[Show abstract][Hide abstract] ABSTRACT: Riboflavin (RF) or vitamin B2 is known to have neuroprotective effects. In the present study, we report the attenuation of the neuroprotective effects of RF under UV-B irradiation. Preconditioning of UV-B irradiated riboflavin (UV-B-RF) showed attenuated neuroprotective effects compared to that of RF in SH-SY5Y neuroblostoma cell line and primary cortical neurons in vitro and a rat model of cerebral ischemia in vivo.
[Show abstract][Hide abstract] ABSTRACT: Background: To evaluate serum VEGF-A levels in squamous cell carcinoma of head and neck (SCCHN) patients and relationships with response to therapy. Materials and Methods: Serum VEGF-A levels in patients (n=72) treated with radiotherapy (RT) or radio-chemotherapy (RCT) and controls (n=40) were measured by ELISA. Results: Serum VEGF-A levels of the SCCHN cases were significantly higher (p=0.001) than in healthy controls, and in patients with positive as compared to negative lymph node status (p=0.004). Similarly, patients with advanced stage (Stage III-IV) disease had more greatly elevated levels of serum VEGF-A level than their early stage (Stage I-II) counterparts (p=0.001). In contrast, there was no significant difference (p=0.57) in serum level of VEGF-A in patients with advanced T-stage (T3-4) as compared to early stage (T1-2). Similarly, patients with distant metastasis had no significant (p=0.067) elevation in serum VEGF-A level as compared to non-metastatic disease. However, the non-responder patients had significantly higher serum VEGF-A level as compared to responders (p=0.001). Conclusions: Our results suggest that the serum VEGF-A level may be a useful biomarker for the prediction of response to therapy in SCCHN.
Asian Pacific journal of cancer prevention: APJCP 01/2014; 15(7):3261-5. · 1.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The natural polyphenolic alkanone, (6)-Gingerol (6G) has established anti-inflammatory and anti-tumoral properties. However, its precise mechanism of action in myeloid leukemia cells is unclear. In this study, we investigated the effects of 6G on myeloid leukemia cells in vitro and in vivo. The results of the present study showed that 6G inhibited proliferation of myeloid leukemia cell lines and primary myeloid leukemia cells while sparing the normal peripheral blood mononuclear cells (PBMCs), in a concentration and time dependent manner. Mechanistic studies using U937 and K562 cell lines revealed that 6G treatment induced ROS generation by inhibiting the mitochondrial respiratory complex-I (MRC-I) which in turn increased the expression of the oxidative stress response associated microRNA, miR-27b and DNA damage. Elevated miR-27b expression inhibited PPARγ with subsequent inhibition of the inflammatory cytokine gene expression associated with the oncogenic NF-kappaB (NFkB) pathway, while the increased DNA damage led to G2/M cell cycle arrest. The 6G induced effects were abolished in the presence of anti-miR27b or the ROS scavenger NAC. In addition, the results of the in vivo xenograft experiments in mice indicated that 6G treatment inhibited tumor cell proliferation and induced apoptosis in agreement with the in vitro studies. Our data provide new evidence that 6G induced myeloid leukemia cell death is initiated by the reactive oxygen species and mediated through the increase in miR-27b expression and DNA damage. The dual induction of increased miR-27b expression and DNA damage associated cell cycle arrest by 6G may have implications for myeloid leukemia treatment.
Free Radical Biology & Medicine 12/2013; · 5.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Novel trioxane 97/78, developed by Central Drug Research Institute (CDRI), Lucknow has shown promising antimalarial activity. Clinical experience of anti-malarial drugs registered the occurrence of phototoxicity in patients exposed with sunlight subsequent to medication. Photodegradation study has identified one photo-product up to 4h under UV-B/Sunlight by LC-MS/MS. UV-B irradiated 97/78 compound produced (1)O2 via type-II dependent reaction mechanism, corroborated by its specific quencher. 2'-dGua degradation and % tail development in photochemical as well as comet test, advocated the genotoxic potential of 97/78. The photocytotoxicity assays (MTT and NRU) on HaCaT cell line revealed the considerable decline in cell viability by 97/78. Cell cycle and AnnexinV/PI double stain along with AO/EB demonstrated the G2/M phase arrest and apoptosis. Significant caspase-3 activity was measured in photoexcited 97/78 by colorimetric assay. Fluorescence stain with AO/JC-1 confirmed the Lysosomal disruption and mitochondrial membrane destabilization by UV-B irradiated 97/78. Gene expression by RT-PCR showed significant upregulation of p21 and pro-apoptotic Bax, but no change observed in Bcl-2. In conclusion, the study highlights ROS mediated DNA damage, lysosomal and mitochondrial destabilization via upregulation of Bax and activation of caspase-3 which further leads to apoptosis.
[Show abstract][Hide abstract] ABSTRACT: Beta-catenin (β-catenin) is a multifunction protein with a central role in physiological homeostasis. Its abnormal expression leads to various diseases including cancer. In normal physiology, β-catenin either maintains integrity of epithelial tissues or controls transcription of various genes on extracellular instigations. In epithelial tissues, β-catenin functions as a component of the cadherin protein complex and regulates epithelial cell growth and intracellular adhesion. In Wnt signalling, β-catenin is a major transcriptional modulator and plays a crucial role in embryogenesis, stem cell renewal and organ regeneration. Aberrant expression of β-catenin can induce malignant pathways in normal cells and its abnormal activity is also exploited by existing malignant programmes. It acts as an oncogene and modulates transcription of genes to drive cancer initiation, progression, survival and relapse. Abnormal expression and function of β-catenin in cancer makes it a putative drug target. In the past decade, various attempts have been made to identify and characterize various pharmacological inhibitors of β-catenin. Many of these inhibitors are currently being investigated for their anticancer activities in a variety of cancers. The first half of this review will focus on the role of β-catenin in cancer initiation, maintenance, progression and relapse whereas the second half will briefly summarize the recent progress in development of agents for the pharmacological modulation of β-catenin activity in cancer therapeutics.
Journal of Cellular and Molecular Medicine 03/2013; · 4.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Proteasomes are multicatalytic protease complexes in the cell, involved in the non-lysosomal recycling of intra-cellular proteins. Proteasomes play a critical role in regulation of cell division in both normal as well as cancer cells. In cancer cells this homeostatic function is deregulated leading to the hyperactivation of the proteasomes. Proteasome inhibitors (PIs) are a class of compounds, which either reversibly or irreversibly block the activity of proteasomes and induce cancer cell death. Interference of PIs with the ubiquitin proteasome pathway (UPP) involved in protein turnover in the cell leads to the accumulation of proteins engaged in cell cycle progression, which ultimately put a halt to cancer cell division and induce apoptosis. Upregulation of many tumor suppressor proteins involved in cell cycle arrest are known to play a role in PI induced cell cycle arrest in a variety of cancer cells. Although many PIs target the proteasomes, not all of them are effective in cancer therapy. Some cancers develop resistance against proteasome inhibition by possibly activating compensatory signaling pathways. However, the details of the activation of these pathways and their contribution to resistance to PI therapy remain obscure. Delineation of these pathways may help in checking resistance against PIs and deducing effective combinational approaches for improved treatment strategies. This review will discuss some of the signaling pathways related to proteasome inhibition and cell division that may help explain the basis of resistance of some cancers to proteasome inhibitors and underline the need for usage of PIs in combination with traditional chemotherapy.
[Show abstract][Hide abstract] ABSTRACT: The synthesis and SAR studies of 10 new chemical entities (NCEs) that have shown BMP-2 stimulation and osteoblast differentiation are reported. Among these, 2-((1-(benzyl(2-hydroxy-2-phenylethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)benzoic acid (11) was the most effective while its analogue 13 also showed good activity in inducing osteoblast BMP-2 production. Compound 11 induced osteoblast differentiation in vitro, and this effect was abrogated by a physiological BMP-2 inhibitor, noggin. It also exhibited dose dependent increase in nascent bone formation (2.16- and 3.12-fold more than the control at 1 and 5 mg/kg dose, respectively) at the fracture site in rats. At the maximum osteogenic concentration, compound 11 significantly inhibited osteoblastic proteosomal activity. This compound was safe, as it had no effect on BMP synthesis in cardiovascular tissue.
Journal of Medicinal Chemistry 09/2012; 55(19):8248-59. · 5.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present report describes development of a novel, bifunctional molecule possessing both selective antiproliferative activity and siRNA transfection ability. We synthesized a series of cationic lipo-benzamides and screened for in vitro anticancer activities against a panel of cancer and non-cancer cells. The molecule with a ten carbon chain-length (C10M) significantly inhibited proliferation of cancer cells via arresting the cell cycle predominantly in the G1 phase; but did not affect non-cancerous cells. C10M effectively mediated siRNA delivery in vitro. The combined anticancer effect of the delivery of C10M together with its survivin-targeting siRNA cargo was significantly (p < 0.05) superior to that of agent alone. To our knowledge, this is the first report of a dual-purpose molecule with intrinsic anticancer activity and suitability for use in siRNA delivery.
European journal of medicinal chemistry 07/2012; 56:400-8. · 3.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is induced in energy-starved conditions and is a key regulator of energy homeostasis. This makes PGC-1α an attractive therapeutic target for metabolic syndrome and diabetes. In our effort to identify new regulators of PGC-1α expression, we found that GW4064, a widely used synthetic agonist for the nuclear bile acid receptor [farnesoid X receptor (FXR)] strongly enhances PGC-1α promoter reporter activity, mRNA, and protein expression. This induction in PGC-1α concomitantly enhances mitochondrial mass and expression of several PGC-1α target genes involved in mitochondrial function. Using FXR-rich or FXR-nonexpressing cell lines and tissues, we found that this effect of GW4064 is not mediated directly by FXR but occurs via activation of estrogen receptor-related receptor α (ERRα). Cell-based, biochemical and biophysical assays indicate GW4064 as an agonist of ERR proteins. Interestingly, FXR disruption alters GW4064 induction of PGC-1α mRNA in a tissue-dependent manner. Using FXR-null [FXR knockout (FXRKO)] mice, we determined that GW4064 induction of PGC-1α expression is not affected in oxidative soleus muscles of FXRKO mice but is compromised in the FXRKO liver. Mechanistic studies to explain these differences revealed that FXR physically interacts with ERR and protects them from repression by the atypical corepressor, small heterodimer partner in liver. Together, this interplay between ERRα-FXR-PGC-1α and small heterodimer partner offers new insights into the biological functions of ERRα and FXR, thus providing a knowledge base for therapeutics in energy balance-related pathophysiology.
[Show abstract][Hide abstract] ABSTRACT: Centchroman (CC; 67/20; INN: Ormeloxifene) is a non-steroidal antiestrogen extensively used as a female contraceptive in India. In the present study, we report the anti-proliferative effect of CC in head and neck squamous cell carcinoma (HNSCC) cells. CC inhibited cell proliferation in a dose dependent manner at 24 h of treatment. Further studies showed that CC treatment induced apoptosis, inhibited Akt/mTOR and signal transducers and activators of transcription protein 3 (STAT3) signaling, altered proteins associated with cell cycle regulation and DNA damage and inhibited colony forming efficiency of HNSCC cells. In addition, CC displayed anti-proliferative activity against a variety of non-HNSCC cell lines of diverse origin. The ability of CC to serve as a dual-inhibitor of Akt/mTOR and STAT3 signaling warrants further studies into its role as a therapeutic strategy against HNSCC.
Biochemical and Biophysical Research Communications 01/2011; 404(1):40-5. · 2.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cellular apoptosis appears to be a constant feature in the adult testis and during early development. This is essential because mammalian spermatogenesis is a complex process that requires precise homeostasis of different cell types. This review discusses the latest information available on male germ cell apoptosis induced by hormones, toxins and temperature in the context of the type of apoptotic pathway either the intrinsic or the extrinsic that may be used under a variety of stimuli. The review also discusses the importance of mechanisms pertaining to cellular apoptosis during testicular development, which is independent of exogenous stimuli. Since instances of germ cell carcinoma have increased over the past few decades, the current status of research on apoptotic pathways in teratocarcinoma cells is included. One other important aspect that is covered in this review is microRNA-mediated control of germ cell apoptosis, a field of research that is going to see intense activity in near future. Since knockout models of various kinds have been used to study many aspects of germ cell development, a comprehensive summary of literature on knockout mice used in reproduction studies is also provided.
Philosophical Transactions of The Royal Society B Biological Sciences 05/2010; 365(1546):1501-15. · 6.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: From the viewpoint of improving germ cell production and treatment of testicular cancers, understanding the control of testicular cell death is of great relevance. One of the prominent features of spermatogenesis is apoptosis of germ cells at different stages of differentiation, by which excess and unfit cells are discarded to maintain proper tissue homeostasis. A phase of heightened apoptosis known as the 'first wave of spermatogenesis' occurs when the gonocytes differentiate into spermatogonia. The germ cells use an extrinsic pathway of apoptosis involving the Fas/FasL molecules as well as the mitochondrial pathway of death using the Bcl-2 family of proteins. A comprehensive view of the involvement of the different pro- and anti-apoptotic molecules has been defined through the use of mutant and knockout mice and toxin-induced cell death models. In addition, hormones such as estrogens in the male are of great interest. The presence of estrogen receptors on germ cells makes these cells susceptible to environmental agents which can mimic estrogens and potentially cause functional impairment of the male gamete. Post-industrialization, an increase in testicular cancers has been recorded and carcinoma of germ cell origin is susceptible to platinum-based compounds that induce multiple apoptotic pathways. This review covers recent progress made on the above issues. The challenge is now to identify the precise signaling pathways and the mechanisms by which germ cells and germ cell tumors initiate cell death processes, and to utilize this information for improving reproductive health related issues.
Journal of Reproductive Immunology 11/2009; 83(1-2):31-5. · 2.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bcl-x exists in two isoforms, the anti-apoptotic form Bcl-xL and the proapoptotic form Bcl-xS. The critical balance between the two forms appears to be important for cell survival; however, it is still not clear exactly how the vital balance is maintained. Using an in vitro spermatogenic cell apoptosis model, this study provides a new insight into the possible role of Ca2+ in regulating the Bcl-xS and Bcl-xL expression. 2,5-Hexanedione, a metabolite of the common industrial solvent n-hexane, caused a significant increase in reactive oxygen species followed by an enhancement of intracellular Ca2+ through the T-type Ca2+ channels. Consequent to the above changes, expression of Bcl-xS increased with a concomitant drop in Bcl-xL expression, thus altering the ratio of the two proteins. Impediment of Ca2+ influx by using a T-type Ca2+ channel blocker pimozide resulted in a decrease in Bcl-xS and an increase in Bcl-xL expression. This caused prevention of mitochondrial potential loss, reduction of caspase-3 activity, inhibition of DNA fragmentation, and increase in cell survival. Alternatively, Ca2+ ionophores caused an increase of Bcl-xS encoding isoform over the Bcl-xL-encoding isoform. Therefore, this study proposes a role for Ca2+ in regulation of Bcl-xS and Bcl-xL expression and ultimately cell fate.
Journal of Biological Chemistry 02/2006; 281(4):2133-43. · 4.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The detrimental effects of estrogen on testicular function provide a conceptual basis to examine the speculative link between increased exposure to estrogens and spermatogenic cell death. Using an in vitro model, we provide an understanding of the events leading to estrogen-induced apoptosis in cells of spermatogenic lineage. Early events associated with estrogen exposure were up-regulation of FasL and increased generation of H(2)O(2), superoxide, and nitric oxide. The ability of anti-FasL antibodies to prevent several downstream biochemical changes and cell death induced by 17beta-estradiol substantiates the involvement of the cell death receptor pathway. Evidence for the amplification of the death-inducing signals through mitochondria was obtained from the transient mitochondrial hyperpolarization observed after estradiol exposure resulting in cytochrome c release. A combination of nitric oxide and superoxide but not H(2)O(2) was responsible for the mitochondrial hyperpolarization. Mn(III) tetrakis(4-benzoic acid)porphyrin chloride, an intracellular peroxynitrite scavenger, was able to reduce mitochondrial hyperpolarization and cell death. Although nitric oxide augmentation occurred through an increase in the expression of inducible nitric-oxide synthase, superoxide up-regulation was a product of estradiol metabolism. All of the above changes were mediated through an estrogen receptor-based mechanism because tamoxifen, the estrogen receptor modulator, was able to rescue the cells from estrogen-induced alterations. This study establishes the importance of the independent capability of cells of the spermatogenic lineage to respond to estrogens and most importantly suggests that low dose estrogens can potentially cause severe spermatogenic cellular dysfunction leading to impaired fertility even without interference of the hypothalamo-hypophyseal axis.
Journal of Biological Chemistry 03/2005; 280(7):6181-96. · 4.65 Impact Factor