Esophageal cancer (EC) is a disease often marked by aggressive growth and poor prognosis. Lack of targeted therapies, resistance to chemoradiation therapy, and distant metastases among patients with ...advanced disease account for the high mortality rate. The tumor microenvironment (TME) contains several cell types, including fibroblasts, immune cells, adipocytes, stromal proteins, and growth factors, which play a significant role in supporting the growth and aggressive behavior of cancer cells. The complex and dynamic interactions of the secreted cytokines, chemokines, growth factors, and their receptors mediate chronic inflammation and immunosuppressive TME favoring tumor progression, metastasis, and decreased response to therapy. The molecular changes in the TME are used as biological markers for diagnosis, prognosis, and response to treatment in patients. This review highlighted the novel insights into the understanding and functional impact of deregulated cytokines and chemokines in imparting aggressive EC, stressing the nature and therapeutic consequences of the cytokine-chemokine network. We also discuss cytokine-chemokine oncogenic potential by contributing to the Epithelial-Mesenchymal Transition (EMT), angiogenesis, immunosuppression, metastatic niche, and therapeutic resistance development. In addition, it discusses the wide range of changes and intracellular signaling pathways that occur in the TME. Overall, this is a relatively unexplored field that could provide crucial insights into tumor immunology and encourage the effective application of modulatory cytokine-chemokine therapy to EC.
Summary Background & aim Prostate cancer is one of the frequently diagnosed cancers in men. Increased Growth factor IGF-1/IGF-1R axis activation mediated by both PI3K/Akt or RAF/MEK/ERK system and AR ...expression remains important in the development and progression of prostate cancer. Targeting such system by dietary agents quercetin in vivo model could aid its application in both treatment as well as prevention of prostate cancer. Methods In our study the rats were divided into four groups; Group I: control (propylene glycol-vehicle), Group II: cancer-induced (MNU and Testosterone treated) rats, Group III: cancer-induced + Quercetin (200 mg/kg body wt/orally) and Group IV: Quercetin (200 mg/kg body wt) thrice a week. After the treatment period rats were sacrificed and the ventral and dorsolateral prostate lobes were dissected. Results Antioxidant enzymes and apoptotic proteins were significantly decreased in cancer-induced animal and upon quercetin supplement its level was increased. The IGFIR, AKT, AR, cell proliferative and anti-apoptotic proteins were increased in cancer-induced group whereas supplement of quercetin decreased its expression. Conclusions Quercetin down regulates the cell survival, proliferative and anti-apoptotic proteins thereby prevents prostate cancer, by acting as a chemopreventive agent in preclinical model.
Genomic selection (GS) is a promising approach exploiting molecular genetic markers to design novel breeding programs and to develop new markers-based models for genetic evaluation. In plant ...breeding, it provides opportunities to increase genetic gain of complex traits per unit time and cost. The cost-benefit balance was an important consideration for GS to work in crop plants. Availability of genome-wide high-throughput, cost-effective and flexible markers, having low ascertainment bias, suitable for large population size as well for both model and non-model crop species with or without the reference genome sequence was the most important factor for its successful and effective implementation in crop species. These factors were the major limitations to earlier marker systems viz., SSR and array-based, and was unimaginable before the availability of next-generation sequencing (NGS) technologies which have provided novel SNP genotyping platforms especially the genotyping by sequencing. These marker technologies have changed the entire scenario of marker applications and made the use of GS a routine work for crop improvement in both model and non-model crop species. The NGS-based genotyping have increased genomic-estimated breeding value prediction accuracies over other established marker platform in cereals and other crop species, and made the dream of GS true in crop breeding. But to harness the true benefits from GS, these marker technologies will be combined with high-throughput phenotyping for achieving the valuable genetic gain from complex traits. Moreover, the continuous decline in sequencing cost will make the WGS feasible and cost effective for GS in near future. Till that time matures the targeted sequencing seems to be more cost-effective option for large scale marker discovery and GS, particularly in case of large and un-decoded genomes.
The development of Barrett's esophagus (BE) and its progression to esophageal adenocarcinoma (EAC) is highly linked to exposure to acidic bile salts due to chronic gastroesophageal reflux disease ...(GERD). In this study, we investigated the role of Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/REF-1) in STAT3 activation in response to acidic bile salts. Our results indicate that APE1 is constitutively overexpressed in EAC, whereas its expression is transiently induced in response to acidic bile salts in non-neoplastic BE. Using overexpression or shRNA knockdown of APE1, we found that APE1 is required for phosphorylation, nuclear localization, and transcriptional activation of STAT3. By using an APE1 redox-specific mutant (C65A) and APE1 redox inhibitor (E3330), we demonstrate that APE1 activates STAT3 in a redox-dependent manner. By using pharmacologic inhibitors and genetic knockdown systems, we found that EGFR is a required link between APE1 and STAT3. EGFR phosphorylation (Y1068) was directly associated with APE1 levels and redox function. Co-immunoprecipitation and proximity ligation assays indicated that APE1 coexists and interacts with the EGFR-STAT3 protein complex. Consistent with these findings, we demonstrated a significant induction in mRNA expression levels of STAT3 target genes (IL-6, IL-17A, BCL-xL, Survivin, and c-MYC) in BE and EAC cells, following acidic bile salts treatment. ChIP assays indicated that acidic bile salts treatment enhances binding of STAT3 to the promoter of its target genes, Survivin and BCL-xL. Inhibition of APE1/REF-1 redox activity using E3330 abrogated STAT3 DNA binding and transcriptional activity. The induction of APE1-STAT3 axis in acidic bile salts conditions provided a survival advantage and promoted cellular proliferation. In summary, our study provides multiple pieces of evidence supporting a critical role for APE1 induction in activating the EGFR-STAT3 signaling axis in response to acidic bile salts, the main risk factor for Barrett's carcinogenesis.
The lipophilic derivative of thalidomide (4-(1,3-dioxo-1,3-dihydro-2
-isoindol-2-yl)-
-(4-ethoxyphenyl)methylidenebenzohydrazide,
) was synthesized to enhance its characteristics and efficacy. ...Earlier studies have proved the immunomodulatory and anti-inflammatory effects of
. In this study the interaction between bovine serum albumin (BSA) and
was studied using a multi-spectroscopic approach which included UV spectrophotometry, spectrofluorimetry and three dimensional spectrofluorometric and molecular docking studies. Static quenching was involved in quenching the fluorescence of BSA by
, because a complex formation occurred between the
and BSA. The binding constant decreased with higher temperature and was in the range of 2.5 × 10⁵-4.8 × 10³ L mol
suggesting an unstable complex at higher temperatures. A single binding site was observed and the the site probe experiments showed site II (sub-domain IIIA) of BSA as the binding site for
. The negative values of ∆G⁰, ∆H⁰ and ∆S⁰ at (298/303/308 K) indicated spontaneous binding between
and BSA as well as the interaction was enthalpy driven and van der Waals forces and hydrogen bonding were involved in the interaction. The docking results and the results from the experimental studies are complimentary to each other and confirm that
binds at site II (sub-domain IIIA) of BSA.
•Cortical hyper-connectivity in the first year precedes overt signs of ASD seen in the second year.•fNIRS examined functional activation (FA) and connectivity (FC) in high- and low-risk ...infants.•Compared to LR infants, HR infants showed reduced right and left hemispheric FA in the social period and greater FC in the non-social period.•Early differences in cortical FA and FC may be associated with ASD risk.
Behavioral signs of Autism Spectrum Disorder (ASD) are typically observable by the second year of life and a reliable diagnosis of ASD is possible by 2 to 3 years of age. Studying infants with familial risk for ASD allows for the investigation of early signs of ASD risk within the first year. Brain abnormalities such as hyper-connectivity within the first year may precede the overt signs of ASD that emerge later in life. In this preliminary study, we use functional near-infrared spectroscopy (fNIRS), an infant-friendly neuroimaging tool that is relatively robust against motion artifacts, to examine functional activation and connectivity during naturalistic social interactions in 9 high-risk (HR; older sibling with ASD) and 6 low-risk (LR; no family history of ASD) infants from 6 to 9 months of age. We obtained two 30-second baseline periods and a 5-minute social interaction period. HR infants showed reduced right and left-hemispheric activation compared to LR infants based on oxy (HbO2) and deoxy (HHb) signal trends. HR infants also had greater functional connectivity than LR infants during the pre- and post-social periods and showed a drop in connectivity during the social period. Our findings are consistent with previous work suggesting early differences in cortical activation associated with familial risk for ASD, and highlight the promise of fNIRS in evaluating potential markers of ASD risk during naturalistic social contexts.
Trans-synaptic interactions involving Neurexins and Neuroligins are thought to promote adhesive interactions for precise alignment of the pre- and postsynaptic compartments and organize synaptic ...macromolecular complexes across species. In Drosophila, while Neurexin (Dnrx) and Neuroligins (Dnlg) are emerging as central organizing molecules at synapses, very little is known of the spectrum of proteins that might be recruited to the Dnrx/Dnlg trans-synaptic interface for organization and growth of the synapses. Using full length and truncated forms of Dnrx and Dnlg1 together with cell biological analyses and genetic interactions, we report novel functions of Dnrx and Dnlg1 in clustering of pre- and postsynaptic proteins, coordination of synaptic growth and ultrastructural organization. We show that Dnrx and Dnlg1 extracellular and intracellular regions are required for proper synaptic growth and localization of Dnlg1 and Dnrx, respectively. dnrx and dnlg1 single and double mutants display altered subcellular distribution of Discs large (Dlg), which is the homolog of mammalian post-synaptic density protein, PSD95. dnrx and dnlg1 mutants also display ultrastructural defects ranging from abnormal active zones, misformed pre- and post-synaptic areas with underdeveloped subsynaptic reticulum. Interestingly, dnrx and dnlg1 mutants have reduced levels of the Bone Morphogenetic Protein (BMP) receptor Wishful thinking (Wit), and Dnrx and Dnlg1 are required for proper localization and stability of Wit. In addition, the synaptic overgrowth phenotype resulting from the overexpression of Dnrx fails to manifest in wit mutants. Phenotypic analyses of dnrx/wit and dnlg1/wit mutants indicate that Dnrx/Dnlg1/Wit coordinate synaptic growth and architecture at the NMJ. Our findings also demonstrate that loss of Dnrx and Dnlg1 leads to decreased levels of the BMP co-receptor, Thickveins and the downstream effector phosphorylated Mad at the Neuromuscular Junction (NMJ) synapses indicating that Dnrx/Dnlg1 regulate components of the BMP signaling pathway. Together our findings reveal that Dnrx/Dnlg are at the core of a highly orchestrated process that combines adhesive and signaling mechanisms to ensure proper synaptic organization and growth during NMJ development.
•Drosophila neurexin and neuroligin 1 display genetic and biochemical interactions.•Dnrx and Dnlg1 are required for subcellular localization of Dlg at the synapse.•Dnrx and Dnlg1 are required for the localization and stability of BMP receptor Wit.•Dnrx and Dnlg1 regulate levels of BMP co-receptor Tkv and downstream effector Mad.•Proper trans-synaptic adhesion is crucial for BMP receptor stability and signaling.
Autism spectrum disorders (ASDs) are a complex neurodevelopmental disorder that display a triad of core behavioral deficits including restricted interests, often accompanied by repetitive behavior, ...deficits in language and communication, and an inability to engage in reciprocal social interactions. ASD is among the most heritable disorders but is not a simple disorder with a singular pathology and has a rather complex etiology. It is interesting to note that perturbations in synaptic growth, development, and stability underlie a variety of neuropsychiatric disorders, including ASD, schizophrenia, epilepsy, and intellectual disability. Biological characterization of an increasing repertoire of synaptic mutants in various model organisms indicates synaptic dysfunction as causal in the pathophysiology of ASD. Our understanding of the genes and genetic pathways that contribute toward the formation, stabilization, and maintenance of functional synapses coupled with an in-depth phenotypic analysis of the cellular and behavioral characteristics is therefore essential to unraveling the pathogenesis of these disorders. In this review, we discuss the genetic aspects of ASD emphasizing on the well conserved set of genes and genetic pathways implicated in this disorder, many of which contribute to synapse assembly and maintenance across species. We also review how fundamental research using animal models is providing key insights into the various facets of human ASD.
The cerebellar cortex receives neural information from other brain regions to allow fine motor coordination and motor learning. The primary output neurons from the cerebellum are the Purkinje neurons ...that transmit inhibitory responses to deep cerebellar nuclei through their myelinated axons. Altered morphological organization and electrical properties of the Purkinje axons lead to detrimental changes in locomotor activity often leading to cerebellar ataxias. Two cytoskeletal scaffolding proteins Band 4.1B (4.1B) and Whirlin (Whrn) have been previously shown to play independent roles in axonal domain organization and maintenance in myelinated axons in the spinal cord and sciatic nerves. Immunoblot analysis had indicated cerebellar expression for both 4.1B and Whrn; however, their subcellular localization and cerebellum‐specific functions have not been characterized. Using 4.1B and Whrn single and double mutant animals, we show that both proteins are expressed in common cellular compartments of the cerebellum and play cooperative roles in preservation of the integrity of Purkinje neuron myelinated axons. We demonstrate that both 4.1B and Whrn are required for the maintenance of axonal ultrastructure and health. Loss of 4.1B and Whrn leads to axonal transport defects manifested by formation of swellings containing cytoskeletal components, membranous organelles, and vesicles. Moreover, ablation of both proteins progressively affects cerebellar function with impairment in locomotor performance detected by altered gait parameters. Together, our data indicate that 4.1B and Whrn are required for maintaining proper axonal cytoskeletal organization and axonal domains, which is necessary for cerebellum‐controlled fine motor coordination.
Purkinje neurons myelinated fibers require intact axonal cytoskeletal organization and axonal transport to effectively transmit neural signals. We show that proteins Band 4.1B and Whirlin cooperatively maintain axonal cytoskeletal integrity at the paranodal and juxtaparanodal regions, and their loss leads to axonal cytoskeletal disorganization and formation of swellings leading to axonal degeneration.
Arglabin belongs to guaianolide class of sesquiterpene lactones, isolated from Artemisia species. The molecule bears a 5,7,5-tricyclic ring system having five contiguous stereo centers in which the ...two five membered rings are trans-annulated. Arglabin shows promising antitumor activity against different tumor cell lines. The antitumor activity of arglabin proceeds through its inhibition of farnesyl transferase which leads to the activation of RAS proto-oncogene, a process that is believed to play a pivotal role in 20–30% of all human tumors. It actually inhibits the incorporation of farnesyl pyrophosphate into human H-ras proteins by the enzyme farnesyl transferase (FTase). The present review is an attempt to summarize the chemistry and biology of this molecule since its isolation in 1982. It embodies the isolation, structure elucidation, stereo chemical description, structural classification, chemical synthesis, structural modifications and antitumor evaluation reported till date.
Display omitted
•Arglabin is a clinically significant and noteworthy antitumor agent.•The review summarizes the chemistry and biology of arglabin.•It embodies the isolation, synthesis and antitumor activity reported till date.
PDF
