Anti-tumor effect of fruit rind of Myristica malabarica in an Ehrlich ascites carcinoma model

Background: Among the various modalities of anti-cancer treatment, cancer chemotherapy plays a very vital role. The alarming side effects being its main drawback leads to relentless research for newer agents. A new natural agent with promising anti-cancer properties from in-vitro studies leads to this study. Here we have evaluated the anti-tumor activity of a crude extract of fruit rind of Myristica malabarica in an Ehrlich ascites carcinoma model in mice.Methods: A murine model of cancer was established with i.p. inoculation of Ehrlich Ascites carcinoma (EAC) cells; animals were divided into five groups (including normal control) to observe the inhibitory effect of a crude extract of the fruit rind of Myristica malabarica/rampatri (0-100mg/kg b.w. i.p.) as compared with methotrexate (0.4mg/kg bw., i.p.). Blood and ascitic fluid were collected on the 10th day for analysis.Results: In the EAC model, there was an increase in tumor volume, tumor weight, and tumor packed cell volume, which was decreased by rampatri (50 and 100mg/kg bw) along with an increase in the mean survival time (MST). Rampatri caused minimal alterations in hematological parameters, renal functions remained unchanged but an increase in hepatic SGOT was demonstrated.Conclusions: The crude extract of rampatri (containing Malabaricones) exhibited significant anti-tumor activity with minimal effect on hematological and renal functions

Effectiveness of malabaricone-A in P-glycoprotein over-expressing cancer cell lines

Background: A major impediment in treatment for cancers is resistance to chemotherapy and is primarily attributed to over-expression of efflux pumps. This study aimed to establish the cytotoxicity of malabaricone-A (MAL-A) in P-glycoprotein/multidrug resistance (P-gp/MDR) over-expressing hematopoietic cancer cell lines.Methods: Leukemia and multiple myeloma cell lines were indirectly evaluated for their P-gp/MDR status by examining Calcein-AM fluorescence and cell viability was assessed by the MTS-PMS assay.Results: The fluorescence of calcein was significantly decreased in three cell lines LP-1, RPMI-8226 and CEM-ADR 5000 and reversal with verapamil endorsed their P-gp/MDR activity. The mean IC50 of MAL-A in these MDR+ cell lines (5.40±1.41 to 12.33±0.78 µg/ml) was comparable with the MDR- leukemic (9.72±1.08 to 19.26±0.75 µg/ml) and multiple myeloma cell lines (9.65±0.39 to 18.05±0.17 μg/ml).Conclusions: Irrespective of their P-gp activity, the cytotoxicity of MAL-A was comparable, making it worthy of future pharmacological consideration in multidrug resistance

Malabaricone-A Induces A Redox Imbalance That Mediates Apoptosis in U937 Cell Line

BACKGROUND: The 'two-faced' character of reactive oxygen species (ROS) plays an important role in cancer biology by acting both as secondary messengers in intracellular signaling cascades and sustaining the oncogenic phenotype of cancer cells, while on the other hand, it triggers an oxidative assault that causes a redox imbalance translating into an apoptotic cell death. PRINCIPAL FINDINGS: Using a tetrazolium [{3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl}-2H-tetrazolium] based cell viability assay, we evaluated the cytotoxicity of a plant derived diarylnonanoid, malabaricone-A on leukemic cell lines U937 and MOLT-3. This cytotoxicity hinged on its ability to cause a redox imbalance via its ability to increase ROS, measured by flow cytometry using 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate and by decreasing glutathione peroxidase activity. This redox imbalance mediated apoptosis was evident by an increase in cytosolic [Ca(2+)], externalization of phosphatidyl serine as also depolarization of the mitochondrial membrane potential as measured by flow cytometry. There was concomitant peroxidation of cardiolipin, release of free cytochrome c to cytosol along with activation of caspases 9, 8 and 3. This led to cleavage of the DNA repair enzyme, poly (ADP-ribose) polymerase that caused DNA damage as proved by labeling with 4',6-diamidino-2-phenylindole (DAPI); furthermore, terminal deoxy ribonucleotide transferase catalysed incorporation of deoxy uridine triphosphate confirmed DNA nicking and was accompanied by arrest of cell cycle progression. CONCLUSIONS: Taken together, compounds like MAL-A having pro-oxidant activity mediate their cytotoxicity in leukemic cells via induction of oxidative stress triggering a caspase dependent apoptosis

Berberine Chloride Mediates Its Anti-Leishmanial Activity via Differential Regulation of the Mitogen Activated Protein Kinase Pathway in Macrophages

BACKGROUND: A complex interplay between Leishmania and macrophages influences parasite survival and necessitates disruption of signaling molecules, eventually resulting in impairment of macrophage function. In this study, we demonstrate the immunomodulatory activity of Berberine chloride in Leishmania infected macrophages. PRINCIPAL FINDINGS: The IC(50) of Berberine chloride, a quaternary isoquinoline alkaloid was tested in an amastigote macrophage model and its safety index measured by a cell viability assay. It eliminated intracellular amastigotes, the IC(50) being 2.8 fold lower than its IC(50) in promastigotes (7.10 µM vs. 2.54 µM) and showed a safety index >16. Levels of intracellular and extracellular nitric oxide (NO) as measured by flow cytometry and Griess assay respectively showed that Berberine chloride in Leishmania infected macrophages increased production of NO. Measurement of the mRNA expression of iNOS, IL-12 and IL-10 by RT-PCR along with levels of IL-12p40 and IL-10 by ELISA showed that in infected macrophages, Berberine chloride enhanced expression of iNOS and IL-12p40, concomitant with a downregulation of IL-10. The phosphorylation status of extracellular signal related kinase (ERK1/2) and p38 mitogen activated protein kinase (p38 MAPK) was studied by western blotting. In infected macrophages, Berberine chloride caused a time dependent activation of p38 MAPK along with deactivation of ERK1/2; addition of a p38 MAPK inhibitor SB203580 inhibited the increased generation of NO and IL-12p40 by Berberine chloride as also prevented its decrease of IL-10. CONCLUSIONS: Berberine chloride modulated macrophage effector responses via the mitogen activated protein kinase (MAPK) pathway, highlighting the importance of MAPKs as an antiparasite target

A generalization of Gerzon’s bound on spherical s-distance sets

Using the method of linearly independent polynomials, we derive an upper bound for the cardinality of a spherical s-distance set F where the sum of distinct inner products of any two elements from F is zero. Our result generalizes the well-known Gerzon’s bound for the cardinality of an equiangular spherical set to a significantly broader class of spherical s-distance sets. © 2022, Akadémiai Kiadó, Budapest, Hungary

Effect of an axial hole on natural convection heat transfer from a cylindrical pin fin attached to a horizontal plate

Heat transfer under laminar natural convection from a hollow cylindrical fin mounted on a horizontal base plate has been numerically studied. The flow outside the fin is much stronger than that inside the hole and as a consequence the rate of heat transfer from a hollow fin is primarily due to the contribution by the outer surface of the fin. Fortunately, the rate of heat transfer is not negatively affected by the presence of the hole at the fin centre. On the contrary, when the Grashof number is higher or the hole diameter is bigger, the inside surface contributes marginally to the heat transfer. A hollow fin saves material and weighs less compared to a solid fin. So, this feature may be exploited

Generation of redox imbalance mediates the cytotoxic effectof Malabaricone-A in a multidrug resistant cell line

Multidrug resistance (MDR) refers to cross-resistance to a range of structurally and functionally unrelated compounds, and is accompanied by an elevated expression of ATP driven cell-membrane transporters. The cytotoxicity of Malabaricone-A (MAL-A), a diarylnonanoid derived from Myristica malabarica was demonstrated in leukemic cell lines, but its effectiveness in drug-resistant cancer cell lines has not been evaluated. Accordingly, this study tested its cytotoxic potential in a T-lymphoblastic leukemic cell line, CCRF CEM and its MDR counterpart, CEM/ADR5000. The effectiveness of MAL-A was 1.8 fold higher in CEM/ADR5000 than CCRF CEM cell line, the IC50 being value 5.40 ± 1.41 vs. 9.72 ± 1.08 µg/ml, respectively, suggesting that MAL-A demonstrated ‘collateral sensitivity’. This cytotoxicity of MAL-A was attributed to an enhanced generation of oxidative stress, as the IC50 value increased following the addition of an anti-oxidant, N-acetyl cysteine (NAC). Furthermore, MAL-A depleted glutathione and inhibited glutathione peroxidase activity, which too contributed towards generation of a redox imbalance. This culminated in an apoptosis mediated cell death as evident by mitochondrial membrane depolarization, enhanced caspase-3 activity, increased externalization of phosphatidylserine and an increase in the sub G0/G1 population. Collectively, compounds with pro-oxidant activity have promising therapeutic potential in drug resistant phenotypes, worthy of future pharmacological consideration

Recent advances in alginate based gastroretentive technologies for drug delivery applications

The efficacy of orally delivered medicines can be maximized through enhancing the gastric residence period and modifying the drug release pattern according to therapeutic need. Several technologies were investigated through recent years for increasing gastric retention of medicines. Biopolymers are one of the widely studied materials for increasing the retention of drug delivery systems in the stomach region. The biodegradability, biocompatibility and non-toxic behavior in combination with the easy fabrication technologies has made biopolymers an interesting option to pharmaceutical scientists for developing gastroretentive drug delivery systems (GRDDS). Several gastroretentive approaches are reported to be efficacious to localize the drug delivery system in the gastric region. Alginates are commonly employed polysaccharide for developing various GRDDS including low density systems, mucoadhesive systems, swellable systems, hydrogel forming systems, in situ gelling systems, raft forming systems, magnetic systems. The abundant availability from marine and bacterial sources in combination with its attractive physicochemical nature has encouraged pharmaceutical researchers to investigate its suitability in developing various drug delivery system. The mucoadhesive, hydrogel forming and raft forming behavior of alginates makes alginate suitable for GRDDS. The attractive properties of alginate makes it a useful biopolymer in the biomedical field. This review focuses on the source and chemistry of alginates and describes the applications of alginates in developing novel gastroretentive drug delivery systems

Mega-Hertz repetition rate broadband nano-second pulses from an actively mode-locked Yb-fiber laser

This work demonstrates an actively mode-locked all-normal dispersion Yb-fiber ring laser, delivering pulses of few nano-seconds (ns) to sub-ns duration at a 4 MHz repetition rate. Employing a filterless cavity architecture and different, long-length intra-cavity nonlinear fibers; a broadband output spectrum in the 1060-1140 nm wavelength region was obtained. With an increasing pump power, the pulse width reduced along with the appearence of new pulses, resulting into a muti-pulsing output. For a fixed pump power, the number of pulses and the amount of spectral broadening varied for different non-linear fibers. In the multi-pulsing state, the pulses were found to be located seperately in both time and wavelength, where Raman stokes corresponding to individual pulses could also be observed. The maximum output pulse energy achieved in a single pulse state was around 8.7 nJ, which increased to 14.5 nJ in a multi-pulse state. To the best of the authors' knowledge, this is the first demonstration of a filterless active mode-locked fiber ring laser producing high-repetition rate broadband nano-second pulses in single and multi-pulse states at 1 mu m