Graphical representation of mechanism of apoptosis inside the cancer cell using copper oxide nanoparticles.
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Green nanotechnology elucidates highly prioritized anticancer activity. We ...synthesized Copper oxide nanoparticles (CuONPs) using leaves of Azadirachta indica (A. indica) plants and studied the molecular mechanism of cancer cell apoptosis. After their synthesis, with the help of expository tools like Fourier transform infrared spectroscopy (FT-IR), Transmission electron microscopy (TEM), Dynamic light scattering (DLS) and surface zeta potential we confirmed the successful synthesis of CuONPs. Here, crystalline structure of green synthesized CuONPs of 36 ± 8 nm size and spherical shape was able to kill MCF-7 and Hela cells, estimated by MTT assay. Successful internalization of Cu+2 ions inside the cell was estimated by the atomic absorption study. Cellular uptake of Cu+2 ions inflicted significant Reactive Oxygen Species (ROS) generation inside the cancer cells, thereby leading to DNA fragmentation as observed by DAPI staining. In in vivo model, CuONPs reduced the breast tumor volume in Balb/C mice and increased the mean survival time through the alteration of pro-inflammatory cytokines level. In case of both in vivo and in vitro models, CuONPs altered the pro-inflammatory cytokine level and pro-apoptotic protein expressions. In future, green synthesized CuONPs might be beneficial for its application as an anticancer drug in in vivo (mice model) and in vitro, though further study is needed on its toxicity.
Given that basal levels of reactive oxygen species (ROS) are higher in cancer cells, there is a growing school of thought that endorses pro-oxidants as potential chemotherapeutic agents. ...Intriguingly, cerium oxide (CeO2) nanoparticles can manifest either anti- or pro-oxidant activity as a function of differential pH of various subcellular localizations. In an acidic pH environment, for example, in extracellular milieu of cancer cells, CeO2 would function as a pro-oxidant. Based on this concept, the present study is designed to investigate the pro-oxidant activities of CeO2 in human colorectal carcinoma cell line (HCT 116). For comparison, we have also studied the effect of ceria nanoparticles on human embryonic kidney (HEK 293) cells. Dose-dependent viability of cancerous as well as normal cells has been assessed by treating them independently with CeO2 nanoparticles of different concentrations (5–100 μg/mL) in the culture media. The half maximal inhibitory concentration (IC50) of nanoceria for HCT 116 is found to be 50.48 μg/mL while that for the HEK 293 cell line is 92.03 μg/mL. To understand the intricate molecular mechanisms of CeO2-induced cellular apoptosis, a series of experiments have been conducted. The apoptosis-inducing ability of nanoceria has been investigated by Annexin V-FITC staining, caspase 3/9 analysis, cytochrome c release, intracellular ROS analysis, and mitochondrial membrane potential analysis using flow cytometry. Experimental data suggest that CeO2 treatment causes DNA fragmentation through enhanced generation of ROS, which ultimately leads to cellular apoptosis through the p53-dependent mitochondrial signaling pathway.
Various strategies to deliver antimalarials using nanocarriers have been evaluated. However, taking into account the peculiarities of malaria parasites, the focus is placed mainly polymer-based ...chitosan nanocarriers. Our purpose of the study is to develop chitosan–tripolyphosphate (CS–TPP) nanoparticles (NPs) conjugated chloroquine in application for attenuation of Plasmodium berghei infection in Swiss mice. NPs were prepared by ionotropic gelation between CS and sodium TPP. In the study, the interaction of CS and TPP and the presence of chloroquine at the surface of chitosan–TPP NPs have been investigated by means of different methods like FTIR, DLS, and zeta potential. After drug preparation, effective dose of the nanoconjugated chloroquine (Nch) among 100, 250, and 500mg/kg bw/day, was studied against P. berghei infection in Swiss mice by blood smear staining and biochemical assay of different inflammatory markers, and antioxidant enzyme levels also performed. After evaluating the effective dose, dose-dependent duration study was performed for 5, 10, 15 days. From the present study the maximum effect of Nch was found at 250mg/kg bw concentration for 15 days treatment. So, this Nch might have potential of application as therapeutic anti-malarial and antioxidant agent.
Silver nanoparticles (Ag NPs) were successfully synthesized using AgNO3 via an eco-friendly and simple green route using Abelmoschus esculentus (L.) pulp extract at room temperature. The ...phytochemicals present in A. esculentus (L.) pulp extract were used both as a reducing and a stabilizing agent for the synthesis of Ag NPs. The stabilization of Ag NPs with phytochemicals was justified using Fourier-transform infrared spectroscopy. The size of the as-synthesized Ag NPs was examined using dynamic light scattering and confirmed by transmission electron microscopy. The crystalline nature of Ag NPs had been identified using X-ray diffraction. The present study demonstrated the efficacy of Ag NPs against Jurkat cells in vitro. Our study also showed that the IC50 dose of Ag NPs leads to the increase in intracellular reactive oxygen species and significantly diminished mitochondrial membrane potential, indicating the effective involvement of apoptosis in cell death. The synthesized Ag NPs also exhibited good antimicrobial activity against different gram class bacteria.
The detection of toxic and flammable gases entwines a wide diversity of application purposes, such as medical diagnosis, food quality monitoring, environmental tracking, and so forth. In recent, ...polypyrrole (PPy) nanostructure and its hybrid composite have been emerged as an auspicious gas sensing element because of their unique physicochemical attributes. This review article demonstrates a comprehensive outlook of rapid progress in polypyrrole (PPy) and associated hybrid composite based chemiresistive gas sensors till now. Furthermore, the role of PPy nanostructures and organic or inorganic additives (CNT, graphene or its derivative, metal nanoparticle, metal oxides, metal sulfides) in PPy matrix towards improved gas sensing performance are discussed hereunder. The detailed and systematic discussion on the synthesis strategies, gas sensing principle of the PPy nanostructures, and its composites along with the development of sensor device configuration provide an in-depth understanding of the aforesaid topic to the readers. However, some relevant limitations of PPy and associated composites based gas sensor are addressed after investigating the thorough literature survey. Finally, this article will promote an advanced as well as focused direction to the readers for further development of PPy based high-performance gas sensing devices.
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•The toxic and flammable gas sensing performance of polypyrrole (PPy) and associated composite based chemiresistive sensors have been reviewed here.•A comparative inspection of different sensor fabrication techniques, various modifications of the synthesis strategy, and their effects on the gas sensing attributes of PPy nanostructure and associated composite is explored.•The role of organic and inorganic additives towards improved gas sensing performance of PPy based sensor is correlated with their plausible gas sensing mechanism.•The observed shortcomings and future prospects of PPy and the associated composite based chemiresistive gas sensors are also highlighted.
The unicellular organism Leishmania undergoes apoptosis-like cell death in response to external stress or exposure to antileishmanial agents. Here, we showed that 3-O,28-O-disuccinyl betulin (DiSB), ...a potent topoisomerase type IB inhibitor, induced parasitic cell death by generating oxidative stress. The characteristic feature of the death process resembled the programmed cell death (PCD) seen in higher eukaryotes. In the current study, the generation of reactive oxygen species (ROS), followed by the depolarization of mitochondrial membrane potential (ΔΨm), caused a loss in ATP production in Leishmania parasites. This further gave positive feedback to produce a large amount of ROS, which in turn caused oxidative DNA lesions and genomic DNA fragmentation. The treatment of promastigotes with DiSB induced high expression levels of metacaspase protein that led to cell death in this unicellular organism. The PCD was insensitive to benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk), suggesting that the death process was not associated with the activation of caspases. DiSB treatment translocated Leishmania donovani endonuclease G (LdEndoG) from mitochondria to the nucleus, which was responsible for the DNA degradation process. Conditional antisense knockdown of L. donovani metacaspase (LdMC), as well as EndoG, -subverted death of the parasite and rescued cell cycle arrest in G1 phase. The present study on the effector molecules associated with the PCD pathway of the parasite should help to manifest the mechanisms of PCD and also might be exploited in antileishmanial chemotherapy.
The work deals with an environmentally benign process for the synthesis of silver nanoparticle using Butea monosperma bark extract which is used both as a reducing as well as capping agent at room ...temperature. The reaction mixture turned brownish yellow after about 24h and an intense surface plasmon resonance (SPR) band at around 424nm clearly indicates the formation of silver nanoparticles. Fourier transform-Infrared (FT-IR) spectroscopy showed that the nanoparticles were capped with compounds present in the plant extract. Formation of crystalline fcc silver nanoparticles is analysed by XRD data and the SAED pattern obtained also confirms the crystalline behaviour of the Ag nanoparticles. The size and morphology of these nanoparticles were studied using High Resolution Transmission Electron Microscopy (HRTEM) which showed that the nanoparticles had an average dimension of ∼35nm. A larger DLS data of ∼98nm shows the presence of the stabilizer on the nanoparticles surface. The bio-synthesized silver nanoparticles revealed potent antibacterial activity against human bacteria of both Gram types. In addition these biologically synthesized nanoparticles also proved to exhibit excellent cytotoxic effect on human myeloid leukemia cell line, KG-1A with IC50 value of 11.47μg/mL.
After being used vigorously for the previous two decades to treat P. falciparum, chloroquine and sulfadoxine-pyrimethamine were replaced in 2009 with an artemisinin-based combination therapy ...(artesunate-sulfadoxine-pyrimethamine) in an effort to combat multidrug-resistant parasites.
We set out to assess the genetic variants of sulfadoxine-pyrimethamine resistance and the effectiveness of its treatment in eastern India prior to, during, and 6 to 8 years following the introduction of the new pharmacological regime. In 2008-2009, 318 P. falciparum-positive patients got the recommended doses of sulfadoxine-pyrimethamine. We used 379 additional isolates from 2015 to 2017 in addition to the 106 isolates from 2010. All 803 isolates from two study sites underwent in vitro sulfadoxine-pyrimethamine sensitivity testing and genomic characterisation of sulfadoxine-pyrimethamine resistance (pfdhfr and pfdhps).
In Kolkata and Purulia, we observed early treatment failure in 30.7 and 14.4% of patients, respectively, whereas recrudescence was found in 8.1 and 13.4% of patients, respectively, in 2008-2009. In 2017, the proportion of in vitro pyrimethamine and sulfadoxine resistance steadily grew in Kolkata and Purulia despite a single use of sulfadoxine-pyrimethamine. Treatment failures with sulfadoxine-pyrimethamine were linked to quintuple or quadruple pfdhfr- pfdhps mutations (AICII-AGKAT, AICII-AGKAA, AICII-SGKGT, AICII-AGKAA, AICNI-AGKAA) in 2008-2009 (p < 0.001). The subsequent spread of mutant-haplotypes with higher in vitro sulfadoxine-pyrimethamine resistance (p < 0.001), such as the sextuple (dhfr-AIRNI+dhps-AGEAA, dhfr-ANRNL+dhps-AGEAA) and septuple (dhfr-AIRNI+dhps-AGEAT), mutations were observed in 2015-2017.
This successive spread of mutations with high in vitro sulfadoxine-pyrimethamine resistance confirmed the progressive increase in antifolate resistance even after an 8-year withdrawal of sulfadoxine-pyrimethamine.
The emergence of drug resistance to frontline treatments such as Artemisinin-based combination therapy (ACT) is a major obstacle to the control and eradication of malaria. This problem is compounded ...by the inherent genetic variability of the parasites, as many established markers of resistance do not accurately predict the drug-resistant status. There have been reports of declining effectiveness of ACT in the West Bengal and Northeast regions of India, which have traditionally been areas of drug resistance emergence in the country. Monitoring the genetic makeup of a population can help to identify the potential for drug resistance markers associated with it and evaluate the effectiveness of interventions aimed at reducing the spread of malaria. In this study, we performed whole genome sequencing of 53 isolates of Plasmodium falciparum from West Bengal and compared their genetic makeup to isolates from Southeast Asia (SEA) and Africa. We found that the Indian isolates had a distinct genetic makeup compared to those from SEA and Africa, and were more similar to African isolates, with a high prevalence of mutations associated with antigenic variation genes. The Indian isolates also showed a high prevalence of markers of chloroquine resistance (mutations in Pfcrt) and multidrug resistance (mutations in Pfmdr1), but no known mutations associated with artemisinin resistance in the PfKelch13 gene. Interestingly, we observed a novel L152V mutation in PfKelch13 gene and other novel mutations in genes involved in ubiquitination and vesicular transport that have been reported to support artemisinin resistance in the early stages of ACT resistance in the absence of PfKelch13 polymorphisms. Thus, our study highlights the importance of region-specific genomic surveillance for artemisinin resistance and the need for continued monitoring of resistance to artemisinin and its partner drugs.
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CD40 plays dual immunoregulatory roles in Leishmania major infection and tumor regression. The functional duality emerges from CD40-induced reciprocal p38MAPK and ERK-1/2 phosphorylations. Because ...phosphotyrosine-based signaling in hematopoietic cells is regulated by the phosphotyrosine phosphatase SHP-1, which is not implied in CD40 signaling, we examined whether SHP-1 played any roles in CD40-induced reciprocal signaling and anti-leishmanial function. We observed that a weaker CD40 stimulation increased SHP-1 activation. ERK-1/2 inhibition or p38MAPK overexpression inhibited CD40-induced SHP-1 activation. An ultra-low-dose, CD40-induced p38MAPK phosphorylation was enhanced by SHP-1 inhibition but reduced by SHP-1 overexpression. A reverse profile was observed with ERK-1/2 phosphorylation. SHP-1 inhibition reduced syk phosphorylation but increased lyn phosphorylation; syk inhibition reduced but lyn inhibition enhanced CD40-induced SHP-1 phosphorylation. Corroborating these findings, in L. major-infected macrophages, CD40-induced SHP-1 phosphorylation increased and SHP-1 inhibition enhanced CD40-induced p38MAPK activation and inducible NO synthase expression. IL-10 enhanced SHP-1 phosphorylation and CD40-induced ERK-1/2 phosphorylation but reduced the CD40-induced p38MAPK phosphorylation, whereas anti-IL-10 Ab exhibited reverse effects on these CD40-induced functions, identifying IL-10 as a crucial element in the SHP-1-MAPK feedback system. Lentivirally overexpressed SHP-1 rendered resistant C57BL/6 mice susceptible to the infection. Lentivirally expressed SHP-1 short hairpin RNA enhanced the CD40-induced L. major parasite killing in susceptible BALB/c mice. Thus, we establish an SHP-1-centered feedback system wherein SHP-1 modulates CD40-induced p38MAPK activation threshold and reciprocal ERK-1/2 activation, establishing itself as a critical regulator of CD40 signaling reciprocity and mechanistically re-emphasizing its role as a potential target against the diseases where CD40 is involved.
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