/3, and collagen-I. Altogether, the significant reduction of inflammatory signaling, collagen deposition, and epithelial-mesenchymal transdifferentiation by SB suggested that it could be used as a potential therapeutic candidate to treat pulmonary inflammation and fibrosis.

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.

Molecular updates on berberine in liver diseases: Bench to bedside.

Liver diseases are life-threatening illnesses and are the major cause of mortality and morbidity worldwide. These may include liver fibrosis, liver cirrhosis, and drug-induced liver toxicity. Liver diseases have a wide prevalence globally and the fifth most common cause of death among all gastrointestinal disorders. Several novel therapeutic approaches have emerged for the therapy of liver diseases that may provide better clinical outcomes with improved safety. The use of phytochemicals for the amelioration of liver diseases has gained considerable popularity. Berberine (BBR), an isoquinoline alkaloid of the protoberberine type, has emerged as a promising molecule for the treatment of gastrointestinal disorders. Accumulating studies have proved the hepatoprotective effects of BBR. BBR has been shown to modulate multiple signaling pathways implicated in the pathogenesis of liver diseases including Akt/FoxO2, PPAR-γ, Nrf2, insulin, AMPK, mTOR, and epigenetic pathways. In the present review, we have emphasized the important pharmacological activities and mechanisms of BBR in liver diseases. Further, we have reviewed various pharmacokinetic and toxicological barriers of this promising phytoconstituent. Finally, formulation-based novel approaches are also summarized to overcome the clinical hurdles for BBR.

Ferulic acid ameliorates the progression of pulmonary fibrosis via inhibition of TGF-ß/smad signalling.

Natural products are one of the best sources for the discovery of novel drugs and compounds for multiple diseases. Pulmonary fibrosis (PF) is a chronic, progressive, irreversible, and fatal fibrotic disorder of lungs with unknown etiology and finite therapeutic choices. The use of naturally occurring phytomedicines has emerged to counteract many fibrotic disorders involving oxidative stress and inflammation. In the present study, we evaluated the protective effects of ferulic acid (FA), in an animal model of silica-induced PF. Pulmonary function of mice was evaluated by performing radiological analysis, bronchoalveolar lavage fluid (BALF), inflammatory cytokines, histology and protein expression studies. Our findings revealed that mice challenged with silica displayed characteristic features of pulmonary injury and fibrosis. However, treatment with FA significantly restored the accumulation of inflammatory cells in BALF. FA led to a partial reversal of silica-induced fibrotic changes in the pulmonary tissue. Subsequently, FA halts the progression of PF in a dose-dependent manner by ameliorating the expression of fibrotic proteins including collagen-I, TGF-ß, p-smad2/3 and prevented epithelial-mesenchymal transition (EMT). Collectively, the present study suggests that the inhibition of oxidative stress, inflammatory and TGF-ß/smad signalling might be involved in the observed anti-fibrotic benefits of FA against silica-induced PF in mice.

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?

A direct thrombin inhibitor, dabigatran etexilate protects from renal fibrosis by inhibiting protease activated receptor-1.

Chronic kidney disease (CKD) involves interstitial fibrosis as an influential underlying pathological process associated with compromised renal function regardless of etiological cause of the injury. The tubulointerstitial fibrosis is found to be well correlated with declining renal function and its subsequent culmination into renal failure. Given the prominent role of thrombin in multiple diseases, it was tempting for us to investigate the outcome of a direct thrombin inhibitor in renal injury. We investigated the involvement of thrombin in renal injury and fibrosis by using an FDA approved orally active, direct thrombin inhibitor, dabigatran etexilate (DB). We used a robust experimental model of unilateral ureteral obstruction (UUO)-induced renal injury which shows progressive tubulointerstitial fibrosis (TIF) along with tubular injury and inflammation. The obstructed kidney showed severe TIF as compared to control kidneys. The administration of DB significantly inhibited UUO-induced collagen-1 and TIF by inhibition of thrombin activated protease activated receptor (PAR)-1 expression in fibrotic kidney. In addition, DB administration improved histoarchitecture of obstructed kidney, inhibited TGF-ß and SNAI2-induced epithelial-mesenchymal transition (EMT) program. Our study highlights the importance of thrombin signalling in TIF and provides strong evidences to support the notion that a direct thrombin inhibitor ameliorates TIF by PAR-1 mediated mechanism.

Borneol protects against cerulein-induced oxidative stress and inflammation in acute pancreatitis mice model.

Borneol is a commonly used flavouring substance in traditional Chinese medicine, which possesses several pharmacological activities including analgesic, antiinflammatory, and antioxidant properties. The aim of this study was to investigate the effects of borneol on cerulein-induced acute pancreatitis (AP) model. Swiss albino mice were pretreated with borneol (100 and 300 mg/kg) daily for 7 days, before six consecutive injections of cerulein (50 µg/kg/hr, intraperitoneally). The protective effect of borneol was studied by biochemical, enzyme linked immunosorbent assay, histological, immunoblotting, and immunohistochemical analysis. Oral administration of borneol significantly attenuated pancreatic damage by reducing amylase, lipase levels and histological changes. Borneol attenuated cerulein-induced oxidative-nitrosative stress by decreasing malondialdehyde, nitrite levels, and elevating reduced glutathione levels. Pancreatic inflammation was ameliorated by inhibiting myeloperoxidase activity and pro-inflammatory cytokine (Interleukins and TNF-α) levels. Furthermore, borneol administration significantly increased nuclear factor E2-related factor 2 (Nrf2), superoxide dismutase (SOD1) expression and reduced phospho-NF-κB p65 expression. Treatment with borneol significantly inhibited TNF-α, IL-1ß, IL-6, and inducible nitric oxide synthase expression in cerulein-induced AP mouse model. Together, these results indicate that borneol which is currently used as US-FDA approved food adjuvant has the potential to attenuate cerulein-induced AP possibly by reducing the oxidative damage and pancreatic inflammation by modulating Nrf2/NF-κB pathway.

Piperlongumine attenuates bile duct ligation-induced liver fibrosis in mice via inhibition of TGF-ß1/Smad and EMT pathways.

Liver fibrosis (LF) is a progressive liver injury that may result in excessive accumulation of extracellular matrix (ECM). However, transforming growth factor-beta (TGF-ß) and epithelial to mesenchymal transition (EMT) play a central role in the progression of LF through the activation of matrix producing hepatic stellate cells (HSCs). Piperlongumine (PL), an alkaloid extracted from Piper longum, has been reported to possess anti-inflammatory and antioxidant activities in various diseases but its hepatoprotective and antifibrotic effects have not been reported yet. Therefore, in the present study, we investigated the protective effect of PL in bile duct ligation (BDL)-induced LF model and explored the molecular mechanisms underlying its antifibrotic effect. BDL group displayed a significant degree of liver damage, oxidative-nitrosative stress, hepatic inflammation and collagen deposition in the liver while these pathological changes were effectively attenuated by treatment with PL. Furthermore, we found that PL treatment greatly inhibited HSCs activation and ECM deposition via downregulation of fibronectin, α-SMA, collagen1a, and collagen3a expression in the fibrotic livers. We further demonstrated that PL administration significantly inhibited TGF-ß1/Smad and EMT signaling pathways. Our study demonstrated that PL exerted strong hepatoprotective and antifibrotic activities against BDL-induced LF and might be an effective therapeutic agent for the treatment of LF.

Riociguat ameliorates kidney injury and fibrosis in an animal model.

Chronic kidney disease (CKD) is one of the greatest health burdens with an increasing global prevalence. Renal fibrosis (RF) is the hallmark of all forms of CKD which shows a strong positive correlation with severity of the disease. However, there are no therapeutic options available for treatment of RF. In the present study, we used an animal model based on unilateral ureteral obstruction (UUO), for renal injury and fibrosis. The UUO animals were treated with soluble guanylyl cyclase (sGC) stimulator, riociguat (RIO) (1, 3 and 10 mg/kg) to investigate its possible renoprotective effects. Kidneys of animals treated with RIO were found to show less abnormalities as compared to UUO control. Further, the levels of proinflammatory cytokines were reduced in RIO treated group. Furthermore, administration of RIO reduced expression of collagen-1, TGF-ß, CTGF, α-SMA, vimentin along with transcription factors including Snail and Slug. The results of the present study provided strong evidence to support the antifibrotic activity of RIO.

Inhibition of lysyl oxidase ameliorates renal injury by inhibiting CD44-mediated pericyte detachment and loss of peritubular capillaries.

Renal fibrosis is a common pathological manifestation of almost all forms of kidney disease irrespective of the etiological cause. Microvascular rarefaction represents itself as an important phenomenon associated with renal fibrosis and shows strong correlation with decline in renal functions. Lysyl oxidase (LOX) catalyzes crosslinking of extracellular matrix (ECM) proteins including collagens, plays an important role in stabilization of degradation resistant matrix. Since, there seems to be a causal link between deposition of excessive ECM and microvascular rarefaction, we investigated the effects of reduction in renal fibrosis on microvascular rarefaction in acute as well as end stage kidney. We used a well-established unilateral ureteral obstruction (UUO)-induced renal fibrosis model to produce renal fibrosis in animals. We treated animals with a LOX inhibitor, ß-aminopropionitrile (BAPN, 100 mg/kg, i.p.) and investigated effects on renal fibrosis and microvascular rarefaction. We observed that LOX inhibition was associated with reduction in collagen deposition in UUO-induced renal fibrosis animal model. Further, ECM normalization by LOX inhibition decreased the loss of peritubular capillaries (PTCs) in fibrotic kidney in acute study while the LOX inhibition failed to inhibit PTCs loss in end stage kidney. The results of present study suggested that inhibition of LOX reduces collagen deposition and renal fibrosis. Further, the reduction in fibrosis fails to protect from PTCs loss in chronic study suggesting the absence of strong link between reduction in fibrosis and improvement in PTCs in an end stage kidney.

Leveraging the Pathophysiological Alterations of Obstructive Nephropathy to Treat Renal Fibrosis by Cerium Oxide Nanoparticles.

Chronic kidney disease (CKD) has wide prevalence globally that affects a considerable population and has renal fibrosis (RF) as a hallmark feature. RF is characterized by abnormal deposition of extracellular matrix (ECM) in the interstitial space of renal tissue. There are only few studies where nanoparticles (NPs) were used for targeting the kidney mainly due to their size-dependent constraints. Further, most of the studies have been carried out in healthy animals. As the diseased kidney becomes susceptible to accumulation of nanoparticles, we hypothesized that nanoparticles (size ∼10 nm) could reach the kidney and might provide protective effects due to their inherent properties. We investigated the protective effects of cerium oxide nanoparticles (CONPs) with promising antioxidant activity in a CKD model. We, to the best of our knowledge, are first to report that CONPs abrogated RF by inhibiting transforming growth factor-ß (TGF-ß) signaling and epithelial-mesenchymal transition (EMT) in a fibrotic kidney.