Cancer is one of the high-profile diseases and is responsible for millions of deaths worldwide every year. Even though there are many therapeutic strategies (natural and chemical), many issue have been still unresolved in order to advance cancer therapy. For this, a lot of efforts are being put forwarded by oncology research to find new and efficient anticancer therapeutical strategies that can overcome the discomfort caused by conventional methods. Many of the chemically derived drugs and anticancer treatments already exist, but are known to have toxic effects. Hence, the demand for naturally derived anticancer agents is used as an alternative for which nature remains the main supplier, especially plants. Many plant-derived secondary metabolites, like alkaloids, brassinosteroids, flavonoids, polyphenols, and phytosterols, have potential as anticancer agents, unaided or in formulations, and have antioxidant activity, apoptosis induction, cancer cell line inhibition and cytotoxicity, multitarget specificity, etc. Many of these plant-derived drugs preexist in research and have been cleared for clinical trials, mostly in phases I–III. This chapter provides a thorough overview of the therapeutic drugs derived from plants and also advances a clinical assessment of recently investigated natural compounds in terms of their anticancer modes of action. Besides, some new technologies like nanococheleates, nanoparticles, and nanoliposomes are being used in the administration of anticancer therapies for target specificity. These plant-derived anticancer agents are in high demand as they are efficient inhibitors of cancer cells lines; hence, their exploration needs to be managed to be sustainable. These have the potential to minimize the harmful effects typically associated with conventional medicines. Unlike certain synthetic drugs, herbal medicines being derived from plant sources and may possess compounds that have a lower risk of toxicity or adverse reactions. Finally, the current review describes an in-depth analysis of the most innovative advances of several efficient therapeutic natural agents for the encapsulation and target specificity in basic and applied cancer research.

The contribution of the Ubiquitin-Proteasome System (UPS) to mitophagy has been largely attributed to the E3 ubiquitin ligase Parkin. Here we show that in response to the oxidative stress associated with hypoxia or the hypoxia mimic CoCl2, the damaged and fragmented mitochondria are removed by Parkin-independent mitophagy. Mitochondria isolated from hypoxia or CoCl2-treated cells exhibited extensive ubiquitination, predominantly Lysine 48-linked and involves the degradation of key mitochondrial proteins such as the mitofusins MFN1/2, or the import channel component TOM20. Reflecting the critical role of mitochondrial protein degradation, proteasome inhibition blocked CoCl2-induced mitophagy. The five conserved ubiquitin-binding autophagy receptors (p62, NDP52, Optineurin, NBR1, TAX1BP1) were dispensable for the ensuing mitophagy, suggesting that the mitophagy step itself was independent of ubiquitination. Instead, the expression of two ubiquitin-independent mitophagy receptor proteins BNIP3 and NIX was induced by hypoxia or CoCl2-treatment followed by their recruitment to the oxidation-damaged mitochondria. By employing BNIP3/NIX double knockout and DRP1-null cell lines, we confirmed that mitochondrial clearance relies on DRP1-dependent mitochondrial fragmentation and BNIP3/NIX-mediated mitophagy. General antioxidants such as N-Acetyl Cysteine (NAC) or the mitochondria-specific Mitoquinone prevented HIF-1α stabilization, ameliorated hypoxia-related mitochondrial oxidative stress, and suppressed mitophagy. We conclude that the UPS and receptor-mediated autophagy converge to eliminate oxidation-damaged mitochondria.

Of all ubiquitin-like small protein modifiers, Rub1/NEDD8 is the closest kin of ubiquitin in sequence and in structure. Despite their profound similarities, prevalence of ubiquitin and of Rub1 is starkly different: targets of ubiquitin modification reach into the thousands, whereas unique targets of Rub1/NEDD8 appear limited to one family of proteins, Cullins. This distinction is likely due to dedicated E1 activating enzymes that select either one or the other and relay the modifier until it is covalently attached to a target. To convert typical neddylation targets for modification by ubiquitin, and vice versa, we designed reciprocal substitutions at position 72 of Rub1 and of ubiquitin to render them substrates for activation by their non-cognate E1 activating enzymes. We found that this single amino acid is sufficient to distinguish between Ub and Rub1 in living cells, and determine their targets. Thus, modification of Cullins by UbR72T could compensate for loss of Rub1, even as it maintained its ability to polymerize and direct conjugates for degradation. Conversely, Rub1T72R activated by ubiquitin-activating enzyme entered into the ubiquitination cascade, however was not efficiently polymerized, essentially capping polyubiquitin chains. Upon shortage of free ubiquitin under stress, even native Rub1 spilled-over into the ubiquitinome suppressing polyubiquitination. By contrast, the need to maintain monomeric modifications on unique targets is a likely explanation for why the Rub1-activating enzyme strictly discriminates against ubiquitin. Swapping Rub1 and ubiquitin signals uncovered a reason for maintaining two separate pathways across eukaryotic kingdom. ### Competing Interest Statement The authors have declared no competing interest.

Strict quality control for mitochondrial proteins is necessary to ensure cell homeostasis. Two cellular pathways-Ubiquitin Proteasome System (UPS) and autophagy-contribute to mitochondrial homeostasis under stressful conditions. Here, we investigate changes to the mitochondria proteome and to the ubiquitin landscape at mitochondria in response to proteasome inhibition. Treatment of HeLa cells devoid of Parkin, the primary E3 ligase responsible for mitophagy, with proteasome inhibitor MG132 for a few hours caused mitochondrial oxidative stress and fragmentation, reduced energy output, and increased mitochondrial ubiquitination without inducing mitophagy. Overexpression of Parkin did not show any induction of mitophagy in response to MG132 treatment. Analysis of ubiquitin chains on isolated mitochondria revealed predominance of K48, K29 and K63linked polyubiquitin. Interestingly, of all ubiquitinated mitochondrial proteins detected in response to MG132 treatment, a majority (>= 90%) were intramitochondrial irrespective of Parkin expression. However, overall levels of these ubiquitinated mitochondrial proteins did not change significantly upon proteasome inhibition when evaluated by quantitative proteomics (LFQ and SILAC), suggesting that only a small portion are ubiquitinated under basal conditions. Another aspect of proteasome inhibition is significant enrichment of UPS, lysosomal and phagosomal components, and other heat shock proteins associated with isolated mitochondria. Taken together, our study highlights a critical role of UPS for ubiquitinating and removing imported proteins as part of a basal mitochondrial quality control system independent of Parkin. Significance: As centers of cellular bioenergetics, numerous metabolic pathways and signaling cascades, the health of mitochondria is of utmost importance for ensuring cell survival. Due to their unique physiology, mitochondria are constantly subjected to damaging oxidative radicals (ROS) and protein import-related stress due to buildup of unfolded aggregate-prone proteins. Thus, for quality control purposes, mitochondria are constantly under surveillance by Autophagy and the Ubiquitin Proteasome System (UPS), both of which share ubiquitin as a common signal. The ubiquitin landscape of mitochondria has been studied in detail under stressful conditions, however, little is known about basal mitochondrial ubiquitination. Our study reveals that the extent of ubiquitination at mitochondria greatly increases upon proteasome inhibition, pointing to a large number of potential substrates for proteasomal degradation. Interestingly, most of the ubiquitination occurs on intramitochondrial proteins, components of the electron transport chain (ETC) and matrix-resident metabolic enzymes in particular. Moreover, numerous cytosolic UPS components, chaperones and autophagy-lysosomal proteins were recruited to mitochondria upon proteasome inhibition. Taken together, this suggests that the levels and functions of mitochondrial proteins are constantly regulated through ubiquitin-dependent proteasomal degradation even under basal conditions. Unclogging mitochondrial import channels may provide a mechanism to alleviate stress associated with mitochondrial protein import or to adapt cells according to their metabolic needs. Therefore, targeting the mitochondrial ubiquitination/deubiquitination machinery, such as improving the therapeutic potency of proteasome inhibitors, may provide an additional therapeutic arsenal against tumors.

Synthesis of nanoparticles using green synthetic route achieving much more importance, because of its simple, clean, nontoxic and eco-friendly approach and it is a better alternate for chemical and physical methods.This work demonstrates the bio-synthetic route for the synthesis of zinc oxide nanoparticles using Paspalidium flavidum (weed grass) plant extract.The synthesized nanoparticles were characterized using various analytical techniques.The photocatalytic degradation of amido black 10B dye was also performed using prepared nanoparticles under sunlight luminance.The antibacterial activity against Bacillus subtilis and Pseudomonas aeruginosa bacteria confirmed that biosynthesized nanoparticles exhibit excellent activity against B. subtilis.

The discovery of ubistatins, small molecules that impair proteasomal degradation of proteins by directly binding to polyubiquitin, makes ubiquitin itself a potential therapeutic target. Although ubistatins have the potential for drug development and clinical applications, the lack of structural details of ubiquitin-ubistatin interactions has impeded their development. Here, we characterized a panel of new ubistatin derivatives using functional and binding assays. The structures of ubiquitin complexes with ubistatin B and hemi-ubistatin revealed direct interactions with ubiquitin's hydrophobic surface patch and the basic/polar residues surrounding it. Ubistatin B binds ubiquitin and diubiquitin tighter than a high-affinity ubiquitin receptor and shows strong preference for K48 linkages over K11 and K63. Furthermore, ubistatin B shields ubiquitin conjugates from disassembly by a range of deubiquitinases and by the 26S proteasome. Finally, ubistatin B penetrates cancer cells and alters the cellular ubiquitin landscape. These findings highlight versatile properties of ubistatins and have implications for their future development and use in targeting ubiquitin-signaling pathways.

The present investigation describes the conversion of waste product into effective adsorbent and its application for the treatment of wastewater, i.e., chemically modified solid waste from paper industry has been tested for its adsorption ability for the successful removal of Rhodamine B dye from its aqueous solution. The adsorption isotherm, kinetics and thermodynamic parameters of process have been determined by monitoring the different parameters, such as effect of pH, amount of adsorbent dose, concentration, contact time and temperature. The equilibrium data has been well described on the basis of various adsorption isotherms, namely Langmuir, Freundlich and Temkin adsorption isotherm. From Langmuir isotherm, the maximum monolayer adsorption capacity has been found to be 6.711 mg g −1 at 308 K temperature. The kinetics of adsorption has been studied using pseudo-first order, pseudo-second order and intra-particle diffusion model and the results show that kinetics has been well described by pseudo-second order. Thermodynamic parameters, such as free energy change (Δ G ), enthalpy change (Δ H ) and entropy change (Δ S ), have been evaluated. The free energy has been obtained as −11.9452 kJ mol −1 for 75 mg L −1 concentration at 308 K temperature. Desorption and recycling efficiency of adsorbent has been studied and the adsorbent shows good recycling efficiency.

Excess cellular iron increases reactive oxygen species (ROS) production and causes cellular damage. Mitochondria are the major site of iron metabolism and ROS production; however, few studies have investigated the role of mitochondrial iron in the development of cardiac disorders, such as ischemic heart disease or cardiomyopathy (CM). We observe increased mitochondrial iron in mice after ischemia/reperfusion (I/R) and in human hearts with ischemic CM, and hypothesize that decreasing mitochondrial iron protects against I/R damage and the development of CM. Reducing mitochondrial iron genetically through cardiac-specific overexpression of a mitochondrial iron export protein or pharmacologically using a mitochondria-permeable iron chelator protects mice against I/R injury. Furthermore, decreasing mitochondrial iron protects the murine hearts in a model of spontaneous CM with mitochondrial iron accumulation. Reduced mitochondrial ROS that is independent of alterations in the electron transport chain's ROS producing capacity contributes to the protective effects. Overall, our findings suggest that mitochondrial iron contributes to cardiac ischemic damage, and may be a novel therapeutic target against ischemic heart disease.

Department of Chemistry, Punjabi University, Patiala, India. Corresponding Author: preetjudge@yahoo.co.in _____________________________________________________________________________________ Abstract Various severe environmental problems have been caused by the effluents coming from dye industries, as it contain a mixture of chemicals and dyestuff, which are very toxic to living organisms. The present work has been designed with an aim to use inexpensive and efficient technique for the removal of dyes. The present investigation revealed a potential use of Pine cone charcoal (PCC), pretreated with H2SO4 for the removal of hazardous Rhodamine B dye from aqueous solution. The adsorbent has been characterized with the help of FT-IR and SEM analysis. The adsorption studies have been carried out at different temperatures, adsorbent dose, dye concentrations and pH. The experimental data has been analyzed by Langmuir, Freundlich and Temkin adsorption isotherms and data fitted well for all these models. Thermodynamic parameters, i.e. change in free energy, enthalpy and entropy have also been evaluated. The negative value of free energy indicates the spontaneous nature and the positive value of enthalpy suggest the endothermic nature of the process. The adsorption of Rhodamine B follows Pseudo-second-order kinetics and intra-particle-diffusion model.

Despite recent advances, the role of ROS in mediating hypertrophic and apoptotic responses in cardiac myocytes elicited by norepinephrine (NE) is rather poorly understood. We demonstrate through our experiments that H9c2 cardiac myoblasts treated with 2 µM NE (hypertrophic dose) generate DCFH-DA positive ROS only for 2h; while those treated with 100 µM NE (apoptotic dose) sustains generation for 48 h, followed by apoptosis. Though the levels of DCFH fluorescence were comparable at early time points in the two treatment sets, its quenching by DPI, catalase and MnTmPyP suggested the existence of a different repertoire of ROS. Both doses of NE also induced moderate levels of H2O2 but with different kinetics. Sustained but intermittent generation of highly reactive species detectable by HPF was seen in both treatment sets but no peroxynitrite was generated in either conditions. Sustained generation of hydroxyl radicals with no appreciable differences were noticed in both treatment sets. Nevertheless, despite similar profile of ROS generation between the two conditions, extensive DNA damage as evident from the increase in 8-OH-dG content, formation of γ-H2AX and PARP cleavage was seen only in cells treated with the higher dose of NE. We therefore conclude that hypertrophic and apoptotic doses of NE generate distinct but comparable repertoire of ROS/RNS leading to two very distinct downstream responses.

Background: Maintaining mitochondrial iron balance is critical for normal cardiac function. We showed earlier that deletion of ATP-binding cassette B8 (ABCB8) protein which facilitates mitochondrial iron export results in mitochondrial iron accumulation, oxidative stress, dysfunction of cytosolic iron-sulfur (Fe/S) cluster proteins, and spontaneous development of cardiomyopathy in mice. Given the complex phenotype, it remains unexplored which of these processes are responsible for cytotoxicity with ABCB8 deletion. This study has characterized the effects of mitochondrial iron accumulation due to ABCB8 knockdown (KD) or knockout (KO) on cellular survival, and potential communication between the mitochondria and cytoplasm in sensing iron levels. Results: To reverse mitochondrial iron accumulation with ABCB8 KD, we treated cells with various iron chelators, or with siRNA against mitoferrin-2 (MFRN2), the primary mitochondrial iron importer in cardiomyocytes. Both iron chelators and MFRN2 siRNA reversed mitochondrial iron accumulation, ROS production and cell death resulting from ABCB8 KD, suggesting that mitochondrial iron overload mediates cytotoxicity of ABCB8 deletion. To determine if the defect in cytosolic Fe/S proteins was primarily due to mitochondrial iron deregulation or was secondary to increased oxidative stress, we measured cytosolic Fe/S protein activity with iron chelators, MFRN2 siRNA, or antioxidant treatments. Neither MFRN2 siRNA nor various antioxidants were able to reverse inactivation of cytosolic Fe/S proteins with ABCB8 KD. However, iron chelator treatment rescued Fe/S protein activities in ABCB8 KD cells. Similarly, iron chelators reversed mitochondrial iron accumulation and restored activity of cytosolic Fe/S proteins in hearts from ABCB8 KO mice. Thus, the defect in maturation of cytosolic Fe/S proteins is independent of the oxidative stress, but is a direct effect of mitochondrial iron overload. Conclusions: Cytotoxicity of ABCB8 KD and the defect in cytosolic Fe/S cluster maturation are due to mitochondrial iron accumulation, but not the associated oxidative stress. Moreover, our results suggest that mitochondrial iron is sensed in the cytoplasm and influences maturation of cytosolic Fe/S proteins.

ATP-binding cassette (ABC)-B8 is an ABC half transporter that resides in the inner mitochondrial membrane. We previously showed that ABCB8 has a role in mitochondrial iron export, and that a reduction in ABCB8 both in vitro and in vivo results in mitochondrial iron accumulation, increased reactive oxygen species (ROS) and cell death, and decreased activity of cytosolic Fe/S proteins. However, it is not known whether the cytotoxic effects of ABCB8 knockdown are due to mitochondrial iron accumulation or decreased cytosolic Fe/S protein or other processes. Furthermore, the link between mitochondrial iron and the activity of cytosolic Fe/S proteins is uncharacterized. Here, we studied whether a reduction in mitochondrial iron can reverse the effects of ABCB8 knockdown on cell survival, ROS production and the activity of Fe/S proteins. We altered the mitochondrial iron using various iron chelators and by decreasing the levels of mitochondrial iron importer, mitoferrin-2 (MFRN2). The increase in mitochondrial iron and ROS levels associated with ABCB8 knockdown was significantly reversed by iron chelators and with MFRN-2 knockdown. Furthermore, cell death was also reversed with iron chelators and MFRN-2 knockdown, suggesting that the cytotoxic effects of ABCB8 knockdown is due to mitochondrial iron accumulation. We then studied the effects of iron chelators on cytosolic Fe/S proteins. Iron chelators reversed the defect in cytosolic Fe/S proteins that is associated with ABCB8 knockdown in cell culture or knockout in mice. However, antioxidants and knockdown of MFRN-2 failed to have similar effects. These results indicated that the defect in the maturation of cytosolic Fe/S proteins due to mitochondrial iron accumulation can be reversed by chelating mitochondrial iron, and is independent of the associated oxidative stress. Thus, mitochondrial iron levels are likely sensed in the cytoplasm and determine the maturation of cytosolic Fe/S proteins. Altogether, these studies provide insights into the role of mitochondrial iron in the cytotoxic effects of ABCB8 knockdown, and suggest that mitochondrial iron is sensed in the cytoplasm and influences the maturation of cytosolic Fe/S proteins.