Formulation of Carnosic-Acid-Loaded Polymeric Nanoparticles: An Attempt to Endorse the Bioavailability and Anticancer Efficacy of Carnosic Acid against Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is considered to be one of the most difficult subtypes of breast cancer (BC) to treat. The sheer absence of certain receptors makes it very tough to target, leaving high-dose chemotherapy as probably the sole therapeutic option at the cost of nonspecific toxic effects. Carnosic acid (CA) has been established as a potential chemotherapeutic agent against a range of cancer cells. However, its in vivo chemotherapeutic potential is significantly challenged due to its poor pharmacokinetic attributes. In this study, poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) were formulated to circumvent the biopharmaceutical limitations of CA. CA-loaded polymeric NPs (CA-PLGA NPs) have been evaluated as a potential therapeutic option in the treatment of TNBC. Different in vitro studies exhibited that CA-PLGA NPs significantly provoked oxidative-stress-mediated apoptotic death in MDA-MB-231 cells. The improved anticancer potential of CA-PLGA NPs over CA was found to be associated with improved cellular uptake of the nanoformulation by TNBC cells. In vivo studies also established the improvement in the chemotherapeutic efficacy of CA-nanoformulation over that of free CA without showing any sign of systemic toxicity. Thus, CA-PLGA NPs emerge as a promising candidate to fix two bugs with a single code, resolving biopharmaceutical attributes of CA as well as introducing a treatment option for TNBC.

Correction: Mangiferin ameliorates collateral neuropathy in tBHP induced apoptotic nephropathy by inflammation mediated kidney to brain crosstalk.

Correction for 'Mangiferin ameliorates collateral neuropathy in tBHP induced apoptotic nephropathy by inflammation mediated kidney to brain crosstalk' by Sukanya Saha et al., Food Funct., 2019, 10, 5981-5999, https://doi.org/10.1039/C9FO00329K.

Biological evaluation of the novel 3,3'-((4-nitrophenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) derivative as potential anticancer agents via the selective induction of reactive oxygen species-mediated apoptosis.

Selective initiation of programmed cell death in cancer cells than normal cells is reflected as an attractive chemotherapeutic strategy. In the current study, a series of synthetic bis-coumarin derivatives were synthesized possessing reactive oxygen species (ROS) modulating functional groups and examined in four cancerous and two normal cell lines for their cytotoxic ability using MTT assay. Among these compounds, 3 l emerged as the most promising derivative in persuading apoptosis in human renal carcinoma cells (SKRC-45) among diverse cancer cell lines. 3 l causes significantly less cytotoxicity to normal kidney cells compared to cisplatin. This compound was able to induce apoptosis and cell-cycle arrest by modulating the p53 mediated apoptotic pathways via the generation of ROS, decreasing mitochondrial membrane potential, and causing DNA fragmentation. Unlike cisplatin, the 3 l derivative was found to inhibit the nuclear localisation of NF-κB in SKRC-45 cells. It was also found to reduce the proliferation, survival and migration ability of SKRC-45 cells by downregulating COX-2/ PTGES2 cascade and MMP-2. In an in vivo tumor model, 3 l showed an anticancer effect by reducing the mean tumor mass, volume and inducing caspase-3 activation, without affecting kidney function. Further studies are needed to establish 3 l as a promising anti-cancer drug candidate.

Enhanced mitochondrial biogenesis promotes neuroprotection in human pluripotent stem cell derived retinal ganglion cells.

Mitochondrial dysfunctions are widely afflicted in central nervous system (CNS) disorders with minimal understanding on how to improve mitochondrial homeostasis to promote neuroprotection. Here we have used human stem cell differentiated retinal ganglion cells (hRGCs) of the CNS, which are highly sensitive towards mitochondrial dysfunctions due to their unique structure and function, to identify mechanisms for improving mitochondrial quality control (MQC). We show that hRGCs are efficient in maintaining mitochondrial homeostasis through rapid degradation and biogenesis of mitochondria under acute damage. Using a glaucomatous Optineurin mutant (E50K) stem cell line, we show that at basal level mutant hRGCs possess less mitochondrial mass and suffer mitochondrial swelling due to excess ATP production load. Activation of mitochondrial biogenesis through pharmacological inhibition of the Tank binding kinase 1 (TBK1) restores energy homeostasis, mitigates mitochondrial swelling with neuroprotection against acute mitochondrial damage for glaucomatous E50K hRGCs, revealing a novel neuroprotection mechanism.

Synthesis, characterization, and evaluation of in vitro cytotoxicity and in vivo antitumor activity of asiatic acid-loaded poly lactic-co-glycolic acid nanoparticles: A strategy of treating breast cancer.

Asiatic acid (AA), an aglycone of pentacyclic triterpene glycoside, obtained from the leaves of Centella asiatica exerts anticancer effects by inhibiting cellular proliferation and inducing apoptosis in a wide range of carcinogenic distresses. However, its chemotherapeutic efficacy is dampened by its low bioavailability. Polymeric nanoparticles (NPs) exhibit therapeutic efficacy and compliance by improving tissue penetration and lowering toxicity. Thus, to increase the therapeutic effectiveness of AA in the treatment of breast cancer, AA-loaded poly lactic-co-glycolic acid (PLGA) NPs (AA-PLGA NPs) have been formulated. The AA-PLGA NPs were characterized on the basis of their average particle size, zeta potential, electron microscopic imaging, drug loading, and entrapment efficiency. The NPs exhibited sustained drug release profile in vitro. Developed NPs exerted dose-dependent cytotoxicity to MCF-7 and MDA-MB-231 cells without damaging normal cells. The pro-oxidant and pro-apoptotic properties of AA-PLGA NPs were determined by the study of the cellular levels of SOD, CAT, GSH-GSSG, MDA, protein carbonylation, ROS, mitochondrial membrane potential, and FACS analyses on MCF-7 cells. Immunoblotting showed that AA-PLGA NPs elicited an intrinsic pathway of apoptosis in MCF-7 cells. In vivo studies on female BALB/c mice exhibited reduced volume of mammary pad tumor tissues and augmented expression of caspase-3 when administered with AA-PLGA NPs. No systemic adverse effect of AA-PLGA NPs was observed in our studies. Thus, AA-PLGA NPs can act as an efficient drug delivery system against breast cancer.

Melatonin counteracts necroptosis and pulmonary edema in cadmium-induced chronic lung injury through the inhibition of angiotensin II.

The renin-angiotensin system (RAS) is an important regulator in pulmonary physiology. In our study, we identified the efficacy of melatonin to control the RAS in cadmium (Cd) induced chronic lung injury in a mouse model. Swiss albino mice exposed to CdCl2 intraperitoneally (I.P.) (1 mg/kg b.w.; 12 weeks) showed increased release of lactate dehydrogenase in bronchoalveolar lavage fluid, generating reactive oxygen species, impaired antioxidant enzymes function, and disrupted alveolar structure along with increased expression of Angiotensin-II (Ang-II) in lung tissue. Cd-induced angiotensin-converting enzyme-2-Ang-II axis imbalance triggered the onset of Ang-II induced tumour necrosis factor alpha  (TNF-α) mediated necroptosis by upregulating the signalling molecules RIP-1, RIP-3, and p-mixed lineage kinase domain-like. In an in vitro study, colocalization of Ang-II-RIP-3 molecule in Cd intoxicated L-132 cells (human alveolar epithelial cell line), as well as pretreatment of Cd exposed cells with the inhibitor's captopril (10 µM), necrostatin-1 (50 µM), and etanercept (5 µg/ml) indicated TNF-α induced necroptotic cell death via activation of the key molecule, Ang-II. Moreover, Ang-II disrupted the alveolar-capillary barrier by decreasing tight junctional proteins (zonula occludens-1 and occludin) and endothelial VE-cadherin expression. The use of human umbilical vein endothelial cells as a model of junctional protein-expressing cells showed that captopril pretreatment (25 µM) restored VE-cadherin expression in Cd-treated human umbilical vein endothelial cells. In CdCl2 intoxicated mice, melatonin pretreatment (10 mg/kg b.w.; 12 weeks, I.P.) inhibited inflammatory mediators (TNF-α, interleukin [IL]-1ß, and IL-6) release and effectively suppressed (Cd-induced) Ang-II mediated necroptotic cell death and alveolar-capillary breaching due to Cd toxicity.

Enhancement of anti-neoplastic effects of cuminaldehyde against breast cancer via mesoporous silica nanoparticle based targeted drug delivery system.

AIMS: Synthesis of novel drug delivery system for targeted delivery of cuminaldehyde to breast cancer cells and the subsequent analyses of anti-neoplastic potential of the drug. MAIN METHODS: 3-carboxy-phenyl boronic acid (PBA) conjugated and polyacrylic acid (PAA) gated mesoporous silica nanoparticles (MSNs) were synthesized for the targeted delivery of cuminaldehyde (CUM) to breast cancer cells. Enhancement of anti-neoplastic effects of cuminaldehyde (4-isopropylbenzaldehyde) by the nanoconjugates was assessed. KEY FINDINGS: The anti-cancer effects of non-targeted and targeted drug-nanoconjugates were examined in vitro and in vivo. The targeted drug-nanoconjugates caused cell cycle arrest and induced the intrinsic pathway of apoptosis in MCF-7 cells through mitochondrial damage. In vivo intravenous injection of the targeted drug-nanoconjugates led to effective reduction in growth of 4 T1 induced mammary pad tumor in female BALB/c mice via augmented accumulation of cuminaldehyde. The drug-nanoconjugates did not exhibit any systemic toxicity. SIGNIFICANCE: Therefore, MSN-PBA-CUM-PAA represents a potent therapeutic model for breast cancer treatment.

Targeted delivery of curcumin in breast cancer cells via hyaluronic acid modified mesoporous silica nanoparticle to enhance anticancer efficiency.

Curcumin (C) is a natural antioxidant which has many beneficial effects. However, poor bioavailability and less water solubility render it unsuitable as an anti-cancer drug. Herein, curcumin was delivered through Mesoporous silica nanoparticle (MSN) based drug delivery system to enhance its anticancer efficacy. Targeted delivery of curcumin in cancer cells was also achieved by conjugating hyaluronic acid (HA) on the surface of MSN. HA showed its targeting ability through the binding with CD-44 receptors in cancer cells. The synthesis of MSN-HA-C was verified by used several characterization techniques like TEM, SEM, XRD and DLS. MSN-HA-C showed diameter of ∼ 75 nm with negatively charged surface and drug loading content of 14.76 %. The synthesized nanohybrid showed MDA-MB-231 cell death by the induction of ROS, cell cycle arrest and modulation of NF-κB and Bax mediated apoptotic pathway. The nanohybrid also effectually decreased tumor volume in tumor-bearing mice compared with free C due to the increased bioavailability and higher cellular uptake of C in tumor tissue. Overall, the study offered that MSN-HA-C has increased anticancer efficacy than that of free curcumin.

Melatonin induced suppression of ER stress and mitochondrial dysfunction inhibited NLRP3 inflammasome activation in COPD mice.

In recent decades, the occurrence of chronic obstructive pulmonary disease (COPD) has been increased remarkably in the population. Cigarette smoke (Cs) plays one of the key roles for COPD development. In our study, we explored the ameliorative role of melatonin on COPD progression by using a Cs inhaled in vivo COPD and cigarette smoke extract (CSE)-treated in vitro L-132 (alveolar epithelial cell) models. Mice exposed to Cs (4hr/day for 4 weeks) exhibited abrupt increase of lactate dehydrogenase (LDH) level in broncho alveolar lavage fluid (BALF) and disrupted alveolar structure in lung tissue. Additionally, increased reactive oxygen species (ROS), decreased cellular antioxidant status with reduced GSH/GSSG ratio were also found in Cs exposed lung. Besides, Cs induced endoplasmic reticulum (ER) stress and mitochondrial dysfunctions causing the activation of NLRP3 inflammasome. Activated NLRP3 inflammasome caused Caspase-1 mediated release of IL-1ß and IL-18 resulting in inflammatory outburst. Melatonin showed protection against COPD both in vitro and in vivo. Exhibiting its anti-inflammatory potential, melatonin also attenuated the lung inflammation. It activated the intracellular antioxidant Thioredoxin-1 (thereby suppressing the TXNIP/NLRP3 pathway) and inhibited the impaired mitophagy mediated inflammasome activation (upregulating PINK-1, Parkin, LC3B-II expression). Melatonin also improved the overall antioxidant status of the COPD lung via NRF-2-HO-1 axis restoration.

Fluorescent Guar Gum-g-Terpolymer via In Situ Acrylamido-Acid Fluorophore-Monomer in Cell Imaging, Pb(II) Sensor, and Security Ink.

The nonconventional purely aliphatic scalable and reusable fluorescent guar gum (GRGM)-grafted-acrylic acid-co-3-(N-isopropylacrylamido)propanoic acid (NIPAPA)-co-N-isopropylacrylamide (GRGM-grafted-1, i.e., 2), was synthesized via grafting of the optimum amount of GRGM and N-H functionalized in situ protrusion of acrylamido-acid fluorophore-monomer, i.e., NIPAPA, in multi C-C/N-C/O-C coupled solution polymerization of two non-emissive monomers in water. The intrinsically fluorescent noncytotoxic 2 envisaged the excellent potentials in sensing and removal of Pb(II), security ink, logic function, and imaging of both cancer and normal cells. The emission intensities of 2 elevated in concentrated solutions and solid state because of concentration-enhanced emission and aggregation-induced enhanced emission (AIEE) characteristics of 2. Additionally, the emission efficiency of 2 elevated considerably with increasing GRGM contents and temperatures. The structure of 2, in situ attached fluorophore-monomer, AIEE, cell-imaging ability, and the superadsorption mechanism were studied employing 1H/13C NMR, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, ultraviolet-visible spectroscopy, atomic absorption spectroscopy, thermogravimetric analysis, differential scanning calorimetry, X-ray diffraction, dynamic light scattering, high-resolution transmission electron microscopy, fluorescence imaging, and fluorescence lifetime, along with measuring isotherms, kinetics, and thermodynamic parameters. The location, geometries, and electronic-structures of fluorophore, along with absorption and emission properties, of 2 were explored via density functional theory (DFT), time-dependent DFT, and natural transition orbital analyses. In solution, cyan light-emitting 2 envisaged an average 1.22 ns lifetime in CHCl3. The limit of detection and the maximum adsorption capacity were 2.94 × 10-7 M and 1100.25 mg g-1 at pH 7.0, 303 K, and 1000 ppm, respectively.

Fluorescent Terpolymers Using Two Non-Emissive Monomers for Cr(III) Sensors, Removal, and Bio-Imaging.

The nonconventional purely aliphatic intrinsically fluorescent multifunctional terpolymers, such as 2-acrylamido-2-methylpropane sulfonic acid-co-2-(3-acrylamidopropylamido)-2-methylpropane sulfonic acid-co-acrylamide (AMPS-co-APMPS-co-AM, 1), acrylic acid-co-3-acrylamidopropanoic acid-co-acrylamide (AA-co-APA-co-AM, 2), and methacrylic acid-co-3-acrylamido-2-methyl propanoic acid-co-acrylamide (MAA-co-AMPA-co-AM, 3), were synthesized via N-H functionalized multi-C-C/N-C coupled in situ attachments of fluorophore monomers, that is, APMPS, APA, and AMPA, in solution polymerization of two non-fluorescent monomers. These terpolymers were suitable for selective Cr(III) sensors, high-performance exclusions of Cr(III), and fluorescence imaging of human osteosarcoma cancer cells. The structures of 1, 2, and 3, in situ attachments of fluorescent amino acid monomers, locations of fluorophores, aggregation-induced enhanced emissions, and the superadsorption mechanism were understood via microstructural analyses. The geometries, electronic structures, and the low-lying singlet-singlet absorption and emission of 1, 2, and 3 were explored using density functional theory (DFT), time-dependent DFT, and natural transition orbital analyses. The ionic and variable interactions of 1, 2, and 3 with Cr(III) were envisaged via analyses of adsorbed microstructures, fitting of kinetics data to a pseudo-second-order model, and the measurements of activation energies. For 1/2/3, limit of detection values and adsorption capacities were 1.88 × 10-7/3.75 × 10-7/1.25 × 10-7 M and 1316.35/1431.40/1372.18 mg g-1, respectively, at pHi = 7.0, 303 K, and 1000 ppm. The better overall properties made 3 to be more suitable in sensing and cell imaging.

Matrix metalloproteinase: An upcoming therapeutic approach for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a debilitating condition where excess collagen deposition occurs in the extracellular matrix. At first sight, it is expected that the level of different kinds of matrix metalloproteinases might be downregulated in IPF as it is a matrix degrading collagenase. However, the role of some matrix metalloproteinases (MMPs) is profibrotic where others have anti-fibrotic functions. These profibrotic MMPs effectively promote fibrosis development by stimulating the process of epithelial to mesenchymal transition. These profibrotic groups also induce macrophage polarization and fibrocyte migration. All of these events ultimately disrupt the balance between profibrotic and antifibrotic mediators, resulting aberrant repair process. Therefore, inhibition of these matrix metalloproteinases functions in IPF is a potential therapeutic approach. In addition to the use of synthetic inhibitor, various natural compounds, gene silencing act as potential natural MMP inhibitor to recover IPF.

Mangiferin ameliorates collateral neuropathy in tBHP induced apoptotic nephropathy by inflammation mediated kidney to brain crosstalk.

The kidneys and brain share similarities in anatomy and vaso-regulation and exhibit clinical interactions in various diseases. To investigate the probable mechanism of kidney to brain crosstalk, we developed an in vivo model of renal injury in mice through intoxication with the oxidative stress inducer, tBHP. Proteinuria, abnormalities in the renal tubules and KIM1 activation were found in tBHP intoxicated animals. Due to this renal pathophysiology, various pro-inflammatory molecules (TNF-α, IL-1ß, IL-6, ICAM-1, VCAM-1) especially TNF-α, entered into the brain from kidneys, triggering cerebral inflammatory cascades leading to behavioral anomalies in association with membrane lipid peroxidation, BBB disruption and brain morphological alterations. Moreover, increased levels of reactive oxygen species, decreased antioxidant enzyme activity and an altered GSH/GSSG ratio were found in both these organs. Here, we introduced mangiferin as a protective molecule because of its anti-inflammatory and antioxidant properties. Mangiferin via inhibition of apoptosis and activation of the PI3K/Akt pathway protected the kidneys. It restored the deleterious phenomena in the damaged brain by downregulating the JNK and p38MAPK mediated pro-apoptotic cascade and activating the intracellular antioxidant thioredoxin, thereby protecting against tBHP induced nephropathy mediated neuropathophysiology.

Natural products: An upcoming therapeutic approach to cancer.

Cancer is one of the leading causes of death across the world. Different environmental and anthropogenic factors initiate mutations in different functional genes of growth factors and their receptors, anti-apoptotic proteins, self-renewal developmental proteins, tumor suppressors, transcription factors, etc. This phenomenon leads to altered protein homeostasis of the cell which in turn induces cancer initiation, development, progression and survival. From ancient times various natural products have been used as traditional medicine against different diseases. Natural products are readily applicable, inexpensive, accessible and acceptable therapeutic approach with minimum cytotoxicity. As most of the target-specific anticancer drugs failed to achieve the expected result so far, new multi-targeted therapies using natural products have become significant. In this review, we have summarized the efficacy of different natural compounds against cancer. They are capable of modulating cancer microenvironment and diverse cell signaling cascades; thus playing a major role in combating cancer. These compounds are found to be effective against several signaling pathways, mainly cell death pathways (apoptosis and autophagy) and embryonic developmental pathways (Notch pathway, Wnt pathway and Hedgehog pathway). This review article is expected to be helpful in understanding the recent progress of natural product research for the development of anticancer drug.

Mangiferin alleviates arsenic induced oxidative lung injury via upregulation of the Nrf2-HO1 axis.

Arsenic contaminated drinking water consumption is a serious health issue around the world. Chronic inorganic arsenic exposure has been associated with respiratory dysfunctions. It exerts various detrimental effects, disrupting normal cellular homeostasis and turning on severe pulmonary complications. This study elucidated the role of mangiferin, a natural xanthone, against arsenic induced lung toxicity. Chronic exposure of sodium arsenite (NaAsO2) at 10 mg/kg bw for 3 months abruptly increased the LDH release in broncho-alveolar lavage fluid, generated reactive oxygen species (ROS), impaired the antioxidant defense and distorted the alveoli architecture. It caused significant inflammatory outburst and promoted the apoptotic mode of cell death via upregulating the expressions of various proapoptotic molecules related to mitochondrial, extra-mitochondrial and ER stress mediated apoptotic pathway. Activation of inflammatory cascade led to disruption of alveolar capillary barrier and impaired Na+/K+-ATPase function that led to detaining of alveolar fluid clearance activity. Mangiferin due to its anti-inflammatory activity suppressed this inflammation and reduced inflammatory cell infiltration in lung tissue. It significantly restored the antioxidant balance and inhibited apoptosis in lung via upregulating Nrf2-HO1 axis.

Mangiferin Ameliorates Cisplatin Induced Acute Kidney Injury by Upregulating Nrf-2 via the Activation of PI3K and Exhibits Synergistic Anticancer Activity With Cisplatin.

Occurrence of oxidative stress is the principal cause of acute kidney injury induced by cisplatin. Mangiferin, a naturally occurring antioxidant molecule, is found to ameliorate several oxidative stress mediated pathophysiological conditions including cancer. Cisplatin induced cytotoxicity was measured in NKE cells by MTT assay and microscopic analysis. Induction of oxidative stress and regulation of proapoptotic molecules were subsequently investigated by using different spectrophotometric analyses, FACS and immunocytochemistry. Induction of nephrotoxicity was determined by analyzing different serum biomarkers and histological parameters in vivo using swiss albino mice. Activation of NF-κB mediated pro-inflammatory and caspase dependent signaling cascades were investigated by semi-quantitative RT-PCR and immunoblotting. Mangiferin was found to ameliorate cisplatin induced nephrotoxicity in vitro and in vivo by attenuating the induction of oxidative stress and upregulating Nrf-2 mediated pro-survival signaling cascades via the activation of PI3K. Additionally, mangiferin showed synergistic anticancer activity with cisplatin in cancer cell lines (MCF-7 and SKRC-45) and EAC cell induced solid tumor bearing experimental mice. The ameliorative effect of mangiferin is primarily attributed to its anti-oxidant and anti-inflammatory properties. It acts differentially in normal tissue cells and tumor cells by modulating different cell survival regulatory signaling molecules. For the first time, the study reveals a mechanistic basis of mangiferin action against cisplatin induced nephrotoxicity. Since Mangiferin shows synergistic anticancer activity with cisplatin, it can be considered as a promising drug candidate, to be used in combination with cisplatin.

Melatonin attenuates arsenic induced nephropathy via the regulation of oxidative stress and inflammatory signaling cascades in mice.

Arsenic is a potent inducer of several acute and chronic nephrotoxic disorders. It promotes deleterious phenomenon like oxidative stress, inflammation, cell death and altered glucose uptake leading to distorted kidney homeostasis that end up in chronic kidney disease. This study investigated the possible protective role of melatonin; a natural antioxidant produced by the pineal gland, against arsenic induced nephrotoxicity. Melatonin successfully ameliorated arsenic induced renal toxicity both in in vitro and in vivo models. Elevated BUN, creatinine, urine glucose and protein levels and altered renal histopathological conditions were observed in arsenic intoxicated mice. Significant oxidative stress induced damage of biomolecules along with downregulation in antioxidant enzymes and thiols were also detected in the kidney tissues of arsenic-intoxicated mice. These alterations along with mitochondrial dysfunction ultimately triggered TNFα mediated inflammatory and cell death cascades. Interestingly arsenic also led to disruption of glucose uptake in the kidney. These findings suggest that melatonin protects the kidney against toxic effect of arsenic, presumably through its antioxidant, anti-inflammatory and antidiabetic properties by inhibiting inflammatory outburst, apoptosis, necroptosis and stimulating glucose uptake. As melatonin is a natural antioxidant molecule, detailed pharmacokinetic and pharmacodynamic studies are expected to establish it as an effective nephro-protective agent in future.