Sepsis is the reflection of systemic immune response that manifests in the sequential inflammator... more Sepsis is the reflection of systemic immune response that manifests in the sequential inflammatory process in presence of infection with excessive production of inflammatory mediators and causes se...
Experiments were carried out to evaluate the toxicity of six botanicals viz. Custartd apple, Olea... more Experiments were carried out to evaluate the toxicity of six botanicals viz. Custartd apple, Oleander, Parashi, Neem, Ramtulsi and Marigold against epilachna beetle. The extracts from leaves and shoots were prepared by using methanol as a solvent. The results showed that extracts from all the six plants had direct toxic effect on epilachna beetle. LC50 values of all six plant extracts were compared from 24 to 120 hours after treatment (HAT). Their order was found with respect to decreasing toxicity in the following way: Parashi (1.29705) > Ramtulsi (1.31635) > Custard apple (1.34735) > Marigold (1.85334) > Neem (2.40967) > Oleander (2.54763) and Ramtulsi (0.33442) > Custard apple (0.36948) = Oleander (0.36948) > Parashi (0.41420) > Neem (0.47818) > Marigold (0.62597) at 24 and 120 hours after treatment respectively. Abbreviations: HAT: Hours after treatment, LC50: Lethal concentration
Understanding the wake characteristics between two in-line vehicles is essential for improving an... more Understanding the wake characteristics between two in-line vehicles is essential for improving and developing new strategies for reducing in-cabin air pollution. In this study, Ahmed bodies are used to investigate the effects of the rear slant angle of a leading vehicle on the mean flow and turbulent statistics between two vehicles. The experiments were conducted with a particle image velocimetry at a fixed Reynolds number, R e H = 1.7 × 10 4 , and inter-vehicle spacing distance of 0.75 L , where H and L are the height and length of the model. The rear slant angles investigated were a reference square back, high-drag angle ( α = 25 ° ) and low-drag angle ( α = 35 ° ). The mean velocities, Reynolds stresses, production of turbulent kinetic energy and instantaneous swirling strength are used to provide physical insight into the wake dynamics between the two bodies. The results indicate that the recirculation region behind the square back Ahmed body increases while those behind the sla...
BackgroundHematopoietic progenitor kinase 1 (HPK1, MAP4K1), is a negative regulator of T and B ce... more BackgroundHematopoietic progenitor kinase 1 (HPK1, MAP4K1), is a negative regulator of T and B cell receptor signaling.1 2 3 A strong anti-tumor immunogenic response and tumor rejection was observed in mice with HPK1 gene knocked out.3 Treatment of HPK1 kinase dead mice with immune check-point blockers (ICBs) demonstrated enhanced tumor growth inhibition.3 Hence, HPK1 is an attractive therapeutic strategy for immuno-oncology based treatment in cancers. In comparison to our previous HPK1 small molecule inhibitor, PCC,4 we present here a differentiated novel HPK1 inhibitor, PCC-1 with good anti-T cell kinases selectivity and stronger anti-tumor efficacy in CT26 tumor model. In addition, using the syngeneic model of MC38 expressing human PD-L1, we present for the first time, the combination efficacy of a HPK1 inhibitor with the clinical ICB, Atezolizumab.MethodsIntuitive medicinal chemistry complemented by structure-based drug design was used to identify & develop potent inhibitors of ...
The current therapy for cancer treatment, especially in leukemic survivor emphasis, needs to be e... more The current therapy for cancer treatment, especially in leukemic survivor emphasis, needs to be evolved more. In the current scenario, the microbial source of different origins, including live, attenuated, or genetically modified microbial species or cellular components in active or inactive form or cellular metabolites could be a very promising therapeutic intervention for leukemic therapy. Leishmania sp. is a protozoal parasite whose bioactive lipid (pLLD) has significant anti-inflammatory and anti-cancer properties. Acute myeloid leukemia shows the highest degrees of malignancies and lethality among the elderly and in children. In addition, the chances of secondary infection in AML are very high. Therefore, it was very interesting to find if pLLD could effectively inhibit proliferation of leukemic cells, including acute promyelocytic leukemia (HL-60), acute lymphoblastic leukemia (MOLT-4), acute myeloid leukemia (U937), and chronic myeloid leukemia (K562). Among the four cell lines, U937 showed most significant death in the presence of pLLD in respect to their morphological changes and DNA fragmentation. As apoptosis is a promising approach for cancer therapy, we also evaluated the effect of pLLD in U937 cells with annexin-PI staining and a cell cycle arrest assay using flow cytometry. In the process of programmed cell death, mitochondria play a major role; we also checked mitochondrial membrane potential and cellular reactive oxygen species of this AML cell line in the presence and absence of pLLD with JC-1 and DCFDA dye and found apoptosis was induced by pLLD in U937 cells in a time-dependent manner. pLLD also regulated the cell signals in U937 cells by altering ERK-JNK-p38 levels of the MAPK pathway and simultaneously maintained pro-/anti-apoptotic protein levels (Bax, Bad, Bcl2, t-Bid) assayed by western blot and flow cytometry analysis. Thus, taken together, it was found that pLLD could induce apoptosis in AML cells through regulating MAPK signaling.
Understanding of electron–phonon coupling (EPC) in two-dimensional (2D) materials manifesting as ... more Understanding of electron–phonon coupling (EPC) in two-dimensional (2D) materials manifesting as phonon renormalization is essential to their possible applications in nanoelectronics. Here we report in situ Raman measurements of electrochemically top-gated 2, 3 and 7 layered 2H-MoTe2 channel based field-effect transistors. While the E 2 g 1 and B2g phonon modes exhibit frequency softening and linewidth broadening with hole doping concentration (p) up to ∼2.3 × 1013/cm2, A1g shows relatively small frequency hardening and linewidth sharpening. The dependence of frequency renormalization of the E 2 g 1 mode on the number of layers in these 2D crystals confirms that hole doping occurs primarily in the top two layers, in agreement with recent predictions. We present first-principles density functional theory analysis of bilayer MoTe2 that qualitatively captures our observations, and explain that a relatively stronger coupling of holes with E 2 g 1 or B2g modes as compared with the A1g mo...
The resistivity of the semiconducting ultra-thin 1T′-MoTe2 shows a clear signature of temperature... more The resistivity of the semiconducting ultra-thin 1T′-MoTe2 shows a clear signature of temperature induced transition to Weyl semimetallic Td phase. Resistivity upturn at low temperature (∼20 K) confirms electron–electron interaction physics at the Weyl nodes.
Melanoma is one of the most aggressive forms of cancer, usually resistant to standard chemotherap... more Melanoma is one of the most aggressive forms of cancer, usually resistant to standard chemotherapeutics. Despite a huge number of clinical trials, any success to find a chemotherapeutic agent that can effectively destroy melanoma is yet to be achieved. Para-phenylenediamine (p-PD) in the hair dyes is reported to purely serve as an external dyeing agent. Very little is known about whether p-PD has any effect on the melanin producing cells. We have demonstrated p-PD mediated apoptotic death of both human and mouse melanoma cellsin vitro. Mouse melanoma tumour growth was also arrested by the apoptotic activity of intraperitoneal administration of p-PD with almost no side effects. This apoptosis is shown to occur primarily via loss of mitochondrial membrane potential (MMP), generation of reactive oxygen species (ROS), and caspase 8 activation. p-PD mediated apoptosis was also confirmed by the increase in sub-G0/G1 cell number. Thus, our experimental observation suggests that p-PD can be...
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, Jan 24, 2016
Cytotoxic effect of attenuated Leishmania on liver cancer cells by inducing ROS generation. Spect... more Cytotoxic effect of attenuated Leishmania on liver cancer cells by inducing ROS generation. Spectrophotometric study to analyze cell death and levels of different active caspases. Flow cytometric study was done to analyze apoptosis induction and ROS generation and levels of different protein. Western blot analysis was performed to study the levels of protein. Confocal microscopy was done to ascertain the expression of different apoptotic markers. We have now observed that attenuated Leishmania donovani UR6 also has potentiality towards growth inhibition of HepG2 cells and investigated the mechanism of action. The effect is associated with increased DNA fragmentation, rise in number of annexinV positive cells, and cell cycle arrest at G1 phase. The detection of unregulated levels of active PARP, cleaved caspases 3 and 9, cytosolic cytochrome C, Bax, and Bad, along with the observed downregulation of Bcl-2 and loss of mitochondrial membrane potential suggested the involvement of mitoc...
Promastigote form of Leishmania, an intracellular pathogen, delays phagosome maturation and resid... more Promastigote form of Leishmania, an intracellular pathogen, delays phagosome maturation and resides inside macrophages. But till date limited study has been done to manipulate the phagosomal machinery of macrophages to restrict Leishmania growth. Attenuated Leishmania strain exposed RAW 264.7 cells showed a respiratory burst and enhanced production of pro-inflammatory mediators. The augmentation of pro-inflammatory activity is mostly attributed to p38 MAPK and p44/42 MAPK. In our study, these activated macrophages are found to induce phagosome maturation when infected with pathogenic Leishmania donovani. Increased co-localization of carboxyfluorescein succinimidyl ester labeled pathogenic L. donovani with Lysosome was found. Moreover, increased co-localization was observed between pathogenic L. donovani and late phagosomal markers viz. Rab7, Lysosomal Associated Membrane Protein 1, Cathepsin D, Rab9, and V-ATPase which indicate phagosome maturation. It was also observed that inhibit...
Chronic exposure to arsenic over a period of time induces toxicity, primarily in liver but gradua... more Chronic exposure to arsenic over a period of time induces toxicity, primarily in liver but gradually in all systems of the body. Andrographolide (AG), a major diterpene lactone of Andrographis paniculata, shows a wide array of physiological functions including hepatoprotection. Therapeutic applications of AG are however seriously constrained because of its insolubility, poor bioavailability, and short plasma half-life. Nanoparticulation of AG is a possible solution to these problems. In the present study we investigated the effectiveness of polylactide co-glycolide (PLGA) nanocapsulated andrographolide (NA) against arsenic induced liver damage in mice. NA of average diameter 65.8 nm and encapsulation efficiency of 64% were prepared. Sodium arsenite at a dose of 40 mg/L supplied via drinking water in mice significantly raised the serum level of liver function markers such as AST, ALT, and ALP, and caused arsenic deposition in liver and ROS generation, though it did not show any lethality up to 30 days of exposure. However, even liver toxicity was not observed when mice were given AG and NA orally at doses up to 100 mg/kg bwt and 20 mg/kg bwt respectively on alternate days for one month. Treatment of non-toxic doses of AG or NA on alternate days along with arsenic significantly decreased the arsenic induced elevation of the serum level of ALT, AST and ALP, and arsenic deposition in liver. AG and NA increased the level of hepatic antioxidant enzymes such as superoxide dismutase (SOD), and catalase (CAT), and the level of reduced glutathione (GSH). Also, the ROS level was lowered in mice exposed to arsenic but treated with AG or NA. Protective efficiency of NA is about five times more than that of AG. Administration of NA to arsenic-treated mice caused signs of improvement in liver tissue architecture. In conclusion, the results of this study suggest that NA could be beneficial against arsenic-induced liver toxicity.
Sepsis is the reflection of systemic immune response that manifests in the sequential inflammator... more Sepsis is the reflection of systemic immune response that manifests in the sequential inflammatory process in presence of infection with excessive production of inflammatory mediators and causes se...
Experiments were carried out to evaluate the toxicity of six botanicals viz. Custartd apple, Olea... more Experiments were carried out to evaluate the toxicity of six botanicals viz. Custartd apple, Oleander, Parashi, Neem, Ramtulsi and Marigold against epilachna beetle. The extracts from leaves and shoots were prepared by using methanol as a solvent. The results showed that extracts from all the six plants had direct toxic effect on epilachna beetle. LC50 values of all six plant extracts were compared from 24 to 120 hours after treatment (HAT). Their order was found with respect to decreasing toxicity in the following way: Parashi (1.29705) > Ramtulsi (1.31635) > Custard apple (1.34735) > Marigold (1.85334) > Neem (2.40967) > Oleander (2.54763) and Ramtulsi (0.33442) > Custard apple (0.36948) = Oleander (0.36948) > Parashi (0.41420) > Neem (0.47818) > Marigold (0.62597) at 24 and 120 hours after treatment respectively. Abbreviations: HAT: Hours after treatment, LC50: Lethal concentration
Understanding the wake characteristics between two in-line vehicles is essential for improving an... more Understanding the wake characteristics between two in-line vehicles is essential for improving and developing new strategies for reducing in-cabin air pollution. In this study, Ahmed bodies are used to investigate the effects of the rear slant angle of a leading vehicle on the mean flow and turbulent statistics between two vehicles. The experiments were conducted with a particle image velocimetry at a fixed Reynolds number, R e H = 1.7 × 10 4 , and inter-vehicle spacing distance of 0.75 L , where H and L are the height and length of the model. The rear slant angles investigated were a reference square back, high-drag angle ( α = 25 ° ) and low-drag angle ( α = 35 ° ). The mean velocities, Reynolds stresses, production of turbulent kinetic energy and instantaneous swirling strength are used to provide physical insight into the wake dynamics between the two bodies. The results indicate that the recirculation region behind the square back Ahmed body increases while those behind the sla...
BackgroundHematopoietic progenitor kinase 1 (HPK1, MAP4K1), is a negative regulator of T and B ce... more BackgroundHematopoietic progenitor kinase 1 (HPK1, MAP4K1), is a negative regulator of T and B cell receptor signaling.1 2 3 A strong anti-tumor immunogenic response and tumor rejection was observed in mice with HPK1 gene knocked out.3 Treatment of HPK1 kinase dead mice with immune check-point blockers (ICBs) demonstrated enhanced tumor growth inhibition.3 Hence, HPK1 is an attractive therapeutic strategy for immuno-oncology based treatment in cancers. In comparison to our previous HPK1 small molecule inhibitor, PCC,4 we present here a differentiated novel HPK1 inhibitor, PCC-1 with good anti-T cell kinases selectivity and stronger anti-tumor efficacy in CT26 tumor model. In addition, using the syngeneic model of MC38 expressing human PD-L1, we present for the first time, the combination efficacy of a HPK1 inhibitor with the clinical ICB, Atezolizumab.MethodsIntuitive medicinal chemistry complemented by structure-based drug design was used to identify & develop potent inhibitors of ...
The current therapy for cancer treatment, especially in leukemic survivor emphasis, needs to be e... more The current therapy for cancer treatment, especially in leukemic survivor emphasis, needs to be evolved more. In the current scenario, the microbial source of different origins, including live, attenuated, or genetically modified microbial species or cellular components in active or inactive form or cellular metabolites could be a very promising therapeutic intervention for leukemic therapy. Leishmania sp. is a protozoal parasite whose bioactive lipid (pLLD) has significant anti-inflammatory and anti-cancer properties. Acute myeloid leukemia shows the highest degrees of malignancies and lethality among the elderly and in children. In addition, the chances of secondary infection in AML are very high. Therefore, it was very interesting to find if pLLD could effectively inhibit proliferation of leukemic cells, including acute promyelocytic leukemia (HL-60), acute lymphoblastic leukemia (MOLT-4), acute myeloid leukemia (U937), and chronic myeloid leukemia (K562). Among the four cell lines, U937 showed most significant death in the presence of pLLD in respect to their morphological changes and DNA fragmentation. As apoptosis is a promising approach for cancer therapy, we also evaluated the effect of pLLD in U937 cells with annexin-PI staining and a cell cycle arrest assay using flow cytometry. In the process of programmed cell death, mitochondria play a major role; we also checked mitochondrial membrane potential and cellular reactive oxygen species of this AML cell line in the presence and absence of pLLD with JC-1 and DCFDA dye and found apoptosis was induced by pLLD in U937 cells in a time-dependent manner. pLLD also regulated the cell signals in U937 cells by altering ERK-JNK-p38 levels of the MAPK pathway and simultaneously maintained pro-/anti-apoptotic protein levels (Bax, Bad, Bcl2, t-Bid) assayed by western blot and flow cytometry analysis. Thus, taken together, it was found that pLLD could induce apoptosis in AML cells through regulating MAPK signaling.
Understanding of electron–phonon coupling (EPC) in two-dimensional (2D) materials manifesting as ... more Understanding of electron–phonon coupling (EPC) in two-dimensional (2D) materials manifesting as phonon renormalization is essential to their possible applications in nanoelectronics. Here we report in situ Raman measurements of electrochemically top-gated 2, 3 and 7 layered 2H-MoTe2 channel based field-effect transistors. While the E 2 g 1 and B2g phonon modes exhibit frequency softening and linewidth broadening with hole doping concentration (p) up to ∼2.3 × 1013/cm2, A1g shows relatively small frequency hardening and linewidth sharpening. The dependence of frequency renormalization of the E 2 g 1 mode on the number of layers in these 2D crystals confirms that hole doping occurs primarily in the top two layers, in agreement with recent predictions. We present first-principles density functional theory analysis of bilayer MoTe2 that qualitatively captures our observations, and explain that a relatively stronger coupling of holes with E 2 g 1 or B2g modes as compared with the A1g mo...
The resistivity of the semiconducting ultra-thin 1T′-MoTe2 shows a clear signature of temperature... more The resistivity of the semiconducting ultra-thin 1T′-MoTe2 shows a clear signature of temperature induced transition to Weyl semimetallic Td phase. Resistivity upturn at low temperature (∼20 K) confirms electron–electron interaction physics at the Weyl nodes.
Melanoma is one of the most aggressive forms of cancer, usually resistant to standard chemotherap... more Melanoma is one of the most aggressive forms of cancer, usually resistant to standard chemotherapeutics. Despite a huge number of clinical trials, any success to find a chemotherapeutic agent that can effectively destroy melanoma is yet to be achieved. Para-phenylenediamine (p-PD) in the hair dyes is reported to purely serve as an external dyeing agent. Very little is known about whether p-PD has any effect on the melanin producing cells. We have demonstrated p-PD mediated apoptotic death of both human and mouse melanoma cellsin vitro. Mouse melanoma tumour growth was also arrested by the apoptotic activity of intraperitoneal administration of p-PD with almost no side effects. This apoptosis is shown to occur primarily via loss of mitochondrial membrane potential (MMP), generation of reactive oxygen species (ROS), and caspase 8 activation. p-PD mediated apoptosis was also confirmed by the increase in sub-G0/G1 cell number. Thus, our experimental observation suggests that p-PD can be...
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, Jan 24, 2016
Cytotoxic effect of attenuated Leishmania on liver cancer cells by inducing ROS generation. Spect... more Cytotoxic effect of attenuated Leishmania on liver cancer cells by inducing ROS generation. Spectrophotometric study to analyze cell death and levels of different active caspases. Flow cytometric study was done to analyze apoptosis induction and ROS generation and levels of different protein. Western blot analysis was performed to study the levels of protein. Confocal microscopy was done to ascertain the expression of different apoptotic markers. We have now observed that attenuated Leishmania donovani UR6 also has potentiality towards growth inhibition of HepG2 cells and investigated the mechanism of action. The effect is associated with increased DNA fragmentation, rise in number of annexinV positive cells, and cell cycle arrest at G1 phase. The detection of unregulated levels of active PARP, cleaved caspases 3 and 9, cytosolic cytochrome C, Bax, and Bad, along with the observed downregulation of Bcl-2 and loss of mitochondrial membrane potential suggested the involvement of mitoc...
Promastigote form of Leishmania, an intracellular pathogen, delays phagosome maturation and resid... more Promastigote form of Leishmania, an intracellular pathogen, delays phagosome maturation and resides inside macrophages. But till date limited study has been done to manipulate the phagosomal machinery of macrophages to restrict Leishmania growth. Attenuated Leishmania strain exposed RAW 264.7 cells showed a respiratory burst and enhanced production of pro-inflammatory mediators. The augmentation of pro-inflammatory activity is mostly attributed to p38 MAPK and p44/42 MAPK. In our study, these activated macrophages are found to induce phagosome maturation when infected with pathogenic Leishmania donovani. Increased co-localization of carboxyfluorescein succinimidyl ester labeled pathogenic L. donovani with Lysosome was found. Moreover, increased co-localization was observed between pathogenic L. donovani and late phagosomal markers viz. Rab7, Lysosomal Associated Membrane Protein 1, Cathepsin D, Rab9, and V-ATPase which indicate phagosome maturation. It was also observed that inhibit...
Chronic exposure to arsenic over a period of time induces toxicity, primarily in liver but gradua... more Chronic exposure to arsenic over a period of time induces toxicity, primarily in liver but gradually in all systems of the body. Andrographolide (AG), a major diterpene lactone of Andrographis paniculata, shows a wide array of physiological functions including hepatoprotection. Therapeutic applications of AG are however seriously constrained because of its insolubility, poor bioavailability, and short plasma half-life. Nanoparticulation of AG is a possible solution to these problems. In the present study we investigated the effectiveness of polylactide co-glycolide (PLGA) nanocapsulated andrographolide (NA) against arsenic induced liver damage in mice. NA of average diameter 65.8 nm and encapsulation efficiency of 64% were prepared. Sodium arsenite at a dose of 40 mg/L supplied via drinking water in mice significantly raised the serum level of liver function markers such as AST, ALT, and ALP, and caused arsenic deposition in liver and ROS generation, though it did not show any lethality up to 30 days of exposure. However, even liver toxicity was not observed when mice were given AG and NA orally at doses up to 100 mg/kg bwt and 20 mg/kg bwt respectively on alternate days for one month. Treatment of non-toxic doses of AG or NA on alternate days along with arsenic significantly decreased the arsenic induced elevation of the serum level of ALT, AST and ALP, and arsenic deposition in liver. AG and NA increased the level of hepatic antioxidant enzymes such as superoxide dismutase (SOD), and catalase (CAT), and the level of reduced glutathione (GSH). Also, the ROS level was lowered in mice exposed to arsenic but treated with AG or NA. Protective efficiency of NA is about five times more than that of AG. Administration of NA to arsenic-treated mice caused signs of improvement in liver tissue architecture. In conclusion, the results of this study suggest that NA could be beneficial against arsenic-induced liver toxicity.
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