A novel compound β-sitosterol-3-O-β-D-glucoside isolated from Azadirachta indica effectively induces apoptosis in leukemic cells by targeting G0/G1 populations

27-32Azadirachta indica, popularly known as ‘Neem’, is an important plant in the Ayurveda system of medicine. It is known to prevent about at least 40 types of diseases in home-practice. A previous report showed that the methanolic extract of this plant can effectively control proliferation of leukemia cells. Here, we explored the eEthanolic extract dried neem leaves for a new molecule with potent anti-leukemic property.Four biomolecules were isolated viz. rutin, isoquercetin, quercetrin and β-sitosterol-3-O-β-D-glucoside from the ethanolic extract by repeated column chromatography and HPLC.Quercetrin structures of the isolated molecules were confirmed by Mass, 1HNMR, 13C NMR spectra analysis. MTT assay revealed that β-sitosterol-3-O-β-D-glucoside effectively reduced the proliferation of MOLT 4 leukemic cells in a dose and time dependent manner. DAPI staining with confocal microscopy indicated that β-sitosterol-3-O-β-D-glucoside efficiently induced nuclear DNA fragmentation in MOLT 4 cells. Finally, flow cytometry after PI staining showed that the compound has potential to check the cell cycle progression at sub G1 phase. With the available results, it can be concluded that β-sitosterol-3-O-β-D-glucoside has potential to be good therapeutic drug in leukemia treatment

Structural sensitivity of chaotic dynamics in Hastings-Powell's model

The classical Hastings-Powell model is well known to exhibit chaotic dynamics in a three-species food chain. Chaotic dynamics appear through period-doubling bifurcation of stable coexistence limit cycle around an unstable interior equilibrium point. A specific choice of parameter value leads to a situation where the chaotic attractor disappears through a collision with an unstable limit cycle. As a result, the top predator goes to extinction. Here we explore the structural sensitivity of this phenomenon by replacing the Holling type II functional responses with Ivlev functional responses. Here we prove the existence of two Hopf-bifurcation thresholds and numerically detect the existence of an unstable limit cycle. The model with Ivlev functional responses does not indicate any possibility of extinction of the top predator. Further, the choice of functional responses depicts a significantly different picture of the coexistence of the three species involved with the model

A novel compound β-sitosterol-3-O-β-D-glucoside isolated from Azadirachta indica effectively induces apoptosis in leukemic cells by targeting G0/G1 populations

Azadirachta indica, popularly known as ‘Neem’, is a very important plant in the Ayurveda system of medicine. It is known toprevent about 40 types of diseases in home-practice. A previous report showed that the methanolic extract of this plant can effectively control the proliferation of leukemia cells. Therefore, this research focuses on searching for a new molecule with potent anti-leukemic property. Ethanolic extract was prepared from the dried leaves. Four bio-molecules were isolated viz. rutin, isoquercetin, quercetrin and β-sitosterol-3-O-β-D-glucoside from the ethanolic extract by repeated column chromatography and HPLC. Quercetrin structures of the isolated molecules were confirmed by Mass, 1HNMR, 13C NMR spectra analysis. MTT assay revealed that β-sitosterol-3-O-β-D-glucosideeffectively reduced the proliferation of MOLT 4 leukemic cells in a dose and time dependent manner. DAPI staining with confocal microscopy indicated that β-sitosterol-3-O-β-D-glucoside efficiently induced nuclear DNA fragmentation in MOLT 4 cells. Finally, flow cytometry after PI staining showed that the compound has potential to check the cell cycle progression at sub G1 phase. In summary, we can conclude that β-sitosterol-3-O-β-D-glucoside has potential to be good therapeutic drug in leukemia treatment in future

Nonlocal Multiscale Interactions in Brain Neurodegenerative Protein Dynamics and Coupled Proteopathic Processes

We take a heterodimer multiscale reaction-diffusion model as a starting point and modify it to account for the nonlocality of the underlying processes. The resulting model is a coupled system of integro-differential equations. The effect of nonlocal interactions is quantified based on the comparisons of the newly developed model with its local counterpart. Our primary focus is given to the estimation of conversion times from healthy to toxic proteins. This is done based on the stability analysis of a simplified model, as well as on the fully coupled numerical implementation. Several clinically relevant patient proteopathies are highlighted. They include the primary tauopathy, as well as the secondary tauopathy where the sustained presence of toxic tau protein requires also to be accompanied by toxic amyloid-beta peptides. We demonstrate the dynamics of concentrations of toxic proteins under several clinically realistic scenarios. Finally, we carry out a detailed parametric study, providing further insight into the role of nonlinear effects controlled via the Holling type II functional response

Coupled Neural–Glial Dynamics and the Role of Astrocytes in Alzheimer’s Disease

Neurodegenerative diseases such as Alzheimer’s (AD) are associated with the propagation and aggregation of toxic proteins. In the case of AD, it was Alzheimer himself who showed the importance of both amyloid beta (Aβ) plaques and tau protein neurofibrillary tangles (NFTs) in what he called the “disease of forgetfulness”. The amyloid beta forms extracellular aggregates and plaques, whereas tau proteins are intracellular proteins that stabilize axons by cross-linking microtubules that can form largely messy tangles. On the other hand, astrocytes and microglial cells constantly clear these plaques and NFTs from the brain. Astrocytes transport nutrients from the blood to neurons. Activated astrocytes produce monocyte chemoattractant protein-1 (MCP-1), which attracts anti-inflammatory macrophages and clears Aβ. At the same time, the microglia cells are poorly phagocytic for Aβ compared to proinflammatory and anti-inflammatory macrophages. In addition to such distinctive neuropathological features of AD as amyloid beta and tau proteins, neuroinflammation has to be brought into the picture as well. Taking advantage of a coupled mathematical modelling framework, we formulate a network model, accounting for the coupling between neurons and astroglia and integrating all three main neuropathological features with the brain connectome data. We provide details on the coupled dynamics involving cytokines, astrocytes, and microglia. Further, we apply the tumour necrosis factor alpha (TNF-α) inhibitor and anti-Aβ drug and analyze their influence on the brain cells, suggesting conditions under which the drug can prevent cell damage. The important role of astrocytes and TNF-α inhibitors in AD pathophysiology is emphasized, along with potentially promising pathways for developing new AD therapies

Spatio-temporal Bazykin’s model with space-time nonlocality

International audienceThis work deals with a reaction-diffusion model for prey-predator interaction with Bazykin's reaction kinetics and a nonlocal interaction term in prey growth. The kernel of the integral characterizes nonlocal consumption of resources and depends on space and time. Linear stability analysis determines the conditions of the emergence of Turing patterns without and with nonlocal term, while weakly nonlinear analysis allows the derivation of amplitude equations. The bifurcation analysis and numerical simulation carried out in this work reveal the existence of stationary and dynamic patterns appearing due to the loss of stability of the coexistence homogeneous steady-state

Somatostatin receptor targeted liposomes with Diacerein inhibit IL-6 for breast cancer therapy

Selective targeting to the tumor niche remains a major challenge in successful cancer therapy. Somatostatin receptor 2 (SSTR2) is overexpressed in breast cancer cells thus making this receptor an attractive target for selective guidance of ligand-conjugated drug liposomes to the tumor site. In this study, a Synthetic Somatostatin analogue (SST) was used as SSTR2 targeting agent and Diacerein was employed as therapeutic molecule. Diacerein Loaded Liposomes (DNL) were prepared and they were further decorated with the Synthetic and Stable analogue of somatostatin (SST-DNL). Fabricated liposomes were nano-size in range and biocompatible. SST-DNL displayed significantly better anti-tumor efficacy as compared to free Diacerein (DN) and DNL in breast cancer models. Enhanced apoptosis in breast cancer cells was detected in SST-DNL treated groups as monitored by cell cycle analysis and changes in expression level of apoptotic/anti-apoptotic proteins Bcl-2, Bax, cleaved Caspase 3 and PARP. SST-DNL more effectively inhibited the oncogenic IL-6/IL-6R/STAT3/MAPK/Akt signalling pathways as compared to DN or DNL in cancer cells. In addition, SST-DNL effectively suppressed angiogenesis and cancer cell invasion. In vivo tumor growth in a MDA-MB-231 mouse xenograft model was significantly suppressed following SST-DNL treatment. In xenograft model, immunohistochemistry of Ki-67 and CD-31 indicated that SST-DNL improved the anti-proliferative and anti-angiogenic impacts of Diacerein. In vivo pharmacokinetic studies in rats showed enhanced circulation time in the DNL or SST-DNL treated groups as compared to free DN. Considering all of these findings, we conclude that SST-DNL provides a novel strategy with better efficacy for breast cancer therapy

Studies on Stibanate unresponsive isolates of Leishmania donovani

Visceral leishmaniasis, also known as kala-azar (KA) is generally caused by Leishmania donovani. Organic pentavalent antimonials (SbV) is the first line of treatment for KA. However, the number of KA patients unresponsive to treatment with Sb(V) is steadily increasing in India and elsewhere. The primary objective of this work is to determine the factor(s) associated with the rise of unresponsiveness. Analysis of the clonal population of parasites clearly indicated that wild type parasites isolated from KA patients who were clinically cured after treatment with Sb(V), were a mixture of resistant and sensitive cells. The resistant promastigotes were also resistant as amastigotes in vivo. It was further observed that Stibanate sensitive parasites can be made resistant to the drug by repeated passages in experimental animals followed by incomplete treatment with suboptimal doses of the drug. These results suggest that the steady rise in Sb(V) unresponsiveness of KA patients in India is due to infection with resistant parasites, generated as a result of irregular and often incomplete treatment of the patients

Sequential release of drugs from hollow manganese ferrite nanocarriers for breast cancer therapy

Single drug therapies for cancer are often suboptimal and may not provide long term clinical benefits. To overcome this obstacle for effective treatment the applications of two or more drugs are preferable. A limitation of multidrug use is the varying pharmacokinetics of different drugs. To overcome these impediments, we designed and synthesized multi-layered polyvinyl alcohol tethered hollow manganese ferrite nanocarriers capable of encapsulating two drugs with unique attributes of sensitivity towards tumor acidic milieu, mono-dispersive, compactness and high encapsulation efficiency. We encapsulated tamoxifen and diosgenin in the peripheral and subsequent inner layers of multilayered nanocarriers. In vitro and in vivo studies evaluated the nanocarrier uptake and retention ability of the tumor through magnetic saturation studies and elucidated the molecular mechanisms mediating drug(s)-induced apoptosis. The acidity of the tumor environment triggers extracellular dissociation of the peripheral coats resulting in release of tamoxifen blocking the estrogen receptor. The partially degraded nanocarriers localize intracellularly through endosomal escape and release diosgenin. Nanocarrier treatment reduced the cellular levels of Bcl2 and p53, while increasing the levels of Bim. This delivery system successfully embodies the sequential release of drugs and may provide a therapeutic strategy for sequentially affecting multiple targets in advanced cancers