UNASSIGNED: Abnormal anillin (ANLN) expression has been observed in multiple tumours and is closely associated with patient prognosis and clinical features. In this study, we systematically elucidated the clinical significance and biological roles of ANLN in patients with clear cell renal cell carcinoma (ccRCC).
UNASSIGNED: We obtained transcriptome and clinical data of patients with ccRCC from public databases. Multi-omics data and clinical samples were combined to analyse the correlation between ANLN expression and the clinical characteristics of patients with renal cancer. Additionally, the immune cell landscape of ANLN expression was evaluated using different immune algorithms in the tumour microenvironment. The tumour-promoting potential of ANLN was confirmed using in vitro assays, including CCK8 and Transwell assays.
UNASSIGNED: Bioinformatics analysis showed that ANLN is over-expressed in patients with ccRCC, as validated by clinical samples. Publicly available clinical data suggest that high ANLN expression may indicate poor outcomes in patients with ccRCC. Moreover, biological function analysis revealed a marked enrichment of the cell cycle and PI3K-Akt pathways. The distribution of immune cells, particularly M2 macrophages, differed in patients with ccRCC. Furthermore, ANLN silencing inhibited the proliferation, migration, and invasion of renal cancer cells in vitro. After ANLN expression was knocked down in 786-O cells, the protein levels of important PI3K signalling pathway components, including PI3K, Akt, and mTOR, drastically decreased.
UNASSIGNED: These findings suggest that ANLN is dysregulated in renal cancer tissues and promotes tumour progression by activating the PI3K/Akt/mTOR signalling pathway.

Resistance to targeted anti-cancer drugs is a complex phenomenon and a major challenge in cancer treatment. It is becoming increasingly evident that a form of acquired drug resistance known as \"adaptive resistance\" is a common cause of treatment failure and patient relapse in many cancers. Unlike classical resistance mechanisms that are acquired via genomic alterations, adaptive resistance is instead driven by non-genomic changes involving rapid and dynamic rewiring of signalling and/or transcriptional networks following therapy, enabled by complex pathway crosstalk and feedback regulation. Such network rewiring allows tumour cells to adapt to the drug treatment, circumvent the initial drug challenge and continue to survive in the presence of the drug. Despite its great clinical importance, adaptive resistance remains largely under-studied and poorly defined. This review is focused on recent findings which provide new insights into the mechanisms underlying adaptive resistance in breast cancer, highlighting how breast tumour cells rewire intracellular signalling pathways to overcome the stress of initial targeted therapy. In particular, we investigate adaptive resistance to targeted inhibition of two major oncogenic signalling axes frequently dysregulated in breast cancer, the PI3K-AKT-mTOR and RAS-MAPK signalling pathways; and discuss potential combination treatment strategies that overcome such resistance. In addition, we highlight application of quantitative and computational modelling as a novel integrative and powerful approach to gain network-level understanding of network rewiring, and rationally identify and prioritise effective drug combinations.

OBJECTIVE: Poly (ADP-ribose) polymerase- (PARP)-1 is predominantly triggered by DNA damage. Overexpression of PARP-1 is known for its association with the pathogenesis of several CNS disorders, such as Stroke, Parkinson\'s disease (PD), Alzheimer\'s disease (AD), Huntington (HD) and Amyotrophic lateral sclerosis (ALS). NAD+ depletion resulted PARP related cell death only happened when the trial used extreme high oxidization treatment. Inhibition of PARP1/2 may induce replication related cell death due to un-repaired DNA damage. This review has discussed PARP-1 modulated downstream pathways in neurodegeneration and various FDA approved PARP-1 inhibitors.
METHODS: A systematic literature review of PubMed, Medline, Bentham, Scopus and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on mechanistic role of Poly (ADP-ribose) polymerase and its inhibition in Neurodegenerative diseases.
RESULTS: Several researchers have put forward number of potential treatments, of which PARP-1 enzyme has been regarded as a potent target intended for the handling of neurodegenerative ailments. Targeting PARP using its chemical inhibitors in various neurodegenerative may have therapeutic outcomes by reducing neuronal death mediated by PARPi. Numerous PARP-1 inhibitors have been studied in neurodegenerative diseases but they haven\'t been clinically evaluated.
CONCLUSIONS: In this review, the pathological role of PARP-1 in various neurodegenerative diseases has been discussed along with the therapeutic role of PARP-1 inhibitors in various neurodegenerative diseases.

IR and insulin-like growth factor-1 receptor (IGF-1R) share high degree of sequence and structural similarity that hinders the development of anticancer drugs targeting IGF1R, which is dysregulated in many cancers. Although IR and IGF1R mediate their activities through similar signalling pathways, yet they show different physiological effects. The exact molecular mechanism(s) how IR and IGF1R exert their distinct functions remain largely unknown. Here, we performed in silico analysis and generated GFP-fusion proteins of wild type IR and its K1079R mutant to analyze their subcellular localization, cytoplasmic and nuclear activities in comparison to IGF1R and its K1055R mutant. We showed that, like K1055R mutation in IGF1R, K1079R mutation does not impede the subcellular localization and nuclear activities of IR. Although K1079R mutation significantly decreases the kinase activity of IR but not as much as K1055R mutation, which was seen to drastically reduce the kinase activity of IGF1R. Moreover, K1079 residue in IR is seen to be sitting in a pocket which is different than the allosteric inhibitor binding pocket present in its homologue (IGF1R). This is for the first time such a study has been conducted to identify structural differences between these receptors that could be exploited for designing small molecule allosteric inhibitor(s) of IGF1R as novel anti-cancer drugs.

Allergic diseases are increasing worldwide. Allergen and IgE dependent mast cell (MC) activation is the major initiator of these clinical symptoms. During this study, the effect of multiple exposures to the same allergen, on MC degranulation was studied. First, MC recovery in terms of surface expression of high affinity receptor FcεRI, and granule content after a primary allergen challenge was confirmed. Overall, previous exposure of MCs to allergen challenge led to a significant reduction in pre-stored mediator release during the secondary challenge at various time points and with various doses of allergen in vitro. The dampened response was not due to any defects in very early steps in signalling involving FcεRI activation. Inhibition of dampening response during secondary challenge by various inhibitors like wortmannin, tranylcypromine and pargyline, indicated the involvement of PI3K signalling and chromatin modifications. Our study provides insight into new therapeutic avenues for treating allergic disorders targeting MCs.

OBJECTIVE: Phosphatidylinositol-3 kinases (PI3Ks) are involved in regulating cell growth, proliferation, differentiation, apoptosis and survival. p110α and p110β, two ubiquitously expressed isoforms of PI3K signalling, are involved in growth factor mediated signaling and survival by generating second messengers. Earlier, we have generated GFP-fusion proteins of p110α and p110β and expressed them in normal and cancer cell-lines to investigate their subcellular localization and their role in various activities. Here, we sought to examine the role of p110α and p110β isoforms in protecting MCF-7 breast cancer cells against oxidative stress.
UNASSIGNED: We performed cytotoxicity assays, DNA transfection, Plasmid DNA preparation, western blotting, flourscence microscopy and statistical analysis.
RESULTS: To know whether p110α and p110β are involved in protecting MCF-7 breast cancer cells against oxidative stress, we subjected MCF-7 cells to H2O2 treatment and observed a dose dependent decrease in cell viability and a marked increase in the levels of pro-apoptotic markers which include PARP, Bcl-2, Bax and procaspase-9. We then over-expressed recombinant GFP-fusion p110α and p110β proteins in MCF-7 cells and observed a significant decrease in apoptosis and a concomitant increase in pAkt levels.
CONCLUSIONS: We report the involvement of p110α and p110β isoforms of Class 1A PI3K signalling in rescue from oxidative stress-induced apoptosis in MCF-7 cells in Akt dependent manner.

Glycans are inherently heterogeneous, yet glycosylation is essential in eukaryotes, and glycans show characteristic cell type-dependent distributions. By using an immortalized human mesenchymal stromal cell (MSC) line model, we show that both N- and O-glycan processing in the Golgi functionally modulates early steps of osteogenic differentiation. We found that inhibiting O-glycan processing in the Golgi prior to the start of osteogenesis inhibited the mineralization capacity of the formed osteoblasts 3 weeks later. In contrast, inhibition of N-glycan processing in MSCs altered differentiation to enhance the mineralization capacity of the osteoblasts. The effect of N-glycans on MSC differentiation was mediated by the phosphoinositide-3-kinase (PI3K)/Akt pathway owing to reduced Akt phosphorylation. Interestingly, by inhibiting PI3K during the first 2 days of osteogenesis, we were able to phenocopy the effect of inhibiting N-glycan processing. Thus, glycan processing provides another layer of regulation that can modulate the functional outcome of differentiation. Glycan processing can thereby offer a novel set of targets for many therapeutically attractive processes.

Induction of apoptotic programmed cell death is one of the underlying principles of most current cancer therapies. In this review, we discuss the limitations and drawbacks of this approach and identify three distinct, but overlapping strategies to avoid these difficulties and further enhance the efficacy of apoptosis-inducing therapies. We postulate that the application of multi-targeted small molecule inhibitor cocktails will reduce the risk of the cancer cell populations developing resistance towards therapy. Following from these considerations regarding population genetics and ecology, we advocate the reconsideration of therapeutic end points to maximise the benefits, in terms of quantity and quality of life, for the patients. Finally, combining both previous points, we also suggest an altered focus on the cellular and molecular targets of therapy, i.e. targeting the (cancer cells\') interaction with the tumour microenvironment.

Androgen receptor (AR) signalling and the PI3K pathway mediate survival signals in prostate cancer, and have been shown to regulate each other by reciprocal negative feedback, such that inhibition of one activates the other. Understanding the reciprocal regulation of these pathways is important for disease management as tumour cells can adapt and survive when either single pathway is inhibited pharmacologically. We recently carried out genome-wide exon-specific profiling of prostate cancer cells to identify novel androgen-regulated transcriptional events. Here we interrogated this dataset for novel androgen-regulated genes associated with the PI3K pathway. We find that the PI3K regulatory subunits PIK3R1 (p85α) and PIK3R3 (p55γ) are direct targets of the AR which are rapidly repressed by androgens in LNCaP cells. Further characterisation revealed that the PIK3CA p110α catalytic subunit is also indirectly regulated by androgens at the protein level. We show that PIK3R1 mRNA is significantly under-expressed in prostate cancer (PCa) tissue, and provide data to suggest a context-dependent regulatory mechanism whereby repression of the p85α protein by the AR results in destabilisation of the PI3K p110α catalytic subunit and downstream PI3K pathway inhibition that functionally affects the properties of prostate cancer cells.

Insulin resistance (IR) in skeletal muscle is an important component of both type 2 diabetes and the syndrome of sarcopaenic obesity, for which there are no effective therapies. Urocortins (UCNs) are not only well established as neuropeptides but also have their roles in metabolism in peripheral tissues. We have shown recently that global overexpression of UCN3 resulted in muscular hypertrophy and resistance to the adverse metabolic effects of a high-fat diet. Herein, we aimed to establish whether short-term local UCN3 expression could enhance glucose disposal and insulin signalling in skeletal muscle. UCN3 was found to be expressed in right tibialis cranialis and extensor digitorum longus muscles of rats by in vivo electrotransfer and the effects studied vs the contralateral muscles after 1 week. No increase in muscle mass was detected, but test muscles showed 19% larger muscle fibre diameter (P=0.030), associated with increased IGF1 and IGF1 receptor mRNA and increased SER256 phosphorylation of forkhead transcription factor. Glucose clearance into the test muscles after an intraperitoneal glucose load was increased by 23% (P=0.018) per unit mass, associated with increased GLUT1 (34% increase; P=0.026) and GLUT4 (48% increase; P=0.0009) proteins, and significantly increased phosphorylation of insulin receptor substrate-1, AKT, AKT substrate of 160 kDa, glycogen synthase kinase-3β, AMP-activated protein kinase and its substrate acetyl coA carboxylase. Thus, UCN3 expression enhances glucose disposal and signalling in muscle by an autocrine/paracrine mechanism that is separate from its pro-hypertrophic effects, implying that such a manipulation may have promised for the treatment of IR syndromes including sarcopaenic obesity.