A common feature of both apoptosis and inflammation is the activation of caspases. Caspases are aspartate-directed cysteine proteases that have numerous cellular targets. It has been discovered that several flavonoids are inhibitors of caspases. Flavonoids are members of a family of polyphenolic compounds from plants that have many biological properties, ...

This paper reviews new drug targets in the treatment of depression and new drug candidates to treat depression. Depression is characterized by aberrations in six intertwined pathways: (1) inflammatory pathways as indicated by increased levels of proinflammatory cytokines, e.g. interleukin-1 (IL-1), IL-6, and tumour necrosis factor α. (2) Activation of ...

Burkitt's lymphoma (BL), driven by translocation and over-expression of the c-MYC gene, is an aggressive, highly proliferative lymphoma and novel therapeutic strategies are required to overcome drug resistance following conventional treatments. The importance of the pro-survival BCL-2 family member BCL-XL in BL cell survival suggests that antagonistic BH3-mimetic compounds may ...

In an attempt to clarify the protective effect of puerarin on toxin-insulted dopaminergic neuronal death, this present study was carried out by using a typical Parkinson's disease (PD) model - 1-methyl-4-phenylpyridinium iodide (MPP(+))-induced dopaminergic SH-SY5Y cellular model. Data are presented, which showed that puerarin up-regulated Akt phosphorylation in both of ...

Selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRI; SNRI) are the first choice pharmacological treatment options for major depression. It has long been assumed that the primary therapeutic mechanism of action of these drugs involves the modulation of monoaminergic systems. However, contemporary investigations have revealed that depression is linked with ...

Trichloroethylene (TCE) is a common chemical pollutant that exists in air, soil, and drinking water. TCE exposure is known to cause severe hepatotoxicity; however, the mechanisms underlying TCE hepatotoxicity remain poorly understood. In a previous proteomics study, we found that TCE exposure up-regulated the expression of the inhibitor 2 of ...

The role of autophagy in cancer is controversial. Melatonin has been linked to several aspects of cancer progression and also to regulation of autophagy. Whether melatonin is involved in an autophagy-induced tumor suppressor mechanism or a cyto-protective mechanism is unknown. Therefore, we investigated the effects of melatonin on autophagy and ...

Systemic inflammatory response syndrome is a fatal disease because of multiple organ failure. Acute kidney injury is a serious complication of systemic inflammatory response syndrome and its genesis is still unclear posing a difficulty for an effective treatment. Aldose reductase (AR) inhibitor is recently found to suppress lipopolysaccharide (LPS)-induced cardiac ...

Caspase-6 is a cysteinyl protease implicated in neurodegenerative conditions including Alzheimer's and Huntington's disease making it an attractive target for therapeutic intervention. A greater understanding of the role of caspase-6 in disease has been hampered by a lack of suitable cellular assays capable of specifically detecting caspase-6 activity in an ...

Within the last decade, it became clear that oxygen contributes to the pathogenesis of neonatal brain damage, leading to neurocognitive impairment of prematurely born infants in later life. Recently, we have identified a critical role for receptor-mediated neuronal apoptosis in the immature rodent brain. However, the contribution of the intrinsic ...

GS-1101(CAL-101) is an oral PI3Kδ-specific inhibitor which has shown preclinical and clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. To investigate the potential role of PI3Kδ in Hodgkin lymphoma (HL), we screened 5 HL cell lines and primary samples from patients with HL for PI3Kδ isoform expression and constitutive ...

Mucus hypersecretion is an important manifestation in patients with chronic inflammatory airway diseases. Excessive production of mucin leads to airway mucus obstruction and contributes to morbidity and mortality in these diseases. The molecular mechanisms underlying mucin overproduction, however, still remain largely unknown. Here, we report that the bacterium Pseudomonas aeruginosa ...

Nuclear factor kappa B (NF-κB) is a key signaling molecule in the elaboration of the inflammatory response. Data indicate that curcumin, a natural ingredient of the curry spice turmeric, acts as a NF-κB inhibitor and exhibits both anti-inflammatory and anti-cancer properties. Curcumin analogs with enhanced activity on the NF-κB and ...

Reactive oxygen species (ROS) are involved in myocardial injury. ROS are known to inactivate lipid phosphatase and tension homolog on chromosome 10 (PTEN), an enzyme that increases apoptosis in neonatal cardiomyocytes. BpV(pic) and bpV(phen), two bisperoxovanadium molecules and PTEN inhibitors, may be involved in limiting myocardial infarction. To compare the ...

Double-stranded RNA (dsRNA) can mediate its therapeutic effect through Toll-like receptor 3 (TLR3) expressed on tumor cells including neuroblastoma. We used synthetic dsRNA polyinosinic-polycytidylic acid [Poly(I:C)] as a TLR3 agonist to treat TLR3-expressing SK-N-AS neuroblatoma (NB) cells. We found up-regulation of endoplasmic reticulum (ER) stress proteins glucose-regulated protein 78 and ...

Artemisia argyi is a widely used medicinal plant in China. The present study was designed to identify the bioactive constituents with antiglioma activity from leaves of Artemesia argyi. A bioactivity guided approach based on MTT assay for cells growth inhibition led to the isolation of a flavonoid, "jaceosidin" from ethanol ...

Evasion of apoptosis may contribute to poor treatment response in pediatric acute lymphoblastic leukemia (ALL), calling for novel treatment strategies. Here, we report that inhibitors of apoptosis (IAPs) at subtoxic concentrations cooperate with various anticancer drugs (that is, AraC, Gemcitabine, Cyclophosphamide, Doxorubicin, Etoposide, Vincristine and Taxol) to induce apoptosis in ...

Wogonin, one of flavonoid compounds isolated from Chinese herbal plants Scutellaria baicalensis Georgi, has been recognized as a potent anti-cancer agent acting through control of growth, differentiation and apoptosis. However, the underlying molecular mechanism of its anti-cancer activity remains to be further elucidated. In this study, we investigated the potential ...

SNX-2112 is an Hsp90 inhibitor which is currently undergoing multiple Phase 1 clinical trials; however, its mechanism of action needs to be further elaborated. Here we investigated the effects of SNX-2112 in A-375 cells. SNX-2112 induced the degradation of multiple Hsp90 client proteins, activated both the mitochondrial-mediated and death receptor-mediated ...

This study investigated the antioxidative and anti-inflammatory activities of aqueous extracts of Schizonepeta tenuifolia Briq. (STE). The results showed that STE displayed radical scavenging and reducing activity, as well as liposome protection activity. In addition, the implementation of an HPLC with a photodiode array detector helped to identify polyphenolic components ...

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rapidly fatal malignancy that is increasing in incidence. The caspase 8 inhibitor FLIP is an anti-apoptotic protein over-expressed in several cancer types including MPM. The histone deacetylase (HDAC) inhibitor Vorinostat (SAHA) is currently being evaluated in relapsed mesothelioma. We examined the roles of ...

Cadmium is a heavy metal that is known to cause toxicity to cells and at low concentrations can initiate apoptosis. The present study was undertaken with the aim of defining the role of phospholipase C (PLC) in mediating cadmium-induced apoptosis in human embryonic kidney HEK 293 cells. We have shown ...

Alpha-1 antitrypsin (AAT) acts as an important neutrophil elastase inhibitor in the lung. Although the hepatocyte is considered as the primary source of AAT, local production by monocytes, macrophages and epithelial cells may contribute to the formation of an anti-elastase screen. Since monocytes can differentiate into a heterogeneous population of ...

OBJECTIVE: Recent data suggested that histone deacetylase (HDAC) inhibitors possessed potent anti-inflammatory and immunomodulatory properties both in vitro and in vivo. This study assayed the ability of the HDAC inhibitor, valproic acid (VPA), to influence the differentiation and functional properties of dendritic cells (DCs) generated from circulating peripheral blood monocytes. ...

Asthma is a chronic inflammatory lung disease with considerable unmet medical requirement for new and effective therapies. Cytosolic phospholipase A(2)α (cPLA(2)α) is the rate-limiting enzyme ultimately responsible for production of eicosanoids implicated in the pathophysiology of asthma. We investigated a novel cPLA(2)α inhibitor, PF-5212372, to establish the potential for this ...

The formation of advanced glycation end products (AGEs) has been considered to be a potential causative factor of injury to lens epithelial cells (LECs). Damage of LECs is believed to contribute to cataract formation. The purpose of this study was to investigate the cytotoxic effect of AGEs on LECs both ...

Mechanisms of cyclosporine A (CsA)-induced nephrotoxicity were generally thought to be hemodynamic in origin; however, there is now accumulating evidence of a direct tubular effect. Although genomic and proteomic experiments by our group and others provided overall information on genes and proteins up- or down-regulated by CsA in proximal tubule ...

Aberrantly activated macrophages, which overproduce inflammatory mediators, are involved in the pathogenesis of many inflammatory diseases. We analyzed the anti-inflammatory activity of lansoprazole (LPZ), a typical proton pump (P-ATPase) inhibitor, on RAW264.7 murine macrophages. Treatment of lipopolysaccharide (LPS)-stimulated RAW264.7 cells with LPZ inhibited the production of nitric oxide (NO) and ...

PURPOSE: Recently, cholinergic anti-inflammatory pathway manipulation has been proposed as a new strategy to control cytokine production in sepsis. We investigated whether hypercytokinemia can be controlled via this pathway in an animal model of sepsis, with concomitant monitoring of autonomic nervous activity involving heart rate variability (HRV) analysis of electrocardiographic ...

Caspases are an evolutionarily conserved family of aspartate-specific cystein-dependent proteases with essential functions in apoptosis and normally exist in cells as inactive proenzymes. In addition to the inflammatory caspases, the initiator and effector caspases have been shown to have an important role in regulating the immune response, but are involved ...

MicroRNAs (miRNAs) are a novel class of powerful, endogenous regulators of gene expression. In an intact rat model of myocardial ischemia caused by coronary artery ligation, this study identified 17 miRNAs that changed more than 1.5-fold in the myocardium subjected to 4-h ischemia. Using miRNA microarray analysis, most of these ...

Cell death is indispensable for normal growth and development of multicellular organisms. Caspases, the effector proteases of apoptosis are normally activated by dimerization in multimeric protein complexes and inhibitors of apoptosis (IAPs) function as endogenous inhibitors of caspases. Recent studies have revealed that cell death stimuli can also trigger programmed ...

The MUC1-C oncoprotein is aberrantly expressed in most multiple myeloma cells. However, the functional significance of MUC1-C expression in multiple myeloma is not known. The present studies demonstrate that treatment of multiple myeloma cells with a MUC1-C inhibitor is associated with increases in reactive oxygen species (ROS), oxidation of mitochondrial ...

Cryopreservation is an essential technique in basic research and clinical applications of human embryonic stem (hES) cells. Cryopreserved hES cells are fragile and undergo post-thaw apoptosis. We performed gene pathway analysis on cryopreserved and thawed hES cells to examine the effect of Y-27632, a Rho-associated kinase (ROCK) inhibitor, on apoptosis ...

Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that regulates inflammatory responses to injury and infection. IL-1β secretion requires the protease caspase-1, which is activated following recruitment to inflammasomes. Endogenous danger associated molecular patterns (DAMPs) released from necrotic cells activate caspase-1 through a NLRP3-inflammasome. Here we show that the endogenous lipid metabolite ...

Our recent microarray analysis of infected human alveolar macrophages (AMs) found serine protease inhibitor 9 (PI-9) to be the most prominently expressed of a cluster of apoptosis-associated genes induced by virulent Mycobacterium tuberculosis. In the current study, we show that induction of PI-9 occurs within hours of infection with M. ...

Hyperthermia induced by heat stress (HS) inhibits the proliferation of cancer cells and induces their apoptosis. However, the mechanism underlying HS-induced apoptosis remains elusive. Here, we demonstrated a novel evidence that checkpoint kinase 1 (Chk1) plays crucial roles in the apoptosis and regulation of cell cycle progression in cells under ...

IL-33 activates eosinophils directly via the ST2 receptor. Like IL-5, IL-33 induces eosinophilia and eosinophilic airway inflammation in mouse models and primes human eosinophil responses. Previously, we reported that IL-5 priming enhances Siglec-8 mediated mitochondrial and reactive oxygen species (ROS)-dependent eosinophilic apoptosis and eliminates caspase dependence of this cell death ...

The leaf of Pinus (P.) densiflora, a pine tree widely distributed in Asian countries, has been used as a traditional medicine. In the present study, we investigated the anticancer activity of essential oil, extracted by steam distillation, from the leaf of P. densiflora in YD-8 human oral squamous cell carcinoma (OSCC) ...

The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas. However, a considerable number of glioblastoma (GBM) cases are refractory to TMZ. Previous studies have revealed that the PI3K/Akt pathway is activated in an ataxia telangiectasia and Rad3 related-dependent manner in response to TMZ. Thus, we hypothesized that PI3K ...

Despite significant advancement in developing therapies for multiple sclerosis (MS), drugs that cure this devastating disorder are an unmet need. Among the remedies showing efficacy in preclinical MS models, inhibitors of poly(ADP-ribose) polymerase (PARP)-1 have gained great momentum. Emerging evidence demonstrates that PARP-1 inhibitors epigenetically regulate gene expression and finely ...

Oligodendroglial damage and loss are typical characteristics of demyelinating diseases such as multiple sclerosis (MS) and the leukodystrophies. Axonal loss is the underlying cause of permanent neurological deficits in MS and it is thought to arise from a combination of immune-mediated axonal damage and the loss of trophic support to ...

BackgroundTumour necrosis factor α (TNFα) inhibitors such as adalimumab and infliximab are frequently prescribed for inflammatory bowel disease (IBD). Despite the clinical success of TNFα inhibitors, their physiological mode of action is not fully understood. The aim of this study was to investigate the mode of action of anti-TNFα agents ...

Gefitinib, a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase, has been shown to induce autophagy as well as apoptosis in tumor cells. Yet, how to exploit autophagy and apoptosis to improve therapeutic efficacy of this drug against cancer remains to be explored. We reported here that ...

The accumulation of advanced glycation end products (AGEs) on micro-vasculature has been demonstrated to be a key factor in diabetes mellitus development. Evidence suggests that AGEs triggered apoptotic changes in human umbilical vein endothelial cells (HUVECs) and protein kinase C (PKC)-beta plays a pivotal role in AGEs-induced micro-vascular dysfunction. Thus ...

Nicotinamide (the amide form of vitamin B3) has been used in dermatology for more than 40 years for a diverse range of conditions including acne, rosacea, autoimmune bullous dermatoses, and now the treatment and prevention of photoaging and photoimmunosuppression. The broad clinical effects of nicotinamide may be explained by its ...

The folk medicine Angelica keiskei (Ashitaba) exhibits antitumor, antioxidant and antidiabetic activities and it has recently attracted attention as a health food. Ashitaba is thought to have antithrombotic properties, but this has not yet been scientifically proven. The elevation of plasma plasminogen activator inhibitor 1 (PAI-1), an inhibitor of fibrinolysis ...

Therapeutic effects of histone deacetylase (HDAC) inhibitors in cancer models were first linked to their ability to cause growth arrest and apoptosis of tumor cells. It is now clear that these agents also have pleiotropic effects on angiogenesis and the immune system, and some of these properties are likely to ...

The resin monomer triethylene glycol dimethacrylate (TEGDMA) disrupts vital cell functions, and the production of oxidative stress is considered a common underlying mechanism. The precise signaling pathways, however, that initiate monomer-induced effects, which disturb responses of the innate immune system, inhibit dentin mineralization processes, or induce apoptosis in target cells ...

Genotoxic stress induced apoptosis is mediated by the formation of PIDDosome, which is a caspase-2 activating complex composed of three protein components, PIDD, RAIDD, and caspase-2. Here, synthetic TAT-fused peptides designed by the structure of PIDD and RAIDD, TAT-Y814A and TAT-R147E, respectively, were produced and tested for their ability to ...