An Overview of the Anticancer Potential of Silver Nanostructures against Cervical Cancer.

Women are impacted by the extremely common cancer known as cervical cancer worldwide. Although preventive vaccines for cervical cancer are successful, treatment of cervical cancer is far less satisfactory because of multidrug resistance and side effects. There is an increasing need for alternative treatment modalities due to the rather aggressive and non-specific nature of conventional chemotherapeutics. With the advent of new technologies, scientists are working harder to create novel drug delivery strategies for chemotherapy of cervical cancer. Metal nanoparticles, and particularly silver nanoparticles, are a relatively new class with a lot of promise in the field of cancer biology. Nanoparticle therapeutics are attractive platforms for clinically relevant drug development because of their powerful anti-cancer properties, correspondingly attenuated side effects, and cancer-specific targeting. In this review, we provide an overview of the most recent uses of nanotechnology, particularly silver nanostructures, in the diagnosis and treatment of cervical cancer. The salient features of silver nanoparticle-based therapeutic concepts that are novel, viable, and attainable are emphasized in this review, along with those that pose a significant obstacle to their progress toward clinical application.

P53: A key player in diverse cellular processes including nuclear stress and ribosome biogenesis, highlighting potential therapeutic compounds.

The tumor suppressor proteins are key transcription factors involved in the regulation of various cellular processes, such as apoptosis, DNA repair, cell cycle, senescence, and metabolism. The tumor suppressor protein p53 responds to different type of stress signaling, such as hypoxia, DNA damage, nutrient deprivation, oncogene activation, by activating or repressing the expression of different genes that target processes mentioned earlier. p53 has the ability to modulate the activity of many other proteins and signaling pathway through protein-protein interaction, post-translational modifications, or non-coding RNAs. In many cancers the p53 is found to be mutated or inactivated, resulting in the loss of its tumor suppressor function and acquisition of new oncogenic properties. The tumor suppressor protein p53 also plays a role in the development of other metabolic disorders such as diabetes, obesity, and fatty liver disease. In this review, we will summarize the current data and knowledge on the molecular mechanisms and the functions of p53 in different pathways and processes at the cellular level and discuss the its implications for human health and disease.

Advances in molecular function of UPF1 in Cancer.

It is known that more than 10 % of genetic diseases are caused by a mutation in protein-coding mRNA (premature termination codon; PTC). mRNAs with an early stop codon are degraded by the cellular surveillance process known as nonsense-mediated mRNA decay (NMD), which prevents the synthesis of C-terminally truncated proteins. Up-frameshift-1 (UPF1) has been reported to be involved in the downregulation of various cancers, and low expression of UPF1 was shown to correlate with poor prognosis. It is known that UPF1 is a master regulator of nonsense-mediated mRNA decay (NMD). UPF1 may also function as an E3 ligase and degrade target proteins without using mRNA decay mechanisms. Increasing evidence indicates that UPF1 could serve as a good biomarker for cancer diagnosis and treatment for future therapeutic applications. Long non-coding RNAs (lncRNAs) have the ability to bind different proteins and regulate gene expression; this role in cancer cells has already been identified by different studies. This article provides an overview of the aberrant expression of UPF1, its functional properties, and molecular processes during cancer for clinical applications in cancer. We also discussed the interactions of lncRNA with UPF1 for cell growth during tumorigenesis.

Advances in Nrf2 Signaling Pathway by Targeted Nanostructured-Based Drug Delivery Systems.

Nanotechnology has gained significant interest in various applications, including sensors and therapeutic agents for targeted disease sites. Several pathological consequences, including cancer, Alzheimer's disease, autoimmune diseases, and many others, are mostly driven by inflammation and Nrf2, and its negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (Keap1), plays a crucial role in maintaining redox status, the expression of antioxidant genes, and the inflammatory response. Interestingly, tuning the Nrf2/antioxidant response element (ARE) system can affect immune-metabolic mechanisms. Although many phytochemicals and synthetic drugs exhibited potential therapeutic activities, poor aqueous solubility, low bioavailability, poor tissue penetration, and, consequently, poor specific drug targeting, limit their practical use in clinical applications. Also, the therapeutic use of Nrf2 modulators is hampered in clinical applications by the absence of efficient formulation techniques. Therefore, we should explore the engineering of nanotechnology to modulate the inflammatory response via the Nrf2 signaling pathway. This review will initially examine the role of the Nrf2 signaling pathway in inflammation and oxidative stress-related pathologies. Subsequently, we will also review how custom-designed nanoscale materials encapsulating the Nrf2 activators can interact with biological systems and how this interaction can impact the Nrf2 signaling pathway and its potential outcomes, emphasizing inflammation.

An intricate rewiring of cancer metabolism via alternative splicing.

All human genes undergo alternative splicing leading to the diversity of the proteins. However, in some cases, abnormal regulation of alternative splicing can result in diseases that trigger defects in metabolism, reduced apoptosis, increased proliferation, and progression in almost all tumor types. Metabolic dysregulations and immune dysfunctions are crucial factors in cancer. In this respect, alternative splicing in tumors could be a potential target for therapeutic cancer strategies. Dysregulation of alternative splicing during mRNA maturation promotes carcinogenesis and drug resistance in many cancer types. Alternative splicing (changing the target mRNA 3'UTR binding site) can result in a protein with altered drug affinity, ultimately leading to drug resistance.. Here, we will highlight the function of various alternative splicing factors, how it regulates the reprogramming of cancer cell metabolism, and their contribution to tumor initiation and proliferation. Also, we will discuss emerging therapeutics for treating tumors via abnormal alternative splicing. Finally, we will discuss the challenges associated with these therapeutic strategies for clinical applications.

Cancer Prevention and Therapy by Targeting Oxidative Stress Pathways.

Oxidative stress arises from the inadequate production of reactive oxygen species (ROS) which couldn't be neutralized by antioxidant defense [...].

Recoding of Nonsense Mutation as a Pharmacological Strategy.

Approximately 11% of genetic human diseases are caused by nonsense mutations that introduce a premature termination codon (PTC) into the coding sequence. The PTC results in the production of a potentially harmful shortened polypeptide and activation of a nonsense-mediated decay (NMD) pathway. The NMD pathway reduces the burden of unproductive protein synthesis by lowering the level of PTC mRNA. There is an endogenous rescue mechanism that produces a full-length protein from a PTC mRNA. Nonsense suppression therapies aim to increase readthrough, suppress NMD, or are a combination of both strategies. Therefore, treatment with translational readthrough-inducing drugs (TRIDs) and NMD inhibitors may increase the effectiveness of PTC suppression. Here we discuss the mechanism of PTC readthrough and the development of novel approaches to PTC suppression. We also discuss the toxicity and bioavailability of therapeutics used to stimulate PTC readthrough.

Ribosomopathies and cancer: pharmacological implications.

INTRODUCTION: The ribosome is a ribonucleoprotein organelle responsible for protein synthesis, and its biogenesis is a highly coordinated process that involves many macromolecular components. Any acquired or inherited impairment in ribosome biogenesis or ribosomopathies is associated with the development of different cancers and rare genetic diseases. Interference with multiple steps of protein synthesis has been shown to promote tumor cell death. AREAS COVERED: We discuss the current insights about impaired ribosome biogenesis and their secondary consequences on protein synthesis, transcriptional and translational responses, proteotoxic stress, and other metabolic pathways associated with cancer and rare diseases. The modulation of different therapeutic chemical entities targeting cancer in in vitro and in vivo models have also been detailed. EXPERT OPINION: Despite the association between inherited mutations affecting ribosome biogenesis and cancer biology, the development of therapeutics targeting the essential cellular machinery has only started to emerge. New chemical entities should be designed to modulate different checkpoints (translating oncoproteins, dysregulation of specific ribosome-assembly machinery, ribosomal stress, and rewiring ribosomal functions). Although safe and effective therapies are lacking, consideration should be given to using existing drugs alone or in combination for long-term safety, with known risks for feasibility in clinical trials and synergistic effects.

Oxidative Stress and Cancer Heterogeneity Orchestrate NRF2 Roles Relevant for Therapy Response.

Oxidative stress and its end-products, such as 4-hydroxynonenal (HNE), initiate activation of the Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)/Kelch Like ECH Associated Protein 1 (KEAP1) signaling pathway that plays a crucial role in the maintenance of cellular redox homeostasis. However, an involvement of 4-HNE and NRF2 in processes associated with the initiation of cancer, its progression, and response to therapy includes numerous, highly complex events. They occur through interactions between cancer and stromal cells. These events are dependent on many cell-type specific features. They start with the extent of NRF2 binding to its cytoplasmic repressor, KEAP1, and extend to the permissiveness of chromatin for transcription of Antioxidant Response Element (ARE)-containing genes that are NRF2 targets. This review will explore epigenetic molecular mechanisms of NRF2 transcription through the specific molecular anatomy of its promoter. It will explain the role of NRF2 in cancer stem cells, with respect to cancer therapy resistance. Additionally, it also discusses NRF2 involvement at the cross-roads of communication between tumor associated inflammatory and stromal cells, which is also an important factor involved in the response to therapy.

Activation of Nrf2 signaling pathway by natural and synthetic chalcones: a therapeutic road map for oxidative stress.

Introduction:Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway plays a key role in diverse gene expressions responsible for protection against oxidative stress and xenobiotics. Chalcones with a common chemical scaffold of 1,3-diaryl-2- propen-1-one, are abundantly present in nature with a wide variety of pharmacological properties. This review will discuss the interactions of natural and synthetic chalcones with Nrf2 signaling.Areas covered:Chalcones are reportedly found to activate Nrf2 signaling pathway, expression of Nrf2-regulated antioxidant genes, induce cytoprotective proteins and upregulate multidrug resistance-associated proteins. Chalcones being soft electrophiles are less prone to hostile off-target effects and unlikely to induce carcinogenicity and mutagenicity. Furthermore, their low toxicity, structural diversity, feasibility in structural reorganization and the presence of α,ß-unsaturated carbonyl group which makes them suitable drug candidates targeting Nrf2-dependent diseases.Expert opinion:Nrf2-Keap1 signaling pathway plays a central role in redox signaling. However, available therapeutic agents for Nrf2 activation have limited practical applications due to their associated risks, relatively low efficacy and bioavailability. The designing and fabrication of new chemical entities with chalcone scaffold-based Michael acceptor mechanism should be aimed as potential therapeutic Nrf2 activators to target oxidative stress and inflammation-mediated diseases such as atherosclerosis, Parkinson's disease and many more.

An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation.

Inflammation is a key driver in many pathological conditions such as allergy, cancer, Alzheimer's disease, and many others, and the current state of available drugs prompted researchers to explore new therapeutic targets. In this context, accumulating evidence indicates that the transcription factor Nrf2 plays a pivotal role controlling the expression of antioxidant genes that ultimately exert anti-inflammatory functions. Nrf2 and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH- associated protein 1 (Keap1), play a central role in the maintenance of intracellular redox homeostasis and regulation of inflammation. Interestingly, Nrf2 is proved to contribute to the regulation of the heme oxygenase-1 (HO-1) axis, which is a potent anti-inflammatory target. Recent studies showed a connection between the Nrf2/antioxidant response element (ARE) system and the expression of inflammatory mediators, NF-κB pathway and macrophage metabolism. This suggests a new strategy for designing chemical agents as modulators of Nrf2 dependent pathways to target the immune response. Therefore, the present review will examine the relationship between Nrf2 signaling and the inflammation as well as possible approaches for the therapeutic modulation of this pathway.

Lupeol Counteracts the Proinflammatory Signalling Triggered in Macrophages by 7-Keto-Cholesterol: New Perspectives in the Therapy of Atherosclerosis.

Macrophage activation and polarization play a central role in atherosclerotic plaque fate. The M1/M2 activation phenotypes represent two profiles of the macrophage polarization state. During atherosclerosis regression or stabilization, macrophages switch from M1 proinflammatory phenotype to M2 anti-inflammatory reparative one. Here, we investigated whether the natural compound lupeol, a pentacyclic triterpene, induces phenotypical and functional changes in human M1 macrophages and counteracts the proinflammatory signalling triggered by 7-keto-cholesterol (7KC), a major product of oxidative stress-mediated cholesterol oxidation. Flow cytometric and immunochemical analysis showed that the treatment with lupeol of M1 monocyte-derived macrophages M (IFN-γ/LPS) specifically stimulated these cells to upregulate the expression of the anti-inflammatory cytokines interleukin- (IL-)10 and TGF-ß, and of the scavenger receptor CD36, whereas downregulated the proinflammatory cytokine IL-12 and the M1 activation marker HLA-DR. Pretreatment of macrophages with lupeol prevented the release of IL-12, IL-1ß, and the upregulation of HLA-DR expression triggered by 7KC and increased the IL-10 production and CD36 expression. This treatment also prevented the impairment of endocytosis triggered by 7KC and prevented 7KC-induced foam cell formation by reducing the lipid droplet accumulation in M1-polarized THP-1 macrophages, whereas showed an additive effect in reactive oxygen species (ROS) production. Western blotting analysis of autophagy markers LC3-I/II and p62-SQSTM1 in M1-polarized THP-1 macrophages demonstrated that lupeol activated autophagy as indicated by increased LC3-II levels, and by marked inhibition of p62. These findings indicate that lupeol has a cytoprotective effect on 7KC-proinflammatory signalling by efficiently switching the macrophage polarization toward an anti-inflammatory phenotype, probably through the activation of the autophagy pathway by increasing ROS production, the reduction of cellular lipid accumulation, and an overall reduction of proinflammatory phenotype. Thus, our data demonstrating an anti-inflammatory and immunomodulatory activity of lupeol in human M1 macrophages suggest its usefulness as an adjunctive drug in the therapy of atherosclerosis.

Isolation and prevention of calcium oxalate-induced apoptotic death and oxidative stress in MDCK cells by diosgenin.

Calcium oxalate monohydrate (COM) has been shown to be the most frequent constituent of kidney stones. The interactions of cells with COM crystals produce a variety of physiological and pathological changes including the development of oxidative stress, cellular injury and apoptosis. On the other hand, diosgenin, a steroidal sapogenin, is well known for its antioxidant activity. Therefore, the aim of this study was to evaluate whether diosgenin protects MDCK renal epithelial cells from COM-induced apoptotic death. Diosgenin was isolated from fruits of Solanum xanthocarpum by silica gel column chromatography. It was obtained in high yields (1.23%) and the purity was ascertained by HPTLC analysis. Characterization of diosgenin was done by mp, UV-visible spectrophotometry, elemental analysis, FT-IR, (1)H NMR and (13)C NMR analysis. Cells were co-incubated with COM (80µg/cm(2)) and diosgenin (2.5, 5, 7.5 and 10µg/mL) for 24h. It was found that diosgenin attenuated the apoptotic death induced by COM as measured in terms of cell viability, caspase -9/3 activities and DNA fragmentation percent. The inhibitory role of diosgenin on caspase -9/3 activities was also analyzed using molecular docking experiments, which showed interactions to their active sites by H-bonds. Diosgenin also attenuated the increase in lipid peroxidation and glutathione depletion induced by COM crystals. In conclusion, the preventive effect of diosgenin is associated to the inhibition of oxidative stress and caspases.

Antioxidative mechanism involved in the preventive efficacy of Bergenia ciliata rhizomes against experimental nephrolithiasis in rats.

CONTEXT: Bergenia ciliata Haw. (Saxifragaceae) is widely used in traditional medicines for renal disorders including kidney stones, inflammation and also well known for its antioxidant activity. Use of traditional herbs proved to be an important strategy for the management of kidney stones by modulating the oxidative stress imposed by calcium oxalate nephrolithiasis. OBJECTIVES: To evaluate the antinephrolithiatic and antioxidative activity of B. ciliata rhizomes as a preventive agent on ethylene glycol (EG)-induced nephrolithiasis. MATERIALS AND METHODS: The hydro-methanol extract (30:70, v/v) of B. ciliata rhizomes was orally administrated simultaneously at a dose of 150 and 300 mg/kg body weight/day, to adult female Wistar rats for 28 d along with EG (0.75%, v/v) in drinking water. The results were compared to a parallel study conducted with marketed polyherbal drug cystone under identical dosage conditions. The biochemical parameters were measured in urine, serum and kidney followed by histochemistry. A validated HPLC method was used for standardization using gallic acid as a marker. RESULTS: EG caused a significant increase in calcium, oxalate and phosphate levels in urine and kidney and concurrent decrease in calcium, sodium and magnesium in serum (p<0.001). EG also caused an increase in lipid peroxidation and a decrease in activities of antioxidative enzymes in kidney. Co-treatment with B. ciliata rhizomes extract caused restoration of all these parameters (p<0.001). Histochemical studies showed reduced calcifications with extract treatment. CONCLUSION: B. ciliata has a significant prophylactic effect in preventing the nephrolithiasis, which might be mediated through antioxidant activity of these active compounds.

Inhibition of calcium oxalate crystallisation in vitro by an extract of Bergenia ciliata.

OBJECTIVE: To evaluate the effectiveness of an extract obtained from the rhizomes of Bergenia ciliata (Saxifragaceae) on the inhibition of calcium oxalate (CaOx) crystallisation in vitro. MATERIALS AND METHODS: A hydro-alcoholic extract (30:70, v/v) of rhizomes of B. ciliata was prepared at different concentrations (1-10 mg/mL). The crystallisation of CaOx monohydrate (COM) was induced in a synthetic urine system. The nucleation and aggregation of COM crystals were measured using spectrophotometric methods. The rates of nucleation and aggregation were evaluated by comparing the slope of the turbidity of a control system with that of one exposed to the extract. The results were compared with a parallel study conducted with a marketed poly-herbal combination, Cystone, under identical concentrations. Crystals generated in the urine were also analysed by light microscopy. Statistical differences and percentage inhibitions were calculated and assessed. RESULTS: The extract of B. ciliata was significantly more effective in inhibiting the nucleation and aggregation of COM crystals in a dose-dependent manner than was Cystone. Moreover, the extract induced more CaOx dihydrate crystals, with a significant reduction in the number and size of COM crystals. CONCLUSION: An extract of the traditional herb B. ciliata has an excellent inhibitory activity on crystalluria and therefore might be beneficial in dissolving urinary stones. However, further study in animal models of urolithiasis is needed to evaluate its potential anti-urolithiatic activity.

Bergenia ciliata extract prevents ethylene glycol induced histopathological changes in the kidney.

The present investigation is an attempt to evaluate the effect of Bergenia ciliata extract on kidney of ethylene glycol induced urolithiasis in adult female Wistar rats. The hydro-alcoholic extract of Bergenia ciliata/standard drug cystone were administrated simultaneously at a dose of 150 and 300 mg/kg body weight/day, p.o. along with ethylene glycol (0.75% v/v) for 28 days. Significant changes were observed in body weight and absolute organ weight of ethylene glycol treated rats. Also histopathological results showed disrupted renal parenchyma, degenerative changes in glomeruli and focal calcification in glomerulo-tubular structures in ethylene glycol treated animals. Administration of Bergenia ciliata extract/cystone along with ethylene glycol showed significant protective effect in body weight and organ weight with few stray areas of calcifications in glomeruli. Moreover, Bergenia ciliata extract shows higher renoprotective index than cystone at the same dose level.

CXCR7/CXCR4 heterodimer constitutively recruits beta-arrestin to enhance cell migration.

G protein-coupled receptor hetero-oligomerization is emerging as an important regulator of ligand-dependent transmembrane signaling, but precisely how receptor heteromers affect receptor pharmacology remains largely unknown. In this study, we have attempted to identify the functional significance of the heteromeric complex between CXCR4 and CXCR7 chemokine receptors. We demonstrate that co-expression of CXCR7 with CXCR4 results in constitutive recruitment of ß-arrestin to the CXCR4·CXCR7 complex and simultaneous impairment of G(i)-mediated signaling. CXCR7/CXCR4 co-expression also results in potentiation of CXCL12 (SDF-1)-mediated downstream ß-arrestin-dependent cell signaling pathways, including ERK1/2, p38 MAPK, and SAPK as judged from the results of experiments using siRNA knockdown to deplete ß-arrestin. Interestingly, CXCR7/CXCR4 co-expression enhances cell migration in response to CXCL12 stimulation. Again, inhibition of ß-arrestin using either siRNA knockdown or a dominant negative mutant abrogates the enhanced CXCL12-dependent migration of CXCR4/CXCR7-expressing cells. These results show how CXCR7, which cannot signal directly through G protein-linked pathways, can nevertheless affect cellular signaling networks by forming a heteromeric complex with CXCR4. The CXCR4·CXCR7 heterodimer complex recruits ß-arrestin, resulting in preferential activation of ß-arrestin-linked signaling pathways over canonical G protein pathways. CXCL12-dependent signaling of CXCR4 and its role in cellular physiology, including cancer metastasis, should be evaluated in the context of potential functional hetero-oligomerization with CXCR7.

Encodable activators of SRC family kinases.

There is considerable current interest in the design of encodable molecules that regulate intracellular protein circuitry and/or activity, ideally with a high level of specificity. Src homology 3 (SH3) domains are ubiquitous components of multidomain signaling proteins, including many kinases, and are attractive drug targets because of the important role their interactions play in diseases as diverse as cancer, osteoporosis, and inflammation. Here we describe a set of miniature proteins that recognize distinct SH3 domains from Src family kinases with high affinity. Three of these molecules discriminate effectively between the SH3 domains of Src and Fyn, which are expressed ubiquitously, and two of these three activate Hck kinase with potencies that rival HIV Nef, one of the most potent kinase activators known. These results suggest that miniature proteins represent a viable, encodable strategy for selective activation of Src family kinases in a variety of cell types.