A hypothesis concerning the role of PPAR family on cardiac energetics in Adriamycin-induced cardiomyopathy.

Adriamycin is an effective anti-neoplastic drug against a variety of cancer types. However, the drug causes adverse side effects in a number of organ systems. Cardiomyopathy is one of the life-threatening side effects of Adriamycin. In the current work, we have derived a hypothesis with possible involvement of PPAR family members in the development of Adriamycin-induced cardiomyopathy. Dysregulation of PPAR family by Adriamycin causes impairment in the transport and ß-oxidation of fatty acids, the key substrate for ATP synthesis in heart. Evidences suggest that dysregulation of PPAR family alters the recruitment of glucose transporters. Furthermore, heme oxygenase-1 is a crucial enzyme regulating the iron homeostasis in the heart whose expression is regulated by PPAR family. Inverse relationship exists between the expression levels of PPARγ and heme oxygenase-1. Adriamycin upregulates the expression of heme oxygenase-1 which in turn disrupts the iron homeostasis in cardiomyocytes. Our molecular docking results show that Adriamycin has a high affinity for iron-binding sites of heme oxygenase-1, thereby hindering formation of iron-sulfur complex. The lack of iron-sulfur complex impairs the electron transport chain. In addition, succinate dehydrogenase subunit A is downregulated by Adriamycin. The lack of this subunit uncouples Krebs cycle from ETC. Further, lack of this subunit increases the concentration of succinate, which further alters the mitochondrial membrane potential. Overall, in the present work, we hypothesize that alteration in the expression of PPAR family members is one of the major causes of metabolic chaos and oxidative stress caused by Adriamycin during the development of cardiomyopathy.

Aphrodisiac Performance of Bioactive Compounds from Mimosa pudica Linn.: In Silico Molecular Docking and Dynamics Simulation Approach.

Plants and their derived molecules have been traditionally used to manage numerous pathological complications, including male erectile dysfunction (ED). Mimosa pudica Linn. commonly referred to as the touch-me-not plant, and its extract are important sources of new lead molecules in drug discovery research. The main goal of this study was to predict highly effective molecules from M. pudica Linn. for reaching and maintaining penile erection before and during sexual intercourse through in silico molecular docking and dynamics simulation tools. A total of 28 bioactive molecules were identified from this target plant through public repositories, and their chemical structures were drawn using Chemsketch software. Graph theoretical network principles were applied to identify the ideal target (phosphodiesterase type 5) and rebuild the network to visualize the responsible signaling genes, proteins, and enzymes. The 28 identified bioactive molecules were docked against the phosphodiesterase type 5 (PDE5) enzyme and compared with the standard PDE5 inhibitor (sildenafil). Pharmacokinetics (ADME), toxicity, and several physicochemical properties of bioactive molecules were assessed to confirm their drug-likeness property. Molecular dynamics (MD) simulation modeling was performed to investigate the stability of PDE5-ligand complexes. Four bioactive molecules (Bufadienolide (-12.30 kcal mol-1), Stigmasterol (-11.40 kcal mol-1), Isovitexin (-11.20 kcal mol-1), and Apigetrin (-11.20 kcal mol-1)) showed the top binding affinities with the PDE5 enzyme, much more powerful than the standard PDE5 inhibitor (-9.80 kcal mol-1). The four top binding bioactive molecules were further validated for a stable binding affinity with the PDE5 enzyme and conformation during the MD simulation period as compared to the apoprotein and standard PDE5 inhibitor complexes. Further, the four top binding bioactive molecules demonstrated significant drug-likeness characteristics with lower toxicity profiles. According to the findings, the four top binding molecules may be used as potent and safe PDE5 inhibitors and could potentially be used in the treatment of ED.

Capsaicin-loaded solid lipid nanoparticles: design, biodistribution, in silico modeling and in vitro cytotoxicity evaluation.

Lower doses of capsaicin (8-methyl-N-vanillyl-6-nonenamide) have the potential to serve as an anticancer drug, however, due to its pungency, irritant effect, poor water solubility and high distribution volume often linked to various off-target effects, its therapeutic use is limited. This study aimed to determine the biodistribution and anticancer efficacy of capsaicin loaded solid lipid nanoparticles (SLNs) in human hepatocellular carcinoma in vitro. In this study, SLNs of stearic acid loaded with capsaicin was formulated by the solvent evaporation-emulsification technique and were instantly characterized for their encapsulation efficiency, morphology, loading capacity, stability, particle size, charge and in vitro drug release profile. Synthesized SLNs were predominantly spherical, 80 nm diameter particles that proved to be biocompatible with good stability in aqueous conditions. In vivo biodistribution studies of the formulated SLNs showed that 48 h after injection in the lateral tail vein, up to 15% of the cells in the liver, 1.04% of the cells in the spleen, 3.05% of the cells in the kidneys, 3.76% of the cells in the heart, 1.31% of the cells in the lungs and 0% of the cells in the brain of rats were determined. Molecular docking studies against the identified targets in HepG2 cells showed that the capsaicin is able to bind Abelson tyrosine-protein kinase, c-Src kinase, p38 MAP kinase and VEGF-receptor. Molecular dynamic simulation showed that capsaicin-VEGF receptor complex is highly stable at 50 nano seconds. The IC50 of capsaicin loaded SLNs in HepG2 cells in vitro was 21.36 µg × ml-1. These findings suggest that capsaicin loaded SLNs are stable in circulation for a period up to 3 d, providing a controlled release of loaded capsaicin and enhanced anticancer activity.

Paeonol Reverses Adriamycin Induced Cardiac Pathological Remodeling through Notch1 Signaling Reactivation in H9c2 Cells and Adult Zebrafish Heart.

Adriamycin is a commonly prescribed chemotherapeutic drug for a wide range of cancers. Adriamycin causes cardiotoxicity as an adverse effect that limits its clinical application in cancer treatment. Several mechanisms have been proposed to explain the toxicity it causes in heart cells. Disruption of inherent cardiac repair mechanism is the least understood mechanism of Adriamycin-induced cardiotoxicity. Adriamycin induces pathological remodeling in cardiac cells by promoting apoptosis, hypertrophy, and fibrosis. We found that Adriamycin inhibited Notch1 in a time- and dose-dependent manner in H9c2 cells. We used Paeonol, a Notch1 activator, and analyzed the markers of apoptosis, hypertrophy, and fibrosis in H9c2 cells in vitro and in adult zebrafish heart in vivo as model systems to study Adriamycin-induced cardiotoxicity. Paeonol activated Notch1 signaling and expression of its downstream target genes effectively in the Adriamycin-treated condition in vitro and in vivo. Also we detected that Notch activation using Paeonol protected the cells from apoptosis, collagen deposition, and hypertrophy response using functional assays. We conclude that Adriamycin induced cardiotoxicity by promoting the pathological cardiac remodeling through inhibition of Notch1 signaling and that the Notch1 reactivation by Paeonol protected the cells and reversed the cardiotoxicity.

Design, in silico modelling and functionality theory of folate-receptor-targeted myricetin-loaded bovine serum albumin nanoparticle formulation for cancer treatment.

Targeted drug delivery systems are a promising field of research. Nano-engineered material-mediated drug delivery possesses remarkable potential for the treatment of various malignancies. Here, folic acid (FA)-conjugated bovine serum albumin (BSA) nanoparticles (NPs) were used to encapsulate myricetin (Myr). Subsequently, the delivery of Myr via naturally overexpressed folate receptor (FR) to FR-positive breast cancer cells was studied. Myr-loaded BSA NPs were assembled by modified desolvation cross-linking technique. An FA-conjugated carrier, N-hydroxysuccinimide (NHS)-FA ester, was successfully synthesized. Its functional and structural characteristics were confirmed by ultraviolet, Fourier-transform infrared, and proton nuclear magnetic resonance spectroscopy. Biocompatible FA-conjugated, Myr-loaded BSA NPs (FA-Myr-BSA NPs) were successfully formulated using a carbonate/bicarbonate buffer. Their morphology, size, shape, physiological stability, and drug release kinetics were studied. Molecular docking studies revealed that FA-Myr-BSA NPs readily bound non-covalently to folate receptors and facilitated active drug endocytosis. FA-Myr-BSA NPs could trigger fast release of Myr in an acidic medium (pH 5.4), and showed high biocompatibility in a physiological medium. FA-Myr-BSA NPs effectively decreased the viability of MCF-7 cells after 24 h with 72.45 µg ml-1 IC50 value. In addition, FA-Myr-BSA NPs enhanced the uptake of Myr in MCF-7 cells. After incubation, a typical apoptotic morphology of condensed nuclei and distorted membrane bodies was observed. The NPs also targeted mitochondria of MCF-7 cells, significantly increasing reactive oxygen species release and contributing to the loss of mitochondrial membrane integrity. The observed results confirm that the newly developed FA-Myr-BSA NPs can serve as a potential carrier for Myr to increase the anticancer activity of this chemotherapeutic.

Adriamycin inhibits embryonic development in zebrafish through downregulation of Kruppel-like factor4.

Adriamycin is an effective anticancer drug used in a wide range of cancers. Anticancer drugs modulate oncogenes and nodal regulatory molecules that affect cell differentiation and organismal development. In this study, we explore the effect of adriamycin on Kruppel-like factor4 (Klf4), an essential pluripotent factor by choosing zebrafish embryos as a model system. Klf4 is involved in the regulation of cellular growth, proliferation, and differentiation. In zebrafish embryogenesis, Klf4 is a major regulator of differentiation of polster in the anterior mesendoderm region of cells into hatching gland cells. The importance of this study is to check the effect of adriamycin on embryonic development. We found, adriamycin dose dependently altered the gene expression level of Klf4 that occurs in parallel to its detrimental effect on hatching. Supportively, cathepsin L and cyclase-associated protein1 are the other two markers of hatching that are altered along with Klf4.

Emu oil decreases atherogenic plaque formation in cafeteria diet-induced obese rats.

BACKGROUND: Atherosclerosis-induced coronary heart disease - caused by elevated levels of low-density lipoproteins (LDL) and inflammation - is one of the most prevalent diseases. Monounsaturated fatty acids are reported to prevent atherosclerosis; emu oil is a rich source of monounsaturated fatty acid, and we hypothesize that emu oil supplementation could lower inflammation and prevent atherosclerosis in diet-induced obese (DIO) animals. Male Wistar rats were randomly divided into five groups (n = 6), and fed with normal diet (chow pellet; ND), or with cafeteria diet (CD), or with CD along with emu oil supplementation at three different doses: ED1 (2 mL), ED2 (4 mL) and ED3 (8 mL) kg(-1) body weight (BW), respectively. RESULTS: After 12 weeks, the animals were sacrificed and serum was analysed for measuring lipid profile, C-reactive proteins, testosterone and luteinizing hormone. Histopathological studies were performed to observe atherogenic changes in thoracic aorta. Restoration of altered lipid and hormonal profiles, and inhibition of atherogenic changes in thoracic aorta, were observed with supplementation of emu oil, confirming its anti-atherosclerotic activity. CONCLUSION: The high content of oleic acid in emu oil could have orchestrated - either solely or in combination with linoleic and linolenic acids - causing the upregulation of testosterone biosynthesis and inhibition of atheromatous plaque formation in diet-induced obese animals. © 2015 Society of Chemical Industry.

Adriamycin downregulates the expression of KLF4 in cardiomyocytes in vitro and contributes to impaired cardiac energy metabolism in Adriamycin-induced cardiomyopathy.

Adriamycin is a well-known anthracycline chemotherapeutic agent widely used in treating a variety of malignancies. However, Adriamycin's clinical use is limited due to its adverse side-effects, most importantly cardiomyopathy. Adriamycin-induced cardiotoxicity reportedly includes mitochondrial dysfunction. We hypothesize that modulation of KLF4, a key regulator of cardiac mitochondrial homeostasis might play a role in the development of Adriamycin-induced cardiomyopathy. Therefore, in the current work, we evaluated the interaction of Adriamycin with KLF4 and its subsequent downstream targets. Molecular docking revealed that Adriamycin interacts strongly with KLF4 at residues Thr 448, Arg 452, Ser 444 falls within C2H2 motif which is the active site. Quantitative real-time PCR also revealed that KLF4 is downregulated by Adriamycin in cardiomyocytes in vitro. The expression of KLF4 is downregulated in a dose-dependent manner, with a 0.12 ± 0.09-fold (p ≤ 0.05, n = 3) downregulation at a low dosage and 0.21 ± 0.02-fold (p ≤ 0.05, n = 3) downregulation at high dosage. Deficiency of KLF4 leads to an impairment of PPARγ that consequently supresses the proteins/enzymes involved in the fatty acid metabolism. Adriamycin-mediated suppression of KLF4 also affected the expression of PPARα in vitro. PPARα dysfunction is likely to cause defects in ß-oxidation which ultimately results in impaired ATP synthesis. Cardiac cells are thus forced to switch over the substrate from free fatty acid to glucose. Moreover, Adriamycin elevates the expression of PPARß due to downregulation of KLF4 leads to increased myocardial glucose utilization. Thus, a change in substrate preference affects the flexibility of metabolic network culminating in diminished energy production and other regulatory activities, altogether contributing to the development of cardiomyopathy. Thus, we conclude that the effect of Adriamycin on KLF4 disrupts mitochondrial homeostasis and lipid/glucose homeostasis resulting in a reduction of ATP synthesis which ultimately results in dilated cardiomyopathy.

Adriamycin inhibits adipogenesis through the modulation of PPARγ and restoration of adriamycin-mediated inhibition of adipogenesis by PPARγ over-expression.

Adriamycin is an anti-cancer drug, effective against a wide range of cancers. However, its clinical application is limited by its cardiotoxicity. A number of reports suggest that adriamycin induces bodyweight loss also. The aim of this study was to investigate the effect of adriamycin on adipogenesis as bodyweight chancges can be directly correlated with adipocytes. Fat accumulation in 3T3-L1 pre-adipocytes, as a result of adipogenesis was detected using oil red O staining. We performed western immunoblot for the expression of adipocyte differentiation related genes to analyze the molecular mechanism of adriamycin-mediated inhibition of adipogenesis. Over-expression of target gene was done by using recombinant adenoviruses. Adriamycin inhibited adipogenesis in a dose-dependent manner. It was observed that adriamycin down-regulated the expression of PPARγ. Moreover, up-stream elements of PPARγ were also found to be down-regulated by adriamycin. Adriamycin might prevent bodyweight gain through inbibition of adipogenesis by the down-regulation of PPARγ and its up-stream transcriptional regulators like C/EBPß and KLF4. To reverse the adriamycin-mediated inhibition of adipogenesis, PPARγ was over-expressed by adenoviral mediated gene delivery. Over-expression of PPARγ partially restored adipogenesis. Moreover, the early regulators of adipogenesis were also found to be restored after the over-expression of PPARγ. Adriamycin down-regulates the expression of PPARγ which leads to prevention of bodyweight gain through inhibition of adipogenesis. Activation of PPARγ by either adenoviral mediated gene delivery or by using PPARγ agonist may be useful in controlling the bodyweight loss.

Exploring the Pattern of Metabolic Alterations Causing Energy Imbalance via PPARα Dysregulation in Cardiac Muscle During Doxorubicin Treatment.

Cardiotoxicity by anthracycline antineoplastic drug doxorubicin is one of the systemic toxicity of the cardiovascular system. The mechanism responsible for doxorubicin cardiotoxicity and lipid metabolism remains elusive. The current study tested the hypotheses that the role of peroxisome proliferator-activated receptor α (PPARα) in the progress of doxorubicin-induced cardiomyopathy and its mechanism behind lipid metabolism. In the present study, male rats were subjected to intraperitoneal injection (5-week period) of doxorubicin with different dosages such as low dosage (1.5 mg/kg body weight) and high dosage (15 mg/kg body weight) to induce doxorubicin cardiomyopathy. Myocardial PPARα was impaired in both low dosage and high dosage of doxorubicin-treated rats in a dose-dependent manner. The attenuated level of PPARα impairs the expression of the genes involved in mitochondrial transporter, fatty acid transportation, lipolysis, lipid metabolism, and fatty acid oxidation. Moreover, it disturbs the reverse triacylglycerol transporter apolipoprotein B-100 (APOB) in the myocardium. Doxorubicin elevates the circulatory lipid profile and glucose. Further aggravated lipid profile in circulation impedes the metabolism of lipid in cardiac tissue, which causes a lipotoxic condition in the heart and subsequently associated disease for the period of doxorubicin treatment. Elevated lipids in the circulation translocate into the heart dysregulates lipid metabolism in the heart, which causes augmented oxidative stress and necro-apoptosis and mediates lipotoxic conditions. This finding determines the mechanistic role of doxorubicin-disturbed lipid metabolism via PPARα, which leads to cardiac dysfunction.

In silico, in vitro screening of antioxidant and anticancer potentials of bioactive secondary metabolites from an endophytic fungus (Curvularia sp.) from Phyllanthus niruri L.

The main objective of this research work is to discover novel and efficient phytochemical substances from endophytic fungus found in medicinal plants. Curvularia geniculata L. (C. geniculata L.), an endophytic fungus isolated from Phyllanthus niruri L. (P. niruri L.), was tested against hepatoma cell lines (HepG2) in order to screen their antioxidant and anticancer potentials. The profiling of phytochemicals from the fungal extract was characterized using gas chromatography-mass spectrometry (GC-MS), and molecular docking was done for the identified compounds against one of the potential receptors predominantly present in the hepatocellular carcinoma cell lines. Among the phytochemicals found, 2-methyl-7-phenylindole had the highest binding affinity (- 8.8 kcal mol-1) for the epidermal growth factor receptor (EGFR). The stability of 2-methyl-7-phenylindole in the EGFR-binding pockets was tested using in silico molecular dynamics simulation. The fungal extract showed the highest antioxidant activity as measured by DPPH, ABTS radical scavenging, and FRAP assays. In vitro cytotoxicity assay of fungal extract demonstrated the concentration-dependent cytotoxicity against HepG2 cells after 24 h, and the IC50 (50% cell death) value was estimated to be 62.23 µg mL-1. Typical morphological changes such as condensation of nuclei and deformed membrane structures are indicative of ongoing apoptosis. The mitochondria of HepG2 cells were also targeted by the endophytic fungal extract, which resulted in substantial generation of reactive oxygen species (ROS) leading to the destruction of mitochondrial transmembrane potential integrity. These outcomes suggest that the ethyl acetate extract of C. geniculata L. has the potential to be an antioxidant agent and further to be exploited in developing potential anticancer agents.

Adriamycin inhibits glycolysis through downregulation of key enzymes in Saccharomyces cerevisiae.

Adriamycin is a widely used drug for the treatment of various types of cancers, but its clinical application is limited because of irreversible dilated cardiomyopathy. The incidence of cardiomyopathy is a consequence of disrupted energy production, which could be related to the defects in glycogen, lipid and mucopolysaccharide metabolism. We explored the effect of Adriamycin on enzymes involved in glycolysis and apoptotic genes through molecular docking. We used Saccharomyces cerevisiae as model organism and studied the effect of Adriamycin on selected enzymes involved in glycolysis. The docking studies revealed that Adriamycin interacts with phosphofructokinase and enolase in an efficient manner. In phosphofructokinase, Adriamycin binds at the active site and with enolase the drug interacts at the cofactor-binding site (Mg2+) which might impair the activity of the enzyme. Gene expression studies revealed that Adriamycin causes the dysregulation of glycolysis through dysregulation of hexokinase, phosphoglycerate mutase, enolase and downregulation of pyruvate kinase. The drug shows a biphasic effect on the expression of genes enolase and pyruvate kinase. The impairment in glycolysis might reduce the ATP synthesis, and the cells might be deprived of energy. The condition is further worsened by elevated ROS levels triggering the cell to undergo apoptosis evidenced by downregulation of SOD and upregulation of BAX and caspase. In conclusion, our study reveals that Adriamycin impairs glycolysis and cause cell to undergo apoptosis due to oxidative stress in yeast cells.

Mechanisms of doxorubicin-mediated reproductive toxicity - A review.

The anticancer drug doxorubicin has been associated with several adverse side-effects including reproductive toxicity in both genders. The current review has complied the mechanisms of doxorubicin induced reproductive toxicity. The articles cited in the review were searched using Google Scholar, PubMed, Scopus, Science Direct. Doxorubicin treatment has been found to cause a decrease in testicular mass along with histopathological deformities, oligospermia and abnormalities in sperm morphology. Apart from severely affecting the normal physiological role of both Leydig cells and Sertoli cells, doxorubicin also causes chromosome abnormalities and affects DNA methylase enzyme. Testicular lipid metabolism has been found to be negatively affected by doxorubicin treatment resulting in altered profile of sphingolipids glycerophospholipids and neutral lipids. Dysregulation of 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and 17ß- hydroxysteroid dehydrogenase (17ß-HSD) are strongly linked to testicular exposure to doxorubicin. Further, oxidative stress along with endoplasmic reticulum stress are also found to aggravate the male reproductive functioning in doxorubicin treated conditions. Several antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase (GPx) are downregulated by doxorubicin. It also disturbs the hormones of the hypothalamic-pituitary-gonadal (HPG)-axis including testosterone, luteinizing hormone, follicle stimulating hormone etc. In females, the drug disturbs folliculogenesis and oogenesis leading to failure of ovulation and uterine cycle. In rodent model the drug shortens pro-estrous and estrous phases. It was also found that doxorubicin causes mitochondrial dysfunction in oocytes with impaired calcium signaling along with ER stress. The goal of the present review is to comprehends various pathways due to which doxorubicin treatment promotes toxicity in male and female reproductive system.

Pharmacoinformatics-based investigation of bioactive compounds of Rasam (South Indian recipe) against human cancer.

Spice-rich recipes are referred to as "functional foods" because they include a variety of bioactive chemicals that have health-promoting properties, in addition to their nutritional value. Using pharmacoinformatics-based analysis, we explored the relevance of bioactive chemicals found in Rasam (a South Indian cuisine) against oxidative stress-induced human malignancies. The Rasam is composed of twelve main ingredients, each of which contains a variety of bioactive chemicals. Sixty-six bioactive compounds were found from these ingredients, and their structures were downloaded from Pubchem. To find the right target via graph theoretical analysis (mitogen-activated protein kinase 6 (MAPK6)) and decipher their signaling route, a network was built. Sixty-six bioactive compounds were used for in silico molecular docking study against MAPK6 and compared with known MAPK6 inhibitor drug (PD-173955). The top four compounds were chosen for further study based on their docking scores and binding energies. In silico analysis predicted ADMET and physicochemical properties of the selected compounds and were used to assess their drug-likeness. Molecular dynamics (MD) simulation modelling methodology was also used to analyse the effectiveness and safety profile of selected bioactive chemicals based on the docking score, as well as to assess the stability of the MAPK6-ligand complex. Surprisingly, the discovered docking scores against MAPK6 revealed that the selected bioactive chemicals exhibit varying binding ability ranges between - 3.5 and - 10.6 kcal mol-1. MD simulation validated the stability of four chemicals at the MAPK6 binding pockets, including Assafoetidinol A (ASA), Naringin (NAR), Rutin (RUT), and Tomatine (TOM). According to the results obtained, fifty of the sixty-six compounds showed higher binding energy (- 6.1 to - 10.6 kcal mol-1), and four of these compounds may be used as lead compounds to protect cells against oxidative stress-induced human malignancies.

Adipose-Derived Molecules-Untouched Horizons in Alzheimer's Disease Biology.

The global incidence of Alzheimer's disease (AD) is on the rise with the increase in obesity and metabolic disease epidemic. Obesity is co-morbid with the increase in mass of adipose tissue, which secretes numerous molecules that are biologically important. Obesity and its associated conditions are perhaps involved in the causative pathway of AD. Immunologically important cytokines such as IL-1ß, IL-10, and IL-18, which are released by adipose tissue, are also found to be associated with AD. Besides, the expression of IL-6, IFNγ, and TNF alpha are also associated with AD. Ang-I and Ang-II are found to mediate the progression of AD. Complement factors B, C4b, and H are differentially expressed in AD. Overall, several adipocyte-derived cytokines are found to be dysregulated in AD, and their role in AD remains to be studied. The induction of autophagy is a very promising strategy in the treatment of AD. A variety of adipose-derived molecules have been shown to modulate autophagy. However, very little literature is available on the role of adipose-derived molecules in inducing autophagy in microglial cells of AD. Understanding the role of adipose-derived molecules in the development of AD, especially in the induction of autophagy, would open up new avenues in devising strategies for the treatment of AD.

Targeting complement cascade: an alternative strategy for COVID-19.

The complement system is a stakeholder of the innate and adaptive immune system and has evolved as a crucial player of defense with multifaceted biological effects. Activation of three complement pathways leads to consecutive enzyme reactions resulting in complement components (C3 and C5), activation of mast cells and neutrophils by anaphylatoxins (C3a and C5a), the formation of membrane attack complex (MAC) and end up with opsonization. However, the dysregulation of complement cascade leads to unsolicited cytokine storm, inflammation, deterioration of alveolar lining cells, culminating in acquired respiratory destructive syndrome (ARDS). Similar pathogenesis is observed with the middle east respiratory syndrome (MERS), severe acquired respiratory syndrome (SARS), and SARS-CoV-2. Activation of the lectin pathway via mannose-binding lectin associated serine protease 2 (MASP2) is witnessed under discrete viral infections including COVID-19. Consequently, the spontaneous activation and deposits of complement components were traced in animal models and autopsy of COVID-19 patients. Pre-clinical and clinical studies evidence that the inhibition of complement components results in reduced complement deposits on target and non-target tissues, and aid in recovery from the pathological conditions of ARDS. Complement inhibitors (monoclonal antibody, protein, peptide, small molecules, etc.) exhibit great promise in blocking the activity of complement components and its downstream effects under various pathological conditions including SARS-CoV. Therefore, we hypothesize that targeting the potential complement inhibitors and complement cascade to counteract lung inflammation would be a better strategy to treat COVID-19.

Design and in silico modeling of Indoloquinoxaline incorporated keratin nanoparticles for modulation of glucose metabolism in 3T3-L1 adipocytes.

The following study was done to assess the glucose utilizing efficiency of Indoloquinoxaline derivative incorporated keratin nanoparticles (NPs) in 3T3-L1 adipocytes. Indoloquinoxaline derivative had wide range of biological activities including antidiabetic activity. In this view, Indoloquinoxaline moiety containing N, N-dimethyl (3-fluoro-6H-indolo [3,2-b] quinoxalin-6-yl) methanamine compound was designed and synthesized, and further it is incorporated into keratin nanoparticles. The formulated NPs, drug entrapment efficiency, releasing capacity, stability, and physicochemical properties were characterized by various spectral analyzer and obtained results of characterizations were confirmed the properties of NPs. The analysis of mechanism underlying the glucose utilization of NPs was examined through molecular docking with identified target, and observed in silico study reports shown strong interaction of NPs in the binding pockets of AMPK and PTP1B. Based on the in silico screening, the formulated NPs was performed for in vitro cellular viability and glucose uptake studies on 3T3-L1 adipocytes. Interestingly, 40 µg of NPs displayed 78.2 ± 2.76% cellular viability, and no cell death was observed at lower concentrations. Further, the concentration dependent glucose utilization was observed at different concentrations of NPs in 3T3-L1 adipocytes. The results of NPs (40 µg) on glucose utilization have revealed eminent result 58.56 ± 4.54% compared to that of Metformin (10 µM) and Insulin (10 µM). The identified results clearly indicated that Indoloquinoxaline derivative incorporated keratin NPs significantly increased glucose utilization efficiency and protect the cells against the insulin resistance.

Utilization of plant-derived Myricetin molecule coupled with ultrasound for the synthesis of gold nanoparticles against breast cancer.

Phytochemical mediated synthesis of nanoparticles has gained great interest in the field of cancer therapeutics. We attempted a simple and stable synthesis of gold nanoparticles (AuNPs) with Myricetin (Myr) adopting ultrasound-assisted method. Further, we evaluated anticancer activity of the synthesized nanoparticles. The physico-chemical properties of biosynthesized Myr-AuNPs were characterized by UV-visible spectrophotometer, Fourier-transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and particle size analysis. The study reports of Myr-AuNPs showed spherical-shaped particles with a size of < 50 nm. Stability of the particles was increased in various physiological media. Furthermore, the graph theoretical network analysis of Myr-AuNPs indicated that the probable binding with the mTOR is an effective target for breast cancer cells. In silico molecular docking study of Myr-AuNPs in human mTOR kinase was found to be strong binding. The IC50 value of Myr-AuNPs was calculated as 13 µg mL-1 against MCF-7 cell line. The AO/EB and DAPI stainings confirmed the anticancer activity by Myr-AuNPs-treated cells showed a good proportion of dead cells evidenced with formation of pro-apoptotic bodies. In addition, Myr-AuNPs exhibited depolarization of mitochondrial membrane potential and production of reactive oxygen species. This study proves that Myr-AuNPs holds great promise to use against breast cancer as a potent anticancer drug. Graphical abstract A schematic representation for the biosynthesis of Myr-AuNPs.

Formulation and characterization of folate receptor-targeted PEGylated liposome encapsulating bioactive compounds from Kappaphycus alvarezii for cancer therapy.

This study aimed to formulate and characterize the folate receptor-targeted PEGylated liposome encapsulating bioactive compounds from Kappaphycus alvarezii to enhance the anticancer activity. Twenty valued bioactive compounds (3-hydroxy benzoicacid, gallicacid, chlorogenicacid, cinnamicacid, artemiseole, hydrazine carbothioamide, etc.,) are confirmed from methanol extract of K. alvarezii using analytical techniques like HPLC and GC-MS. The delivery of bioactive compounds of K. alvarezii via naturally overexpressed folate receptor (FR) to FR-positive breast cancer cells was studied. FR targeted PEGylated liposome was constructed by modified thin-film hydration technique using FA-PEG-DSPE/cholesterol/DSPC (5:40:55) and bioactive compounds of K. alvarezii was encapsulated. Their morphology, size, shape, physiological stability and drug release kinetics were studied. The study reports of K. alvarezii extract-encapsulated PEGylated liposome showed spherical shaped particles with amorphous in nature. The mean diameter of K. alvarezii extract-encapsulated PEGylated and FA-conjugated PEGylated liposomes was found to be 110 ± 6 nm and 140 ± 5 nm, respectively. Based on the stability studies, it could be confirmed that FA-conjugated PEGylated liposome was highly stable in various physiological buffer medium. FA-conjugated PEGylated liposome can steadily release the bioactive compounds of K. alvarezii extract in acidic medium (pH 5.4). MTT assay demonstrated the concentration-dependent cytotoxicity against MCF-7 cells after 24 h with IC50 of 81 µg/mL. Also, PEGylated liposome enhanced the delivery of K. alvarezii extract in MCF-7 cells. After treatment, typical apoptotic morphology of condensed nuclei and distorted membrane bodies was picturized. Additionally, PEGylated liposome targets the mitochondria of MCF-7 cells and significantly increased the level of ROS and contributes to the damage of mitochondrial transmembrane potential. Hence, PEGylated liposome could positively deliver the bioactive compounds of K. alvarezii extract into FR-positive breast cancer cells (MCF-7) and exhibit great potential in anticancer therapy.

c-myb stimulates cell growth by regulation of insulin-like growth factor (IGF) and IGF-binding protein-3 in K562 leukemia cells.

c-myb plays an important role in the regulation of cell growth and differentiation, and is highly expressed in immature hematopoietic cells. The human chronic myelogenous leukemia cell K562, highly expresses IGF-I, IGF-II, IGF-IR, and IGF-induced cellular proliferation is mediated by IGF-IR. To characterize the impact of c-myb on the IGF-IGFBP-3 axis in leukemia cells, we overexpressed c-myb using an adenovirus gene transfer system in K562 cells. The overexpression of c-myb induced cell proliferation, compared to control, and c-myb induced cell growth was inhibited by anti-IGF-IR antibodies. c-myb overexpression resulted in a significant increase in the expression of IGF-I, IGF-II, and IGF-IR, and a decrease in IGFBP-3 expression. By contrast, disruption of c-myb function by DN-myb overexpression resulted in significant reduction of IGF-I, IGF-II, IGF-IR, and elevation of IGFBP-3 expression. In addition, exogenous IGFBP-3 inhibited the proliferation of K562 cells, and c-myb induced cell growth was blocked by IGFBP-3 overexpression in a dose-dependent manner. The growth-promoting effects of c-myb were mediated through two major intracellular signaling pathways, Akt and Erk. Activation of Akt and Erk by c-myb was completely blocked by IGF-IR and IGFBP-3 antibodies. These findings suggest that c-myb stimulates cell growth, in part, by regulating expression of the components of IGF-IGFBP axis in K562 cells. In addition, disruption of c-myb function by DN-myb may provide a useful strategy for treatment of leukemia.