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Biomedical subjects

B B Aggarwal

Publications and source records attributed to B B Aggarwal.

At least 37 records · Page 2Linked to original sources
PubMed2000

Leflunomide suppresses TNF-induced cellular responses: effects on NF-kappa B, activator protein-1, c-Jun N-terminal protein kinase, and apoptosis.

Leflunomide is a pyrimidine biosynthesis inhibitor that has recently been approved for treatment of rheumatoid arthritis. However, the mechanism of leflunomide's antiarthritis activity and is not fully understood. The critical role that TNF plays in rheumatoid arthritis led us to postulate that leflunomide blocks TNF signaling. Previously, we have demonstrated that leflunomide inhibits TNF-induced NF-kappaB activation by suppressing I-kappaBalpha (inhibitory subunit of NF-kappaB) degradation. We in this study show that leflunomide also blocks NF-kappaB reporter gene expression induced by TNFR1, TNFR-associated factor 2, and NF-kappaB-inducing kinase (NIK), but not that activated by the p65 subunit of NF-kappaB, suggesting that leflunomide acts downstream of NIK. Leflunomide suppressed TNF-induced phosphorylation of I-kappaBalpha, as well as activation of I-kappaBalpha kinase-beta located downstream to NIK. Leflunomide also inhibited TNF-induced activation of AP-1 and the c-Jun N-terminal protein kinase activation. TNF-mediated cytotoxicity and caspase-induced poly(ADP-ribose) polymerase cleavage were also completely abrogated by treatment of Jurkat T cells with leflunomide. Leflunomide suppressed TNF-induced reactive oxygen intermediate generation and lipid peroxidation, which may explain most of its effects on TNF signaling. The suppressive effects of leflunomide on TNF signaling were completely reversible by uridine, indicating a critical role for pyrimidine biosynthesis in TNF-mediated cellular responses. Overall, our results suggest that suppression of TNF signaling is one of the possible mechanisms for inhibitory activity of leflunomide against rheumatoid arthritis.

Apoptosis↗
PubMed2000

IFN-alpha suppresses activation of nuclear transcription factors NF-kappa B and activator protein 1 and potentiates TNF-induced apoptosis.

We and others have reported that IFN-alpha potentiates the apoptotic effects of TNF through a mechanism that is not understood. Because the nuclear transcription factors NF-kappaB and AP-1 have recently been reported to mediate anti-apoptosis and cell survival, we hypothesized that IFN-alpha potentiates the cytotoxic effects of TNF by suppressing TNF-induced activation of NF-kappaB and AP-1. We tested this hypothesis by pretreating human Jurkat T cells with IFN-alpha, which blocked TNF-induced activation of NF-kappaB and AP-1 in a time- and dose-dependent manner as determined by EMSA. IFN-alpha blocked TNF-induced phosphorylation and degradation of the inhibitor subunit of NF-kappaB, and suppressed NF-kappaB and AP-1 activation induced by various other inflammatory stimuli. NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TNF receptor-associated factor 2, and NF-kappaB-inducing kinase was also abrogated by IFN-alpha pretreatment. The suppression of NF-kappaB and AP-1 correlated with the potentiation of TNF-induced cytotoxicity and caspase activation. Overall our results suggest that IFN-alpha potentiates the apoptotic effects of TNF possibly by suppressing NF-kappaB and AP-1 activation.

Apoptosis↗
PubMed2000

Apoptosis and nuclear factor-kappa B: a tale of association and dissociation.

It is not clear why on treatment with certain killer cytokines or chemotherapeutic agents, some cells undergo apoptosis while others do not. The delineation of sensitivity/resistance pathways should provide a more specific therapy for cancer and other hyperproliferative diseases. Most cells die either by apoptosis or by necrosis. The biochemical pathway that mediates these two modes of cell death has recently been described. The nuclear factor (NF)-kappa B and the genes regulated by this transcription factor have been shown to play a critical role in induction of resistance to killer agents. Thus, inhibitors of NF-kappa B activation have a potential in overcoming resistance to apoptosis induced by various agents. The evidence for and against such a notion is discussed.

Animals↗
PubMed2000

Oleandrin suppresses activation of nuclear transcription factor-kappaB, activator protein-1, and c-Jun NH2-terminal kinase.

Agents that can suppress the activation of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) may be able to block tumorigenesis and inflammation. Oleandrin, a polyphenolic cardiac glycoside derived from the leaves of Nerium oleander, is a candidate NF-kappaB and AP-1 modulator. We investigated the effect of oleandrin on NF-kappaB activation induced by inflammatory agents. Oleandrin blocked tumor necrosis factor (TNF)-induced activation of NF-kappaB in a concentration- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of IkappaBalpha, an inhibitor of NF-kappaB. A proprietary hot water extract of oleander (Anvirzel) also blocked TNF-induced NF-kappaB activation; subsequent fractionation of the extract revealed that this activity was attributable to oleandrin. The effects of oleandrin were not cell type specific, because it blocked TNF-induced NF-kappaB activation in a variety of cells. NF-kappaB-dependent reporter gene transcription activated by TNF was also suppressed by oleandrin. The TNF-induced NF-kappaB activation cascade involving TNF receptor 1/TNF receptor-associated death domain/TNF receptor-associated factor 2/NF-kappaB-inducing kinase/IkappaBalpha kinase was interrupted at the TNF receptor-associated factor 2 and NF-kappaB-inducing kinase sites by oleandrin, thus suppressing NF-kappaB reporter gene expression. Oleandrin blocked NF-kappaB activation induced by phorbol ester and lipopolysaccharide. Oleandrin also blocked AP-1 activation induced by TNF and other agents and inhibited the TNF-induced activation of c-Jun NH2-terminal kinase. Overall, our results indicate that oleandrin inhibits activation of NF-kappaB and AP-1 and their associated kinases. This may provide a molecular basis for the ability of oleandrin to suppress inflammation and perhaps tumorigenesis.

Animals↗
PubMed2000

Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation.

Resveratrol (trans-3,4',5-trihydroxystilbene), a polyphenolic phytoalexin found in grapes, fruits, and root extracts of the weed Polygonum cuspidatum, exhibits anti-inflammatory, cell growth-modulatory, and anticarcinogenic effects. How this chemical produces these effects is not known, but it may work by suppressing NF-kappaB, a nuclear transcription factor that regulates the expression of various genes involved in inflammation, cytoprotection, and carcinogenesis. In this study, we investigated the effect of resveratrol on NF-kappaB activation induced by various inflammatory agents. Resveratrol blocked TNF-induced activation of NF-kappaB in a dose- and time-dependent manner. Resveratrol also suppressed TNF-induced phosphorylation and nuclear translocation of the p65 subunit of NF-kappaB, and NF-kappaB-dependent reporter gene transcription. Suppression of TNF-induced NF-kappaB activation by resveratrol was not restricted to myeloid cells (U-937); it was also observed in lymphoid (Jurkat) and epithelial (HeLa and H4) cells. Resveratrol also blocked NF-kappaB activation induced by PMA, LPS, H2O2, okadaic acid, and ceramide. The suppression of NF-kappaB coincided with suppression of AP-1. Resveratrol also inhibited the TNF-induced activation of mitogen-activated protein kinase kinase and c-Jun N-terminal kinase and abrogated TNF-induced cytotoxicity and caspase activation. Both reactive oxygen intermediate generation and lipid peroxidation induced by TNF were suppressed by resveratrol. Resveratrol's anticarcinogenic, anti-inflammatory, and growth-modulatory effects may thus be partially ascribed to the inhibition of activation of NF-kappaB and AP-1 and the associated kinases.

Apoptosis↗
PubMed2000

Anethole blocks both early and late cellular responses transduced by tumor necrosis factor: effect on NF-kappaB, AP-1, JNK, MAPKK and apoptosis.

Anethole, a chief constituent of anise, camphor, and fennel, has been shown to block both inflammation and carcinogenesis, but just how these effects are mediated is not known. One possibility is TNF-mediated signaling, which has also been associated with both inflammation and carcinogenesis. In the present report we show that anethole is a potent inhibitor of TNF-induced NF-kappaB activation (an early response) as monitored by electrophoretic mobility shift assay, IkappaBalpha phosphorylation and degradation, and NF-kappaB reporter gene expression. Suppression of IkappaBalpha phosphorylation and NF-kappaB reporter gene expression induced by TRAF2 and NIK, suggests that anethole acts on IkappaBalpha kinase. Anethole also blocked the NF-kappaB activation induced by a variety of other inflammatory agents. Besides NF-kappaB, anethole also suppressed TNF-induced activation of the transcription factor AP-1, c-jun N-terminal kinase and MAPK-kinase. In addition, anethole abrogated TNF-induced apoptosis as measured by both caspase activation and cell viability. The anethole analogues eugenol and isoeugenol also blocked TNF signaling. Anethole suppressed TNF-induced both lipid peroxidation and ROI generation. Overall, our results demonstrate that anethole inhibits TNF-induced cellular responses, which may explain its role in suppression of inflammation and carcinogenesis. Oncogene (2000).

Allylbenzene Derivatives↗
PubMed2000

Vesnarinone suppresses TNF-induced activation of NF-kappa B, c-Jun kinase, and apoptosis.

Vesnarinone, a synthetic quinolinone derivative used in the treatment of cardiac failure, exhibits immunomodulatory, anti-inflammatory, and cell growth regulatory properties. The mechanisms underlying these properties are not understood, but due to the critical role of nuclear transcription factor NF-kappa B in these responses, we hypothesized that vesnarinone must modulate NF-kappa B activation. We investigated the effect of vesnarinone on NF-kappa B activation induced by inflammatory agents. Vesnarinone blocked TNF-induced activation of NF-kappa B in a concentration- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of I kappa B alpha, an inhibitor of NF-kappa B. The effects of vesnarinone were not cell type specific, as it blocked TNF-induced NF-kappa B activation in a variety of cells. NF-kappa B-dependent reporter gene transcription activated by TNF was also suppressed by vesnarinone. The TNF-induced NF-kappa B activation cascade involving TNF receptor 1-TNF receptor associated death domain-TNF receptor associated factor 2 NF-kappa B-inducing kinase-IKK was interrupted at the TNF receptor associated factor 2 and NF-kappa B-inducing kinase sites by vesnarinone, thus suppressing NF-kappa B reporter gene expression. Vesnarinone also blocked NF-kappa B activation induced by several other inflammatory agents, inhibited the TNF-induced activation of transcription factor AP-1, and suppressed the TNF-induced activation of c-Jun N-terminal kinase and mitogen-activated protein kinase kinase. TNF-induced cytotoxicity, caspase activation, and lipid peroxidation were also abolished by vesnarinone. Overall, our results indicate that vesnarinone inhibits activation of NF-kappa B and AP-1 and their associated kinases. This may provide a molecular basis for vesnarinone's ability to suppress inflammation, immunomodulation, and growth regulation.

Apoptosis↗
PubMed2000

Differential requirement for p56lck in HIV-tat versus TNF-induced cellular responses: effects on NF-kappa B, activator protein-1, c-Jun N-terminal kinase, and apoptosis.

HIV-tat protein, like TNF, activates a wide variety of cellular responses, including NF-kappa B, AP-1, c-Jun N-terminal kinase (JNK), and apoptosis. Whether HIV-tat transduces these signals through the same mechanism as TNF is not known. In the present study we investigated the role of the T cell-specific tyrosine kinase p56lck in HIV-tat and TNF-mediated cellular responses by comparing the responses of Jurkat T cells with JCaM1 cells, an isogeneic lck-deficient T cell line. Treatment with HIV-tat protein activated NF-kappa B, degraded I kappa B alpha, and induced NF-kappa B-dependent reporter gene expression in a time-dependent manner in Jurkat cells but not in JCaM1 cells, suggesting the critical role of p56lck kinase. These effects were specific to HIV-tat, as activation of NF-kappa B by PMA, LPS, H2O2, and TNF was minimally affected. p56lck was also found to be required for HIV-tat-induced but not TNF-induced AP-1 activation. Similarly, HIV-tat activated the protein kinases JNK and mitogen-activated protein kinase kinase in Jurkat cells but not in JCaM1 cells. HIV-tat also induced cytotoxicity, activated caspases, and reactive oxygen intermediates in Jurkat cells, but not in JCaM1 cells. HIV-tat activated p56lck activity in Jurkat cells. Moreover, the reconstitution of JCaM1 cells with p56lck tyrosine kinase reversed the HIV-tat-induced NF-kappa B activation and cytotoxicity. Overall, our results demonstrate that p56lck plays a critical role in the activation of NF-kappa B, AP-1, JNK, and apoptosis by HIV-tat protein but has minimal or no role in activation of these responses by TNF.

Apoptosis↗
PubMed2000

Protein tyrosine kinase p56lck is required for ceramide-induced but not tumor necrosis factor-induced activation of NF-kappa B, AP-1, JNK, and apoptosis.

Ceramide has been implicated as an intermediate in the signal transduction of several cytokines including tumor necrosis factor (TNF). Both ceramide and TNF activate a wide variety of cellular responses, including NF-kappaB, AP-1, JNK, and apoptosis. Whether ceramide transduces these signals through the same mechanism as TNF is not known. In the present study we investigated the role of the T cell-specific tyrosine kinase p56(lck) in ceramide- and TNF-mediated cellular responses by comparing the responses of Jurkat T cells with JCaM1 cells, isogeneic Lck-deficient T cells. Treatment with ceramide activated NF-kappaB, degraded IkappaBalpha, and induced NF-kappaB-dependent reporter gene expression in a time-dependent manner in Jurkat cells but not in JCaM1 cells, suggesting the critical role of p56(lck) kinase. These effects were specific to ceramide, as activation of NF-kappaB by phorbol 12-myristate 13-acetate, lipopolysaccharide, H(2)O(2), and TNF was minimally affected. p56(lck) was also found to be required for ceramide-induced but not TNF-induced AP-1 activation. Similarly, ceramide activated the protein kinases JNK and mitogen-activated protein kinase kinase in Jurkat cells but not in JCaM1 cells. Ceramide also induced cytotoxicity and activated caspases and reactive oxygen intermediates in Jurkat cells but not in JCaM1 cells. Ceramide activated p56(lck) activity in Jurkat cells. Moreover, the reconstitution of JCaM1 cells with p56(lck) tyrosine kinase reversed the ceramide-induced NF-kappaB activation and cytotoxicity. Overall our results demonstrate that p56(lck) plays a critical role in the activation of NF-kappaB, AP-1, JNK, and apoptosis by ceramide but has minimal or no role in activation of these responses by TNF.

Apoptosis↗
PubMed2000

Human chorionic gonadotropin suppresses activation of nuclear transcription factor-kappa B and activator protein-1 induced by tumor necrosis factor.

Human chorionic gonadotropin (hCG) suppresses cell-mediated allogeneic reactions, viral replication, tumorigenesis, and metastasis, most of which require activation of nuclear transcription factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). In the present report, we investigated the effect of hCG on NF-kappaB and AP-1 activated by tumor necrosis factor (TNF). Treatment of the CaCOV3 human ovarian cell line with hCG blocked TNF-induced activation of NF-kappaB, IkappaBalpha degradation, and NF-kappaB-dependent reporter gene transcription. hCG also blocked NF-kappaB activation induced by ceramide. The effect of hCG on NF-kappaB was mediated through inhibition of phosphorylation of IkappaBalpha. Because hCG also blocked TNF receptor-associated factor-2 and NF-kappaB-inducing kinase reporter gene expression, hCG must act at a step that causes phosphorylation of IkappaBalpha. AP-1 activation induced by TNF and ceramide was also suppressed by hCG. hCG abrogated the TNF-induced activation of mitogen-activated protein kinase kinase and c-Jun N-terminal kinase required for NF-kappaB and AP-1, respectively. Dideoxyadenosine and H-8 reversed the effect, and dibutyryl cAMP mimicked the effect, suggesting that hCG suppresses the transcription factors through cAMP-induced protein kinase A pathway. Overall, our results indicate that hCG inhibits the activation of NF-kappaB and AP-1, which may be the molecular basis by which hCG suppresses viral replication, cell proliferation, tumorigenesis, and metastasis.

Cell Line↗
PubMed2000

Wortmannin inhibits activation of nuclear transcription factors NF-kappaB and activated protein-1 induced by lipopolysaccharide and phorbol ester.

Whether all inflammatory agents activate nuclear transcription factors NF-kappaB and activated protein-1 (AP-1) through the same mechanism is not known. We examined the effect of the phosphatidylinositol-3-kinase (PI-3K) inhibitor wortmannin on the activation of NF-kappaB and AP-1 by different inflammatory agents. Wortmannin blocked NF-kappaB and AP-1 activation by lipopolysaccharide and phorbol ester but had minimal effect on activation by hydrogen peroxide, ceramide, okadaic acid and tumor necrosis factor. Inhibition of NF-kappaB correlated with abrogation of the degradation of IkappaBalpha and of NF-kappaB-dependent reporter gene transcription. Thus, the mechanism of NF-kappaB and AP-1 activation by lipopolysaccharide and phorbol ester involves PI-3K.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2000

All-trans-retinoic acid upregulates TNF receptors and potentiates TNF-induced activation of nuclear factors-kappaB, activated protein-1 and apoptosis in human lung cancer cells.

Retinoids modulate the growth and differentiation effects of TNF but the mechanism is not understood. In this study, we investigated the effect of all-trans-retinoic acid (ATRA) on the cell surface expression of TNF receptors and receptor-mediated signaling in various human lung cancer cell lines. ATRA treatment of cells that express wild-type p53 (A549 and H460), or null p53 (H1299), or mutant p53 (H596) increased the number of TNF receptors, as determined by the specific binding of 125I-labeled TNF to these cells, in a dose- and time-dependent manner. Treatment with 2 microm ATRA for 24 h at 37 degrees C produced the maximal increase. Scatchard analysis indicated that the increase induced by ATRA was due to an increase in receptor number and not to an increase in affinity. The upmodulation of TNF receptors was also confirmed by covalent receptor-ligand cross-linking studies. The increase in TNF receptors sensitized H596 cells to TNF-induced activation of NF-kappaB, AP-1 and apoptosis. A549 cells, however, were completely resistant to TNF-induced activation of NF-kappaB, AP-1 and apoptosis. Treatment of these cells with as little as 0.5 microM ATRA was effective in converting TNF-resistant cells to TNF-sensitive. Overall our results indicate that ATRA induces the TNF receptors in human lung cancer cells, which sensitizes them to TNF-induced signaling leading to activation of NF-kappaB, AP-1 and apoptosis.

Apoptosis↗
PubMed2000

Pervanadate-induced nuclear factor-kappaB activation requires tyrosine phosphorylation and degradation of IkappaBalpha. Comparison with tumor necrosis factor-alpha.

Tumor necrosis factor activates nuclear transcription factor kappaB (NF-kappaB) by inducing serine phosphorylation of the inhibitory subunit of NF-kappaB (IkappaBalpha), which leads to its ubiquitination and degradation. In contrast, pervanadate (PV) activates NF-kappaB and induces tyrosine phosphorylation of IkappaBalpha (Singh, S., Darney, B. G., and Aggarwal, B. B. (1996) J. Biol. Chem. 271, 31049-31054; Imbert, V., Rupec, R. A., Antonia, L., Pahl, H. L., Traenckner, E. B.-M., Mueller-Dieckmann, C., Farahifar, D., Rossi, B., Auderger, P., Baeuerle, P. A., and Peyron, J.-F. (1996) Cell 86, 787-798). Whether PV also induces IkappaBalpha degradation and whether degradation is required for NF-kappaB activation are not understood. We investigated the effect of PV-induced tyrosine phosphorylation on IkappaBalpha degradation and NF-kappaB activation. PV activated NF-kappaB, as determined by DNA binding, NF-kappaB-dependent reporter gene expression, and phosphorylation and degradation of IkappaBalpha. Maximum degradation of IkappaBalpha occurred at 180 min, followed by NF-kappaB-dependent IkappaBalpha resynthesis. N-Acetylleucylleucylnorlucinal, a proteasome inhibitor, blocked both IkappaBalpha degradation and NF-kappaB activation, suggesting that the IkappaBalpha degradation is required for NF-kappaB activation. PV did not induce serine phosphorylation of IkappaBalpha but induced phosphorylation at tyrosine residue 42. Unlike tumor necrosis factor (TNF), PV did not induce ubiquitination of IkappaBalpha. Like TNF, however, PV induced phosphorylation and degradation of IkappaBalpha, and subsequent NF-kappaB activation, which could be blocked by N-tosyl-L-phenylalanine chloromethyl ketone, calpeptin, and pyrrolidine dithiocarbomate, suggesting a close link between PV-induced NF-kappaB activation and IkappaBalpha degradation. Overall, our studies demonstrate that PV activates NF-kappaB, which, unlike TNF, requires tyrosine phosphorylation of IkappaBalpha and its degradation.

Cysteine Endopeptidases↗
PubMed2000

Bcl-x(L) suppresses TNF-mediated apoptosis and activation of nuclear factor-kappaB, activation protein-1, and c-Jun N-terminal kinase.

Tumor necrosis factor (TNF) is a multipotential cytokine that induces apoptosis and activates nuclear factor-kappa B (NF-kappaB), activation protein 1 (AP-1), mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK). Several mechanisms have been suggested to explain these effects of TNF, one of them being the involvement of reactive oxygen intermediates (ROI). Because Bcl-2 family members are known to affect the redox status of the cell, we examined the effect of Bcl-x(L) expression on TNF signaling. Overexpression of Bcl-x(L) in human promyelocytic lymphoma HL-60 cells downregulated TNF-induced cytotoxicity. Cleavage of poly (ADP-ribose) polymerase by caspases, an early indicator of apoptosis, was also blocked by Bcl-x(L) overexpression. Activation of NF-kappaB was significantly suppressed in cells overexpressing Bcl-x(L), as was degradation of IkappaBalpha, the inhibitory subunit of NF-kappaB. NF-kappaB activation induced by serum-activated lipopolysaccharide (SALPS), ceramide, and okadaic acid was also inhibited by overexpression of Bcl-x(L), whereas that by phorbol myristate acetate (PMA) and H2O2 was unaffected. Besides NF-kappaB, the activation of AP-1 by TNF also was blocked by Bcl-x(L). The activation of JNK and MAPK kinase, which regulate these transcription factors, was reduced in Bcl-x(L)-transfected cells. Overall, our results demonstrate that Bcl-x(L) inhibits TNF signaling at an early step common to induction of activation of apoptosis, NF-kappaB, AP-1, MAPK, and JNK.

Apoptosis↗
PubMed2000

Tumour necrosis factors receptor associated signalling molecules and their role in activation of apoptosis, JNK and NF-kappaB.

Tumour necrosis factor (TNF) is a pleiotropic cytokine that mediates apoptosis, cell proliferation, immunomodulation, inflammation, viral replication, allergy, arthritis, septic shock, insulin resistance, autoimmune diseases, and other pathological conditions. TNF transduces these cellular responses through two distinct receptors: type I, which are expressed on all cell types, and type II, which are expressed only on cells of the immune system and endothelial cells. At the cellular level, these receptors activate the pathways leading to the activation of transcription factors NF-kappaB and AP-1, apoptosis and proliferation, and mitogen activated protein kinases. None of these receptors exhibit any enzymatic activity but the signals are transmitted through the recruitment of more than a dozen different signalling proteins, which together form signalling cascades. Inhibitors of TNF signalling have therapeutic value as indicated by the approval of the soluble TNF receptors and anti-TNF antibodies for rheumatoid arthritis and for inflammatory bowl disease.

Apoptosis↗
PubMed2000

Psychosocial profile of suicide ideators, attempters and completers in India.

The study aims to determine the psychological profile of suicide ideators, attempters and completers in a tertiary care teaching hospital. A total of 260 suicidal ideators, 58 attempters and 55 completers were studied. The majority of ideators, attempters and completers were 26-35 years of age, males (except attempters who were predominantly females), married, literate up to high school, employed (ideators) or housewives (attempters and completers). The suicide ideators, attempters and completers who had a past history of attempt were 6.9%, 24.1% and 18.2% respectively. Family history of attempted suicide or completed suicide was also common among patients suffering from depression. In suicidal ideators, mixed anxiety and depressive disorder was the most common psychiatric diagnosis followed by major depression and schizophrenia. Among suicide attempters, adjustment disorder with depression was the most common diagnosis. The most common method of suicide attempt was organophosphorus compound intake whereas in suicide completers, the most common method in use was hanging. The patients with suicidal ideation or attempt need careful evaluation, early intervention and long term follow up.

Adjustment Disorders↗
PubMed1999

Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis.

Silymarin is a polyphenolic flavonoid derived from milk thistle (Silybum marianum) that has anti-inflammatory, cytoprotective, and anticarcinogenic effects. How silymarin produces these effects is not understood, but it may involve suppression of NF-kappa B, a nuclear transcription factor, which regulates the expression of various genes involved in inflammation, cytoprotection, and carcinogenesis. In this report, we investigated the effect of silymarin on NF-kappa B activation induced by various inflammatory agents. Silymarin blocked TNF-induced activation of NF-kappa B in a dose- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of Iota kappa B alpha, an inhibitor of NF-kappa B. Silymarin blocked the translocation of p65 to the nucleus without affecting its ability to bind to the DNA. NF-kappa B-dependent reporter gene transcription was also suppressed by silymarin. Silymarin also blocked NF-kappa B activation induced by phorbol ester, LPS, okadaic acid, and ceramide, whereas H2O2-induced NF-kappa B activation was not significantly affected. The effects of silymarin on NF-kappa B activation were specific, as AP-1 activation was unaffected. Silymarin also inhibited the TNF-induced activation of mitogen-activated protein kinase kinase and c-Jun N-terminal kinase and abrogated TNF-induced cytotoxicity and caspase activation. Silymarin suppressed the TNF-induced production of reactive oxygen intermediates and lipid peroxidation. Overall, the inhibition of activation of NF-kappa B and the kinases may provide in part the molecular basis for the anticarcinogenic and anti-inflammatory effects of silymarin, and its effects on caspases may explain its role in cytoprotection.

Apoptosis↗