RESUMO
Signal transducers and activators of transcription or STAT are proteins that consist of various transcription factors that are responsible for activating genes regarding cell proliferation, differentiation, and apoptosis. They commonly activate several cytokine, growth, or hormone factors via the JAK-STAT signaling pathway by tyrosine phosphorylation which are responsible for giving rise to numerous immune responses. Mutations within the Janus-Kinases (JAKs) or the STATs can set off the commencement of various malfunctions of the immune system of the body; carcinogenesis being an inevitable outcome. STATs are known to act as both oncogenes and tumor suppressor genes which makes it a hot topic of investigation. Various STATs related mechanisms are currently being investigated to analyze its potential of serving as a therapeutic base for numerous immune diseases and cancer; a deeper understanding of the molecular mechanisms involved in the signaling pathways can contribute to the same. This review will throw light upon each STAT member in causing cancer malignancies by affecting subsequent signaling pathways and its genetic and epigenetic associations as well as various inhibitors that could be used to target these pathways thereby devising new treatment options. The review will also focus upon the therapeutic advances made in cancers that most commonly affect people and discuss how STAT genes are identified as prognostic markers.
Assuntos
Neoplasias , Proteínas Tirosina Quinases , Humanos , Proteínas Tirosina Quinases/metabolismo , Transativadores/genética , Transativadores/metabolismo , Proteínas de Ligação a DNA , Prognóstico , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Diospyros malabarica is an ethnomedicinal plant with hypoglycaemic, anti-bacterial, and anti-cancer properties and it belongs to the Ebenaceae family which is well known for its medicinal uses since ancient times and application of its bark and unripened fruit has been significantly mentioned in Ayurvedic texts. The Diospyros malabarica species which is known as the Gaub in Hindi and Indian Persimmon in English is native to India, however, it is distributed throughout the tropics. AIM OF THE STUDY: As Diospyros malabarica fruit preparation (DFP) possesses medicinal values, the study aims to evaluate its role as natural, non-toxic, and cost-effective dendritic cells (DCs) maturing immunomodulatory agent and also as an epigenetic regulator to combat Non-small cell lung cancer (NSCLC) which is a type of lung cancer whose treatment options such as chemotherapy, radiation therapy, etc. are accompanied with some adverse side effects. Thus, immunotherapeutic strategies are in high demand to evoke tumor protective immunity against NSCLC without causing such side effects. MATERIALS AND METHODS: Peripheral Mononuclear Cells (PBMCs) derived monocytes of normal subjects and NSCLC patients were utilized to generate DCs matured with either LPS (LPSDC) or DFP (DFPDC). Mixed Lymphocyte Reaction (MLR) was carried out with the differentially matured DCs co-culturing T cells and cytotoxicity of lung cancer cells (A549) was measured through LDH release assay and cytokine profiling was carried out via ELISA respectively. PBMCs of normal subjects and NSCLC patients have transfected separately in vitrowith CRISPR-activation plasmid of p53 and CRISPR-Cas9 knockout plasmid of c-Myc to analyze epigenetic mechanism(s) in the presence and absence of DFP. RESULTS: Diospyros malabarica fruit preparation (DFP) treated DC upregulates the secretion of T helper (TH)1 cell specific cytokines (IFN-γ and IL-12) and signal transducer and activator of transcription molecules (STAT1 and STAT4). Furthermore, it also downregulates the secretion of TH2-specific cytokines (IL-4 and IL-10). Diospyros malabarica fruit preparation (DFP) enhances p53 expression by reducing methylation levels at the CpG island of the promoter region. Upon c-Myc knockout, epigenetic markers such as H3K4Me3, p53, H3K14Ac, BRCA1, and WASp were enhanced whereas H3K27Me3, JMJD3, and NOTCH1 were downregulated. CONCLUSION: Diospyros malabarica fruit preparation (DFP) not only increases the expression of type 1 specific cytokines but also augments tumor suppression modulating various epigenetic markers to evoke tumor protective immunity without any toxic activities.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Diospyros , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Diospyros/metabolismo , Epigênese Genética , Frutas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Células Dendríticas , Citocinas/metabolismo , ImunoterapiaRESUMO
AIMS: To summarize the evidence on the efficacy and safety of neural stem cell therapy (NSCT) for the treatment of spinal cord injury (SCI). METHODS: A systematic literature review of Medline®, EMBASE® and Cochrane library was performed to identify studies reporting efficacy and safety of NSCT in SCI. Articles were included if they reported efficacy and safety data of SCI patients who received NSCT. RESULTS: Overall, four studies of the 277 records met all the study eligibility criteria. Over the 1-year follow-up period, motor scores were significantly higher among patients who received NSCT compared with those who did not (American Spinal Injury Association [ASIA] motor scores (mean±standard deviation [SD]): 7.9±1.2 versus 3.9±0.6; upper extremity motor score: 7.8±2.1 versus 3.9±0.6, both P<0.05). Sensory scores (pinprick score: 4.8±1.3 versus 2.9±0.6; P=0.5; light touch score: 6.9±3.1 versus 2.3±0.5, P=0.3), ASIA impairment scale (26% versus 7%) or pain score (baseline: 2.4±0.6; 1-year: 3.4±0.4) were comparable in both NSCT and non-NSCT cohorts. Over the 1-year follow-up period, the graded redefined assessment of strength, sensibility, and prehension and international standards for neurological classification of SCI scores showed a mean improvement of 14.8 and 17.8 points respectively. Overall, treatment with NSCT showed favorable safety and tolerability profile. CONCLUSIONS: Due to the limited and poor-quality evidence, it is too early to make robust conclusions on the efficacy of NSCT in the treatment of SCI. However, based on the included studies, NSCT seems to be a potential option worth exploring among patients with SCI. Nonetheless, prospective, randomized trials in larger cohorts are needed to validate the efficacy and safety of NSCT in the treatment of SCI.