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1.
ACS Appl Mater Interfaces ; 16(12): 14645-14660, 2024 Mar 27.
Article in English | MEDLINE | ID: mdl-38478795

ABSTRACT

The greater advantages and wide applications of zero-dimensional nanodots inspire researchers to develop new materials. Therefore, novel borophene quantum dots (QDs) were prepared by a hydrothermal liquid exfoliation technique using water medium. The borophene QDs proved to be highly stable in water medium for more than 120 days. The synthesized borophene QDs revealed intrinsic peroxidase mimetic activity using two chromogenic substrates, 3,3',5,5'-tetramethylbenzidine (TMB) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)diammonium salt (ABTS). The excellent intrinsic peroxidase activity toward TMB and ABTS substrates was executed using optimal reaction conditions (pH, borophene QDs' concentration, incubation time, and temperature). The formation of hydroxyl radicals in the presence of H2O2 upon TMB and ABTS oxidation played a significant role in the peroxidase reaction. The borophene QDs further proved to be successful for the colorimetric detection of antibiotics (oxytetracycline and tetracycline) using both TMB and ABTS peroxidase substrates. The limit of detection (LOD) for oxytetracycline and tetracycline was found to be 1.10 and 1.02 µM using TMB and 1.03 and 1.02 µM using ABTS chromogenic substrates, respectively. In addition, the fluorescence sensing of oxytetracycline and tetracycline over borophene QDs was also examined. The high fluorescence of borophene QDs (turn ON) was quenched (turn OFF) by oxytetracycline and tetracycline through the inner filter effect mechanism. The LOD of the fluorescence sensing of oxytetracycline and tetracycline was 1.14 and 1.08 µM, respectively. Interestingly, the borophene QDs could be used for the sensitive and selective colorimetric and fluorometric sensing of oxytetracycline and tetracycline after 120 days of storage. The synthesized borophene QDs with long-term stability and real sample analysis provide new insight as nanozymes with higher peroxidase mimetic and fluorescence performance and can be further exploited for medical diagnosis and environmental toxicants' detection.


Subject(s)
Benzothiazoles , Oxytetracycline , Quantum Dots , Sulfonic Acids , Peroxidase , Chromogenic Compounds , Hydrogen Peroxide/analysis , Peroxidases , Anti-Bacterial Agents/analysis , Tetracycline , Colorimetry/methods , Water
2.
Chem Commun (Camb) ; 60(17): 2417-2420, 2024 Feb 22.
Article in English | MEDLINE | ID: mdl-38323809

ABSTRACT

Photonanozymes are novel enzyme-mimicking nanomaterials with light-harvesting capacity and have widespread applications in many areas including biosensing, biomedicine, environmental applications, energy, etc. Herein, we introduce freestanding metal-free biocompitable borophene nanosheets (BNSs) exhibiting excellent photoresponsive peroxidase-like activity for biosensing applications. The photo-enhanced peroxidase-like activity of BNSs photonanozyme was indicated to be due to its band gap energy being comparable to the energy of visible light.


Subject(s)
Dopamine , Nanostructures , Colorimetry , Peroxidases , Peroxidase , Metals , Hydrogen Peroxide
3.
ACS Appl Mater Interfaces ; 15(41): 47902-47920, 2023 Oct 18.
Article in English | MEDLINE | ID: mdl-37812745

ABSTRACT

Recently, single atom catalysts (SACs) featuring M-Nx (M = metal) active sites on carbon support have drawn considerable attention due to their promising enzyme-like catalytic properties. However, typical synthesis methods of SACs often involve energy-intensive carbonization processes. Herein, we report a facile one-pot, low-temperature, wet impregnation method to fully utilize M-N4 sites of manganese phthalocyanine (MnPc) by decorating molecular MnPc over the sheets of graphene nanoplatelets (GNP). The synthesized MnPc@GNP exhibits remarkable peroxidase-mimic catalytic activity toward the oxidation of chromogenic 3,3',5,5'-tetramethylbenzidine (TMB) substrate owing to the efficient utilization of atomically dispersed Mn and the high surface-to-volume ratio of the porous catalyst. A nanozyme-based colorimetric sensing probe is developed to detect important biomarker glutathione (GSH) within only 5 min in solution phase based on the ability of GSH to effectively inhibit the TMB oxidation. The high sensitivity and selectivity of the developed colorimetric assay enable us to quantitatively determine GSH concentration in different biological fluids. This work, for the first time, reports a rapid MnPc@GNP nanozyme-based colorimetric assay in the solid substrate by fabricating microfluidic paper-based analytical devices (µPADs). GSH is successfully detected on the fabricated µPADs coated with only 6.0 µg of nanozyme containing 1.6 nmol of Mn in the linear range of 0.5-10 µM with a limit of detection of 1.23 µM. This work also demonstrates the quantitative detection of GSH in mice liver tissue lysate using µPADs, which paves the way to develop µPADs for point-of-care testing.


Subject(s)
Graphite , Animals , Mice , Graphite/chemistry , Manganese , Microfluidics , Oxidoreductases/chemistry , Peroxidase/chemistry , Colorimetry/methods , Glutathione , Hydrogen Peroxide/chemistry
4.
Injury ; 54(8): 110856, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37330403

ABSTRACT

Mikania micrantha (MM) has been traditionally used for various health benefits, including mental health, anti-inflammatory, wound dressing, and healing of sores. However, the molecular mechanisms and dose required for the wound healing activity of MM have yet to be reported. Therefore, a study was conducted to evaluate the wound healing potential of a cold methanolic extract of MM through in vitro and in vivo studies. Human dermal fibroblast adult (HDFa) cells were treated with 0 (control), 75 ng/ml, 125 ng/ml, 250 ng/ml, and 500 ng/ml of MMmethanolic extract (MME) for 24 h. MME at 75 ng/ml has significantly (p˂0.05) promoted HDFa cell proliferation and migration. Further, MME has also been shown to enhance the invasiveness of human umbilical vascular endothelial cells (HUVECs), indicating the neovasculature for wound healing. The tube formation assay demonstrated a significant (p<0.05) increase in the angiogenic effect of the MME starting at a concentration of 75 ng/ml as compared to the control. Treatment of excision wounds in Wistar rats with 5% and 10% MME ointment significantly enhanced wound contraction compared to control animals. Incision wounds in rats treated with 5% and 10% MME showed a significant (p<0.01) increase in tensile strength compared to control. HDFa cells, and granulation tissue collected on day 14 post-wounding, revealed the modulation of the FAK/Akt/mTOR cell signaling pathway during the enhancement of wound healing. The results of gel zymography showed increased activity of MMP-2 and MMP-9 in the HDFa cells after treatment with the extract.  It is concluded that MMEcan potentially accelerate cutaneous wound healing.


Subject(s)
Mikania , Skin , Rats , Humans , Animals , Rats, Wistar , Mikania/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/pharmacology , Plant Extracts/pharmacology , Endothelial Cells/metabolism , Wound Healing/physiology , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/pharmacology , Signal Transduction
5.
Reprod Biol ; 23(2): 100754, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36934663

ABSTRACT

We investigated the role of protein kinase c (PKC) -α and -ß during the ovarian follicular dynamics using estrous cycle, gonadotropin-induced ovulation, and antral follicle culture, 4-vinylcyclohexene diepoxide (VCD)-induced premature ovarian failure (POF) in the SD rat models. We found the higher activity of PKC during the proestrus stage along with expression of PKC-α during the estrus and metestrus stages of the estrous cycle while PKC-ß expression was increased during the diestrus, proestrus, and estrus stages. In response to pregnant mare gonadotropin (PMSG)-induced follicular recruitment and ovulation, the phosphorylated (Thr-642) PKC-ß was increased. PKC activity inhibition by hispidin during the proestrus stage resulted in decreased antral follicles and corpus luteum. Treatment with hispidin resulted in the downregulation of granulosa cell (GC) biomarker, follicle stimulating hormone receptor (FSHR) expression in the cultured pre-antral follicle. During the forskolin-induced luteinization of human granulosa cells, the expression level of PKC-α and ß (I and II) was decreased. In the POF condition, the activity of total PKC and the expression levels of PKC-α and ß (I and II) were increased. Immunostaining depicted ubiquitous expression of PKC-α in the ovary during the estrous cycle and POF conditions. Taken together, we conclude the association of PKC-α and -ß (I and II) during ovarian follicular dynamics where the expression level of PKC-α is increased, but the expression level of PKC-ß (I and II) is suppressed in the POF condition in the SD rat model.


Subject(s)
Primary Ovarian Insufficiency , Animals , Female , Rats , Gonadotropins/pharmacology , Protein Kinase C beta , Rats, Sprague-Dawley
6.
Regul Toxicol Pharmacol ; 123: 104960, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34022260

ABSTRACT

Cassia occidentalis Linn (CO) is an annual/perennial plant having traditional uses in the treatments of ringworm, gastrointestinal ailments and piles, bone fracture, and wound healing. Previously, we confirmed the medicinal use of the stem extract (ethanolic) of CO (henceforth CSE) in fracture healing at 250 mg/kg dose in rats and described an osteogenic mode of action of four phytochemicals present in CSE. Here we studied CSE's preclinical safety and toxicity. CSE prepared as per regulations of Current Good Manufacturing Practice for human pharmaceuticals/phytopharmaceuticals and all studies were performed in rodents in a GLP-accredited facility. In acute dose toxicity as per New Drug and Clinical Trial Rules, 2019 (prior name schedule Y), in rats and mice and ten-day dose range-finding study in rats, CSE showed no mortality and no gross abnormality at 2500 mg/kg dose. Safety Pharmacology showed no adverse effect on central nervous system, cardiovascular system, and respiratory system at 2500 mg/kg dose. CSE was not mutagenic in the Ames test and did not cause clastogenicity assessed by in vivo bone marrow genotoxicity assay. By a sub chronic (90 days) repeated dose (as per OECD, 408 guideline) study in rats, the no-observed-adverse-effect-level was found to be 2500 mg/kg assessed by clinico-biochemistry and all organs histopathology. We conclude that CSE is safe up to 10X the dose required for its osteogenic effect.


Subject(s)
Phytochemicals/toxicity , Plant Extracts/toxicity , Senna Plant , Animals , Ethanol , Mice , No-Observed-Adverse-Effect Level , Rats , Rodentia , Toxicity Tests
7.
Biogerontology ; 22(1): 19-34, 2021 02.
Article in English | MEDLINE | ID: mdl-32926226

ABSTRACT

It has been earlier reported that partially saturated canthaxanthin (PSC) from Aspergillus carbonarius mutant is non-toxic, has anti-lipid peroxidation activity and can induce apoptosis in prostate cancer cell lines. In the present study, the antiaging effect of PSC was explored in D-galactose administered male wistar rats. 8-10 weeks old, male wistar rats were randomly divided into (i) Vehicle Control Group (VCG), (ii) Aged Control Group (ACG), (iii) Aged + α Lipoic Acid Group (ALG) and (iv) Aged + Partially saturated canthaxanthin Group (APG). Rats received D-galactose (300 mg /kg bwt/day; i.p.) alone (ACG) or together with PSC (APG) (20 mg/kg bwt/day; oral) and α Lipoic Acid (ALG) (80 mg/kg bwt/day; oral) for 10 weeks. Rats in VCG were injected with the same volume of physiological saline (i.p.) and fed with olive oil (vehicle). In vitro protein oxidation and DNA oxidation inhibition, in vivo malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), acetylcholinesterase (AChE) and monoamine oxidase (MAO) activities were determined. In addition, brain neurotransmitters, dopamine and serotonin were estimated by NMR. PSC treatment showed inhibition against protein and DNA oxidation. PSC effectively improved D-galactose induced aging rats by inducing a protective effect through up-regulation of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT) and brain neurotransmitters and downregulated malondialdehyde (MDA) and monoamineoxidase (MAO) levels. Thus, PSC appears to be a functional compound having antioxidant and antiaging properties.


Subject(s)
Canthaxanthin , Galactose , Aging , Animals , Antioxidants/pharmacology , Aspergillus , Catalase/metabolism , Glutathione Peroxidase/metabolism , Lipid Peroxidation , Male , Malondialdehyde , Oxidative Stress , Rats , Rats, Wistar , Superoxide Dismutase/metabolism
8.
Neurotox Res ; 37(4): 904-912, 2020 Apr.
Article in English | MEDLINE | ID: mdl-31811585

ABSTRACT

The pattern of copper (Cu) toxicity in humans is similar to Wilson disease, and they have movement disorders and frequent involvement of corpus striatum. The extent of cell deaths in corpus striatum may be the basis of movement disorder and may be confirmed in the experimental study. To evaluate the extent of apoptosis and glial activation in corpus striatum following Cu toxicity in a rat model, and correlate these with spontaneous locomotor activity (SLA), six male Wistar rats were fed normal saline (group I) and another six were fed copper sulfate 100 mg/kgBWt/daily orally (group II). At 1 month, neurobehavioral studies including SLA, rotarod, and grip strength were done. Corpus striatum was removed and was subjected to glial fibrillary acidic protein (GFAP) and caspase-3 immunohistochemistry. The concentration of tissue Cu, total antioxidant capacity (TAC), glutathione (GSH), malondialdehyde (MDA), and glutamate were measured. Group II rats had higher expression of caspase-3 (Mean ± SEM 32.67 ± 1.46 vs 4.47 ± 1.08; p < 0.01) and GFAP (41.81 ± 1.68 vs 31.82 ± 1.27; p < 0.01) compared with group I. Neurobehavioral studies revealed reduced total distance traveled, time moving, the number of rearing, latency to fall on the rotarod, grip strength, and increased resting time compared with group I. The expression of GFAP and caspase-3 correlated with SLA parameters, tissue Cu, GSH, MDA, TAC, and glutamate levels. The impaired locomotor activity in Cu toxicity rats is due to apoptotic and inflammatory-mediated cell death in the corpus striatum because of Cu-mediated oxidative stress and excitotoxicity.


Subject(s)
Apoptosis/physiology , Copper Sulfate/toxicity , Corpus Striatum/pathology , Disease Models, Animal , Movement Disorders/pathology , Oxidative Stress/physiology , Animals , Apoptosis/drug effects , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Inflammation/chemically induced , Inflammation/metabolism , Inflammation/pathology , Locomotion/drug effects , Locomotion/physiology , Male , Movement Disorders/metabolism , Oxidative Stress/drug effects , Rats , Rats, Wistar
9.
Pharm Res ; 35(3): 60, 2018 Feb 09.
Article in English | MEDLINE | ID: mdl-29427248

ABSTRACT

PURPOSE: To fabricate, characterize and evaluate 3-O-sn-Phosphatidyl-L-serine (PhoS) anchored PLGA nanoparticles for macrophage targeted therapeutic intervention of VL. MATERIALS AND METHODS: PLGA-AmpB NPs were prepared by well-established nanoprecipitation method and decorated with Phos by thin film hydration method. Physico-chemical characterization of the formulation was done by Zetasizer nano ZS and atomic force microscopy. RESULTS: The optimized formulation (particle size, 157.3 ± 4.64 nm; zeta potential, - 42.51 ± 2.11 mV; encapsulation efficiency, ∼98%) showed initial rapid release up to 8 h followed by sustained release until 72 h. PhoS generated 'eat-me' signal driven augmented macrophage uptake, significant increase in in-vitro (with ∼82% parasite inhibition) and in-vivo antileishmanial activity with preferential accumulation in macrophage rich organs liver and spleen were found. Excellent hemo-compatibility justified safety profile of developed formulation in comparison to commercial formulations. CONCLUSION: The developed PhoS-PLGA-AmpB NPs have improved efficacy, and necessary stability which promisingly put itself as a better alternative to available commercial formulations for optimized treatment of VL.


Subject(s)
Amphotericin B/administration & dosage , Antiprotozoal Agents/administration & dosage , Drug Carriers/chemistry , Leishmaniasis, Visceral/drug therapy , Macrophages/drug effects , Animals , Cell Line , Delayed-Action Preparations/administration & dosage , Disease Models, Animal , Drug Compounding/methods , Drug Evaluation, Preclinical , Drug Stability , Humans , Leishmania donovani/drug effects , Macrophages/parasitology , Male , Mice , Nanoparticles/chemistry , Phosphatidylserines/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Rats , Rats, Wistar , Treatment Outcome
10.
Mol Neurobiol ; 55(5): 3800-3811, 2018 May.
Article in English | MEDLINE | ID: mdl-28536976

ABSTRACT

The prototype disease of Cu toxicity in human is Wilson disease, and cognitive impairment is the presenting symptom of it. There is no study correlating Cu-induced excitotoxicity, apoptosis, and astrocytic reaction with memory dysfunction. We report excitotoxicity, apoptosis, and astrocytic reaction of the hippocampus and frontal cortex with memory dysfunction in rat model of Cu toxicity. Thirty-six rats were divided into group I (control) and group II (100 mg/kgBwt/day CuSO4 orally). Y-maze was performed for memory and learning at 0, 30, 60, and 90 days. Frontal and hippocampal free Cu concentration, oxidative stress markers [glutathione (GSH), total antioxidant toxicity (TAC), and malondialdehyde (MDA)], and glutamate were measured by atomic absorption spectroscopy, spectrophotometry, and ELISA, respectively. N-methyl-D-aspartate receptors (NMDARs) NR1, NR2A, and NR2B were done by real-time polymerase chain reaction. Immunohistochemistry for caspase-3 and glial fibrillary acidic protein (GFAP) were done and quantified using the ImageJ software. The glutamate level in hippocampus was increased, and NMDAR expression was decreased at 30, 60, and 90 days in group II compared to group I. In the frontal cortex, glutamate was increased at 90 days, but NMDARs were not significantly different in group II compared to group I. Caspase-3 and GFAP expressions were also higher in group II compared to group I, and these changes were more marked in hippocampus than frontal cortex. These changes correlated with respective free tissue Cu, oxidative stress, and Y-maze attention score. Cu toxicity induces apoptosis and astrocytosis of the hippocampus and frontal cortex through direct or glutamate and oxidative stress pathways, and results in impaired memory and learning.


Subject(s)
Apoptosis/drug effects , Copper/toxicity , Frontal Lobe/drug effects , Hippocampus/drug effects , Oxidative Stress/drug effects , Spatial Learning/drug effects , Spatial Memory/drug effects , Animals , Caspase 3/metabolism , Frontal Lobe/metabolism , Glial Fibrillary Acidic Protein/metabolism , Glutamic Acid/metabolism , Glutathione/metabolism , Hippocampus/metabolism , Immunohistochemistry , Male , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/metabolism
11.
Int J Biol Macromol ; 105(Pt 1): 1220-1231, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28780414

ABSTRACT

The goal of study was to develop micellar formulation of Amphotericin B (AmB) to improve its antileishmanial efficacy. AmB loaded pluronic F127 (PF 127) micelles were developed and coated with chitosan (Cs-PF-AmB-M) to accord immunoadjuvant and macrophage targeting properties. Hemolysis and cytotoxicity studies demonstrated that Cs-PF-AmB-M was 7.93 fold (at 20µg/ml AmB concentration) and 9.35 fold less hemolytic and cytotoxic, respectively in comparison to AmB suspension. Flow cytometry studies indicated that Cs-PF-FITC-M was 21.97 fold higher internalized byJ774A.1 macrophage in comparison to PF-FITC-M.Cs-PF-AmB-M showed excellent in-vitro (1.82 fold in compared to AmB suspension) and in-vivo (75.84±7.91% parasitic inhibition) antileishmanial activity against macrophage resident intracellular promastigotes and Leishmania donovani infected Syrian hamsters, respectively. Chitosan coating stimulated a Th1 immune response mediating auxiliary immunotherapeutic action as judged by in-vitro and in-vivo cytokine and mRNA expression. Toxicity studies demonstrated normal blood urea nitrogen (BUN) and plasma creatinine (PC) level and no sign of abnormal histopathology upon intravenous administration of micellar formulations. Pharmacokinetic profiling and tissue distribution studies indicated that AmB was preferentially localized in macrophage harboring tissue instead of kidney, thereby circumventing the characteristic nephrotoxicity. Conclusively, Cs-PF-AmB-M could be a viable alternative for the current immuno and chemotherapy of visceral leishmaniasis (VL).


Subject(s)
Amphotericin B/chemistry , Amphotericin B/pharmacology , Chitosan/chemistry , Drug Carriers/chemistry , Leishmaniasis, Visceral/drug therapy , Micelles , Poloxamer/chemistry , Amphotericin B/pharmacokinetics , Amphotericin B/therapeutic use , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacokinetics , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/therapeutic use , Cell Line , Cricetinae , Cytokines/metabolism , Drug Carriers/toxicity , Drug Compounding , Female , Humans , Leishmania donovani/drug effects , Leishmania donovani/physiology , Macrophages/drug effects , Mice , Tissue Distribution
12.
Mol Cancer Ther ; 16(9): 1791-1805, 2017 09.
Article in English | MEDLINE | ID: mdl-28500231

ABSTRACT

Molecular hybridization of different pharmacophores to tackle both tumor growth and metastasis by a single molecular entity can be very effective and unique if the hybrid product shows drug-like properties. Here, we report synthesis and discovery of a novel small-molecule inhibitor of PP2A-ß-catenin signaling that limits both in vivo tumor growth and metastasis. Our molecular hybridization approach resulted in cancer cell selectivity and improved drug-like properties of the molecule. Inhibiting PP2A and ß-catenin interaction by selectively engaging PR55α-binding site, our most potent small-molecule inhibitor diminished the expression of active ß-catenin and its target proteins c-Myc and Cyclin D1. Furthermore, it promotes robust E-cadherin upregulation on the cell surface and increases ß-catenin-E-Cadherin association, which may prevent dissemination of metastatic cells. Altogether, we report synthesis and mechanistic insight of a novel drug-like molecule to differentially target ß-catenin functionality via interacting with a particular subunit of PP2A. Mol Cancer Ther; 16(9); 1791-805. ©2017 AACR.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Neoplasms/metabolism , Protein Phosphatase 2/metabolism , Signal Transduction/drug effects , beta Catenin/metabolism , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cadherins/genetics , Cadherins/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival , Chalcones/chemistry , Chalcones/pharmacology , Disease Models, Animal , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Models, Molecular , Molecular Conformation , Neoplasm Metastasis , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , Phosphorylation , Protein Binding , Protein Phosphatase 2/chemistry , Semicarbazones/chemistry , Semicarbazones/pharmacology , Tumor Burden , Xenograft Model Antitumor Assays , beta Catenin/chemistry
13.
Regul Toxicol Pharmacol ; 81: 372-380, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27670080

ABSTRACT

Excess of copper is toxic to different organs. We aim to study the histopathological changes of liver, kidney, and brain following oral CuSO4 exposure for different duration and doses in rat model. Fifty-four males Wistar rats (205 ± 10 g) were included and divided into control (group-I) and experimental (group-II and III) arms. An oral dose of 100 and 200 mg/kgBWt/Day CuSO4 was given to group-II and III respectively and group-I received normal saline by gavage. Six rats from each group were sacrificed on days 30, 60 and 90 for biochemical and histopathological examinations. The histopathological changes were graded on 1-5 scores and correlated with respective laboratory parameters. The organ functions were worsened in experimental group with increasing dose and time. Histopathological study revealed edema, hemorrhage, necrosis and fibrosis/gliosis in experimental group. The worst histopathological severity score ranged from 4 to 5(median 5) in liver, 3-5(median 4) in kidney and 4-5(median 5) in brain. The edema and hemorrhage were more marked at 30 days and fibrosis/gliosis at 90 days. In conclusion, high-dose Cu toxicity results in structural damage to liver, kidney, and brain that correlates with organ dysfunction, Cu, GSH, TAC, and MDA concentrations. Liver damage is more severe and occurs earlier than other organs.


Subject(s)
Brain/drug effects , Copper Sulfate/toxicity , Kidney/drug effects , Liver/drug effects , Models, Animal , Temperature , Administration, Oral , Animals , Biomarkers/analysis , Brain/metabolism , Brain/pathology , Copper Sulfate/administration & dosage , Dose-Response Relationship, Drug , Kidney/metabolism , Kidney/pathology , Kinetics , Liver/metabolism , Liver/pathology , Male , Oxidative Stress/drug effects , Rats , Rats, Wistar
14.
Toxicol Appl Pharmacol ; 293: 37-43, 2016 Feb 15.
Article in English | MEDLINE | ID: mdl-26780401

ABSTRACT

Copper (Cu) at a higher level becomes toxic and it can catalyze the formation of highly reactive hydroxyl radical. We report the vulnerability of liver, kidney and brain to different dose of copper sulfate (CuSO4) induced oxidative stress at different time duration. Fifty-four male Wistar rats (weight range=205±10g) were equally divided into three groups. CuSO4 was administered orally to the experimental groups (Group-II and III) up to 90 days in a dose of 100 and 200mg/Kg body weight per day. Saline water was given to the control group (Group-I). At the end of 30, 60 and 90 days of administration, neurobehavioral studies were done and six rats from each group were sacrificed. Their liver, kidney and brain tissues were subjected for Cu, glutathione (GSH), malondialdehyde (MDA) and total antioxidant capacity (TAC) assay. Blood urea nitrogen (BUN), serum creatinine, bilirubin and transaminases were measured. GSH, TAC and MDA levels were correlated with the markers of respective organ dysfunction. Administration of CuSO4 resulted in increased free Cu and MDA level, and decrease GSH and TAC levels in group-II and III compared with group-I. In experimental groups, the reduction in TAC and GSH levels was maximum in liver tissue followed by brain and kidney; whereas increase in MDA level was highest in liver followed by brain and kidney at 30, 60 and 90 days. TAC and GSH levels in the liver inversely correlated with serum transaminases and bilirubin, and tissue free Cu, and positively correlated with MDA levels. Free Cu level in kidney tissue and BUN inversely correlated with TAC and GSH, and positively with MDA level. Grip-strength, rotarod and Y-maze findings were inversely correlated with brain free Cu and MDA levels and positively with GSH and TAC levels. The oxidative stress was highest in liver followed by brain and kidney after oral CuSO4 exposure in a rat model. These levels correlated with the respective organ dysfunction and tissue free Cu concentration.


Subject(s)
Brain/drug effects , Copper/toxicity , Kidney/drug effects , Liver/drug effects , Oxidative Stress/drug effects , Animals , Behavior, Animal/drug effects , Blood Urea Nitrogen , Brain/metabolism , Creatinine/blood , Exploratory Behavior/drug effects , Glutathione/metabolism , Hand Strength , Kidney/metabolism , Liver/metabolism , Male , Malondialdehyde/metabolism , Rats, Wistar , Rotarod Performance Test
15.
Cancer Prev Res (Phila) ; 8(6): 552-62, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25813524

ABSTRACT

Non-small cell lung cancer (NSCLC) represents almost 85% of total diagnosed lung cancer. Studies have shown that combination of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors is effective against various cancers, including lung cancer. However, optimizing the synergistic dose regime is very difficult and involves adverse side effects. Therefore, in this study, we have shown that cucurbitacin B (CuB), a single bioactive triterpenoid compound, inhibits both DNMTs and HDACs starting at a very low dose of 60 nmol/L in NSCLC H1299 cells. The CuB-mediated inhibition of DNMTs and HDACs in H1299 cells leads to the reactivation of key tumor suppressor genes (TSG) such as CDKN1A and CDKN2A, as well as downregulation of oncogenes c-MYC and K-RAS and key tumor promoter gene (TPG), human telomerase reverse transcriptase (hTERT). The upregulation of TSGs and downregulation of TPG were consistently correlated with the alterations in their promoter methylation and histone modifications. This altered expression of TPG and TSGs is, at least in part, responsible for the inhibition of cellular proliferation and induction of cellular apoptosis in NSCLC. Furthermore, CuB treatment significantly inhibited the tumor incidence and multiplicity in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice, which was associated with the induction of apoptosis and inhibition of hyperproliferation in the lung tissues. Together, our study provides new insight into the CuB-mediated epigenetic alterations and its chemotherapeutic effects on lung cancer.


Subject(s)
Carcinoma, Non-Small-Cell Lung/prevention & control , Cell Transformation, Neoplastic/drug effects , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic/drug effects , Lung Neoplasms/prevention & control , Nitrosamines/toxicity , Triterpenes/pharmacology , Animals , Apoptosis/drug effects , Blotting, Southwestern , Blotting, Western , Carcinogens/toxicity , Carcinoma, Non-Small-Cell Lung/chemically induced , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Chromatin Immunoprecipitation , DNA Methylation/drug effects , Female , Genes, Neoplasm , Histone Deacetylases/chemistry , Humans , Immunoenzyme Techniques , Lung Neoplasms/chemically induced , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Mice, Inbred A , Promoter Regions, Genetic , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured
16.
Neurotoxicology ; 48: 44-9, 2015 May.
Article in English | MEDLINE | ID: mdl-25766523

ABSTRACT

Nitrous oxide (N2O) toxicity can result in myelin loss and hyperhomocysteinemia similar to cobalamin (Cbl) deficiency. Studies on N2O exposure can help in understanding the mechanism of demyelination. In view of paucity of studies on N2O toxicity in rats this study was undertaken. Six male wistar rats were exposed to 1.5L/min N2O with 1:1 O2 for 90 min daily for 1 month. After 1-month exposure blood homocysteine (HCY) and oxidative stress parameters glutathione (GSH) and total antioxidant capacity (TAC) were measured. Brain and spinal cord was subjected to histopathological examination. The neurobehavioral changes, oxidative stress parameters and histopathological changes were correlated with serum B12 and HCY level. After 1-month exposure, the rats appeared sluggish, lethargic and developed predominantly hind limb weakness for 1-1.5h. In the exposed group, the total distance traveled (2001.66 ± 118.27 cm; p=0.037), time moving (80.16 ± 5.7s; p=0.028), number of rearing (10.33 ± 1.45; p=0.014) and grip strength (1042.40 ± 51.3N; p=0.041) were significantly decreased whereas, resting time significantly increased (219.83 ± 5.7s; p=0.030) compared to controls. Serum HCY level was significantly increased (20.56 ± 1.296 µm/ml; p=0.0007) in the exposed group. However, serum B12 and folic acid levels were not significantly different. GSH significantly decreased (2.21 ± 0.60 mg/dl; p=0.018) along with TAC (0.76 ± 0.16 Trolox_Eq_mmol/l; p=0.036). The histopathological studies revealed shrinkage and vacuolation of neurons in cerebral cortex, focal myelin loss, vacuolation in subcortical white matter and spinal cord. N2O exposure results in behavioral alterations, hyperhomocysteinemia, cortical and spinal cord demyelination which were associated with decrease GSH and TAC highlighting pathophysiological role of oxidative stress.


Subject(s)
Behavior, Animal/drug effects , Brain/metabolism , Nitrous Oxide , Oxidative Stress , Spinal Cord/metabolism , Animals , Antioxidants/metabolism , Brain/pathology , Brain/physiopathology , Demyelinating Diseases/blood , Demyelinating Diseases/chemically induced , Demyelinating Diseases/pathology , Demyelinating Diseases/physiopathology , Demyelinating Diseases/psychology , Disease Models, Animal , Glutathione/blood , Homocysteine/blood , Hyperhomocysteinemia/blood , Hyperhomocysteinemia/chemically induced , Hyperhomocysteinemia/pathology , Hyperhomocysteinemia/physiopathology , Hyperhomocysteinemia/psychology , Male , Motor Activity , Muscle Strength , Oxidative Stress/drug effects , Rats, Wistar , Spinal Cord/pathology , Spinal Cord/physiopathology , Time Factors , Vitamin B 12/blood , Vitamin B 12 Deficiency/blood , Vitamin B 12 Deficiency/chemically induced , Vitamin B 12 Deficiency/pathology , Vitamin B 12 Deficiency/physiopathology , Vitamin B 12 Deficiency/psychology
17.
Int J Biochem Cell Biol ; 58: 1-16, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25448414

ABSTRACT

Metastatic spread during carcinogenesis worsens disease prognosis and accelerates the cancer progression. Therefore, newer therapeutic options with higher specificity toward metastatic cancer are required. Centchroman (CC), a female oral contraceptive, has previously been reported to possess antiproliferative and proapoptotic activities in human breast cancer cells. Here, we investigated the effect of CC-treatment against breast cancer metastasis and associated molecular mechanism using in vitro and in vivo models. CC significantly inhibited the proliferation of human and mouse mammary cancer cells. CC-treatment also inhibited migration and invasion capacities of highly metastatic MDA-MB-231 and 4T1 cells, at sub-IC50 concentrations. Inhibition of cell migration and invasion was found to be associated with the reversal of epithelial-to-mesenchymal transition (EMT) as observed by the upregulation of epithelial markers and downregulation of mesenchymal markers as well as decreased activities of matrix metalloproteinases. Experimental EMT induced by exposure to TGFß/TNFα in nontumorigenic human mammary epithelial MCF10A cells was also reversed by CC as evidenced by morphological changes and modulation in the expression levels of EMT-markers. CC-mediated inhibition of cellular migration was, at least partially, mediated through inhibition of ERK1/2 signaling, which was further validated by using MEK1/2 inhibitor (PD0325901). Furthermore, CC-treatment resulted in suppression of tumor growth and lung metastasis in 4T1-syngeneic mouse model. Collectively, our findings suggest that CC-treatment at higher doses specifically induces cellular apoptosis and inhibits cellular proliferation; whereas at lower doses, it inhibits cellular migration and invasion. Therefore, CC could further be developed as an effective drug candidate against metastatic breast cancer.


Subject(s)
Breast Neoplasms/drug therapy , Centchroman/therapeutic use , Neoplasm Metastasis/drug therapy , Animals , Apoptosis/drug effects , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Epithelial-Mesenchymal Transition/drug effects , Humans , Immunohistochemistry , MAP Kinase Signaling System/drug effects , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred BALB C , Wound Healing/drug effects
18.
J Biomed Nanotechnol ; 10(11): 3381-91, 2014 Nov.
Article in English | MEDLINE | ID: mdl-26000396

ABSTRACT

An attempt has been made to use curcumin (CUR) in combination with Etoposide (ETP) by encapsulating in nanoemulsion, as two tier approach i.e., to evaluate improvement in efficacy of ETP on prostate cancer cells (PC3 and DU145) and to assess their effect on cross-talk between osteoblast and tumor cells leading to metastatic cascade in bones. Nanoemulsion was developed and evaluated for size, charge, in-vitro drug release and anticancer activity, effect on cross talk between osteoblast and prostate cancer cells and pharmacokinetics in rats. The entrapment efficiency of both ETP and CUR in nanoemulsion was more than 98% while the globule size was less than 150 nm with zeta potential - 29.8 mV. The percent inhibition in case of ETP and ETP: CUR (1:3 w/w) was 55.92 ± 1.2 and 41.13 ± 2.4% (at 5 µM) respectively when tested in PC3 cells. DU-145 seemed to be less responsive in comparison to PC3 cells both in respect of ETP and their mixture (ETP+ CUR). Our data shows that CUR and ETP after encapsulation in nanoemulsion (F5) were effectively delivered intracellularly in PC3 cells and the cytotoxicity of F5 was enhanced by 1.5 fold as compared to ETP + CUR at 5 µM concentration. It has also been observed that mice calvarial osteoblasts cultured and incubated with PC-3 and DU-145 cells conditioned media induces inhibition of osteoblast differentiation event. While this inhibition was significantly reversed by F5 at 5 µM concentration over other treated groups, the pharmacokinetic profile of both ETP and CUR was also significantly improved when administered in nanoemulsion.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bone Neoplasms/secondary , Cell Communication/drug effects , Nanocapsules/chemistry , Osteoblasts/drug effects , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Animals , Antineoplastic Agents/administration & dosage , Bone Neoplasms/drug therapy , Bone Neoplasms/pathology , Cell Line, Tumor , Curcumin/administration & dosage , Drug Combinations , Emulsions , Etoposide/administration & dosage , Humans , Male , Mice , Nanocapsules/ultrastructure , Osteoblasts/pathology , Rats, Sprague-Dawley , Treatment Outcome
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