Unraveling the signaling mechanism behind astrocytoma and possible therapeutics strategies: A comprehensive review.

BACKGROUND: A form of cancer called astrocytoma can develop in the brain or spinal cord and sometimes causes death. A detailed overview of the precise signaling cascade underlying astrocytoma formation has not yet been revealed, although various factors have been investigated. Therefore, our objective was to unravel and summarize our current understanding of molecular genetics and associated signaling pathways with some possible therapeutic strategies for astrocytoma. RECENT FINDINGS: In general, four different forms of astrocytoma have been identified in individuals, including circumscribed, diffuse, anaplastic, and multiforme glioblastoma, according to a recent literature review. All types of astrocytoma have a direct connection with some oncogenic signaling cascade. Common signaling is MAPK cascade, including Ras-Raf-ERK, up-regulated with activating EGFR/AKT/PTEN/mTOR and PDGFR. Recent breakthrough studies found that BRAF mutations, including KIAA1549: BRAF and BRAF V600E are responsible for astrocytoma progression. Additionally, cancer progression is influenced by mutations in some tumor suppressor genes, such as the Tp53/ATRX and MGMT mutant. As synthetic medications must cross the blood-brain barrier (BBB), modulating signal systems such as miRNA is the primary option for treating patients with astrocytoma. However, available surgery, radiation therapy, and experimental therapies such as adjuvant therapy, anti-angiogenic therapy, and EGFR-targeting antibody drug are the usual treatment for most types of astrocytoma. Similar to conventional anticancer medications, some phytochemicals slow tumor growth by simultaneously controlling several cellular proteins, including those involved in cell cycle regulation, apoptosis, metastatic spread, tyrosine kinase, growth factor receptor, and antioxidant-related proteins. CONCLUSION: In conclusion, cellular and molecular signaling is directly associated with the development of astrocytoma, and a combination of conventional and alternative therapies can improve the malignancy of cancer patients.

Application of soil amendments mitigates phytotoxic effects on Solanum melongena L. and Lycopersicon esculentum L. seedlings exposed to chlorpyrifos and dimethoate pesticides.

This field study was done to study the effects of pesticides chlorpyrifos and dimethoate singly and in combination with soil amendments like chemical fertilizer (CF), farmyard manure (FM), and 50% CF + 50% FM (CM) on various indices of growth, physio-biochemical parameters of brinjal, and their residual effect in tomato seedlings. As compared to the control, the decrease of 9.5 and 5.5%, 8.9 and 5.0% in fresh weight, dry weight respectively was recorded in the pesticide-only treatment in the brinjal crop. Pesticides when applied in combination with soil amendments depicted the highest growth of 105.4 and 118.2%, 104.1 and 115.1% in pesticides + CF treatment, 72.7 and 85.1%, 68.1 and 78.1% in pesticides + CM treatment, and 64.4 and 74.0%, 62.7 and 65.7% in pesticides + FM treatment compared to control. In tomato seedlings, the pesticides + CF treatment exhibited the lowest growth indices (25.5 and 31.9%, 26.4 and 28.8%) across the combined treatments while pesticide-only treatment depicted minimum growth compared to the control. In the case of photosynthesis rate and antioxidant activity, the combined treatments showed the trend as pesticides + CF > pesticides + CM > pesticides + FM in the brinjal crop; however, the trend became somewhat reversed in the tomato crop. The results indicated that soil-amended practices modulated pesticide-induced damage by upregulating photosynthetic performance, chlorophyll a fluorescence, and antioxidant balancing which might be associated with the mitigation of ROS-induced pesticide toxicity, and the effect was more pronounced with CM. Furthermore, our study was supported by non-metric-multidimensional scaling (NMDS)-constructed ordination plots by showing spatial patterns in different variables. The study might help in taking management decision to design mitigation actions for government and non-government agency at the farmers' level.

Chick chorioallantoic membrane: a valuable 3D in vivo model for screening nanoformulations for tumor antiangiogenic therapeutics.

Drug discovery is an extensive process. From identifying lead compounds to approval for clinical application, it goes through a sequence of labor-intensive in vitro, in vivo preclinical screening and clinical trials. Among thousands of drugs screened only a few get approval for clinical trials. Furthermore, these approved drugs are often discontinued due to systemic toxicity and comorbidity at clinically administered dosages. To overcome these limitations, nanoformulations have emerged as the most sought-after strategy to safely and effectively deliver drugs within tumors at therapeutic concentrations. Most importantly, the employment of suitably variable preclinical models is considered highly critical for the therapeutic evaluation of candidate drugs or their formulations. A review of literature from the past 10 years on antiangiogenic nanoformulations shows the employment of limited types of preclinical models mainly the 2-dimensional (2D) monolayer cell culture and murine models as the mainstay for drug uptake, toxicity and efficiency studies. To top it all, murine models are highly expensive, time-consuming and require expertise in handling them. The current review highlights the utilization of the age-old chicken chorioallantoic membrane (CAM), a well-defined angiogenic model in the investigation of antiangiogenic compounds and nanoformulations in an economic framework. For practical applicability, we have evaluated the CAM model to demonstrate the screening of antiangiogenic compounds and that tumor cells can be implanted onto developing CAM for growing xenografts by recruiting host endothelial and other cellular components. In addition, the exploitation of CAM tumor xenograft models for the evaluation of nanoparticle distribution has also been reinforced by demonstrating that intravenously administered iron oxide nanoparticles (IONPs) passively accumulate and exhibit intracellular as well as extracellular compartment accumulation in highly vascular xenografts. Finally, the ethical considerations, benefits, and drawbacks, of using CAM as an experimental model for testing potential therapeutics are also highlighted.

Plant metabolite diosmin as the therapeutic agent in human diseases.

Plant-derived flavonoids have been the focus of research for many years mainly in the last decade owing to their therapeutic properties. So far, about 4000 flavonoids have been identified from plants and diosmin (a flavone glycoside) is one of them. Online databases, previous studies, and reviews have been used to gather information on anti-oxidant, immunomodulatory, anti-cancer, anti-parasitic, and anti-microbialproperties of diosmin. Effects of diosmin in combination with other flavonoids have been reviewed thoroughly and its administrative routes are also summarized. Additionally, we studied the effect of diosmin on critical protein networks. It exhibits therapeutic effects in diabetes and its associated complications such as neuropathy and dyslipidemia. Combination of diosmin with hesperidin is found to be very effective in the treatment of chronic venous insufficiency and haemorrhoids. Diosmin is an exquisite therapeutic agent alone as well as in combination with other flavonoids.

FOXO3 gene hypermethylation and its marked downregulation in breast cancer cases: A study on female patients.

Background: FOXO3, a member of the FOX transcription factor family, is frequently described as being deregulated in cancer. Additionally, notable role of FOXO3 can be easily recognized in the process of ageing and survival. Even though various studies have been done to acknowledge the tumour-suppressive or oncogenic role of FOXO3 in cancer, still there exist a lack of understanding in terms of cancer prognosis and treatment. Therefore, to provide better insight, our study aims to evaluate the role and function of FOXO3 in breast cancer in Indian female patients. We examined the FOXO3 expression levels in breast cancer samples by analyzing mRNA and protein expression along with its clinicopathological parameters. Results: A total of 127 cases of breast cancer with equal normal cases (n=127) were assessed with methylation (MS-PCR), Immunohistochemistry (IHC), mRNA expression using Real-time PCR was analysed and 66.14% cases at mRNA level were found to be downregulated, while 81.10% of cases had little or very little protein expression. Our data state, the promoter hypermethylation of the FOXO3 gene and the downregulated protein expression are significantly correlated (p=0.0004). Additionally, we found a significant correlation between the level of FOXO3 mRNA with ER (p=0.04) and status of lymph node (p=0.01) along with this. Conclusion: Data suggests the prognostic significance and the tumour-suppressive role of FOXO3 in breast cancer cases studied in India. However, there is a need for the extended research targeting FOXO3 to measure its clinical potential and develop well-defined therapeutic strategies.

Bulbine frutescens phytochemical inhibits notch signaling pathway and induces apoptosis in triple negative and luminal breast cancer cells.

Breast cancer (BCa) is the most commonly diagnosed lethal cancer in women worldwide. Notch signaling pathway is directly linked to BCa recurrence and aggressiveness. Natural remedies are becoming a prime choice to overcome against cancer due to lesser side effect and cost-effectiveness. Bulbine frutescens (Asphodelaceae), a traditional medicinal plant in South Africa possess bioactive flavonoids and terpenoids. Polar (methanol) and non-polar (hexane) B. frutescens plant extracts were prepared. GC-MS analysis revealed the differential presence of secondary metabolites in both methanolic and hexane extracts. We hereby first time evaluated the anticancer potential of B. frutescens methanolic and hexane extract in triple-negative and luminal BCa cells. B. frutescens extracts significantly decreased cell viability (IC50 4.8-28.4 µg/ml) and induced cell cycle arrest at G1 phase in MDA-MB-231 and T47D cells as confirmed by spectrophotometry and flow cytometry technique. RT-PCR analysis of cell cycle (cyclin D1, CDK4, and p21) and apoptosis modulating genes (caspase 3, Bcl2 and survivin) revealed upexpression of p21, and caspase 3, and down expression of cyclin D1, CDK4, Bcl2 and survivin genes in extract-treated BCa cells. Fluorescence spectrophotometry and confocal microscopy showed B. frutescens induced nuclear morphology and mitochondrial integrity disruption, and increased reactive oxygen species production in MDA-MB-231 and T47D cells. Flow cytometric apoptosis analysis of B. frutescens extracts treated MDA-MB-231 cells showed ≈13% increase in early apoptotic population in comparison to non-treated cells. Dual-Luciferase Reporter assay confirmed notch promoter inhibitory activity of B. frutescens extracts. Moreover, RTPCR analysis showed down regulation of notch responsive genes (Hes1 and Hey1) at transcription levels in extract-treated BCa cells. Western Blot analysis showed increased procaspase 3 protein expression in extract-treated BCa cells. In all the assays methanolic extract showed better anti-cancer properties. Literature-based identification of methanol soluble phytochemicals in B. frutescens and in silico docking study revealed Bulbineloneside D as a potent ϒ-secretase enzyme inhibitor. In comparison to standard notch inhibitor, lead phytochemical showed two additional hydrophobic interactions with Ala80 and Leu81 amino acids. In conclusion, B. frutescens phytochemicals have cell cycle arrest, ROS production, apoptosis induction, and mitochondria membrane potential disruption efficacy in breast cancer cells. B. frutescens phytochemicals have the ability to downregulate the notch signaling pathway in triple-negative and luminal breast cancer cells.

Modulation of immune response and protective efficacy of recombinant outer-membrane protein F (rOmpF) of Aeromonas hydrophila in Labeo rohita.

The outer-membrane proteins (OMPs) of Aeromonas hydrophila, an imperative fish pathogen accountable for massive economic losses to aquaculture industry, are found to be immunogenic and considered as potential vaccine candidates. In spite of development in the formulation of vaccine candidates against Aeromonas infection, no commercial preparation has been done so far; in addition, the molecular mechanisms of immunoprotection induced by various vaccine formulations in Indian major carp, Labeo rohita, are little known. The present study was undertaken to evaluate the modulation of immunity and expression of immune-related genes post-rOmpF (recombinant outer-membrane protein of A. hydrophila, a novel vaccine candidate) immunization and protective efficacy after A. hydrophila challenge. The rOmpF-immunized fish showed a variable expression of the immune-related genes, viz. toll-like receptor 22 (TLR), complement component 3 (C3), chemokine (CXCa), tumor necrosis factor-α (TNFα), interleukin 1ß (IL-1ß), manganese superoxide dismutase (MnSOD) and natural killer enhancing factor (NKEF) in the head kidney tissues, when compared to the control group at different time intervals post-vaccination. A significant increase in serum hemolysin titer, ceruloplasmin level and myeloperoxidase activity was observed on day 140 post immunization. Also, bacterial agglutination titer and antiprotease activity were significantly increased on day 42 post immunization. No significant change was observed in lysozyme activity. Challenge studies with live A. hydrophila on day 140 post-immunization of L. rohita significantly increased the relative percentage survival (∼44%) in the vaccinated group. The results suggest that the rOmpF could be used as a potential vaccine candidate to combat A. hydrophila infection in fish.

Hypermethylated LATS2 gene with decreased expression in female breast cancer: A case control study from North India.

BACKGROUND: LATS2, a presumed tumor suppressor gene located on chromosome 13q11-12 is involved in cell growth related activity like regulation of cell cycle at G1/S. The reduced expression of LATS2 has been reported in many tumors; including tumors of Breast, which is to the best of our knowledge has not been studied in north Indian female breast cancer population. OBJECTIVE: Here, we looked upon the expression pattern and methylation status of the LATS2 gene in north Indian female breast cancer cases to further strengthen its role as a tumor suppressor gene and more importantly as a cancer biomarker. METHODS: mRNA expression level was determined by real time PCR in 140 Breast cancer patients, Protein expression was studied by Immunohistochemistry and Promoter methylation was studied by Methylation specific PCR. All findings were correlated with clinicopathological features. RESULTS: LATS2 mRNA expression was remarkably downregulated in 67.85% (95/140) cases. The expression of Large Associated Tumor Suppressor 2 at protein level was also absent in 67.85% (95/140) cases. The absence of LATS2 protein strongly correlated with promoter hypermethylation where 91 out of a total of 107 hyper methylated cases showed absence of protein (91/107, 85%). The absence of LATS2 protein was strongly significant with HER2 neu status (0.01), TNM staging (0.009) and Molecular subtype (0.024). CONCLUSION: The decreased expression in breast cancer seems to be associated with hypermethylation of LATS2 promoter regions. Further LATS2 as a tumor suppressor can be recognized as a promising Biomarker in Breast cancer pathogenesis. Though, further studies, targeting larger sets of breast cancer population are required to establish LATS2 as a promising biomarker.

In vitro PHYTOTHERAPY OF VECTOR SNAILS BY BINARY COMBINATIONS OF LARVICIDAL ACTIVE COMPONENTS IN EFFECTIVE CONTROL OF FASCIOLIASIS / Fitoterapia in vitro de caramujos vetores por combinações binárias de componentes ativos larvicidas como controle efetivo de fasciolíase

SUMMARY A food-borne trematode infection fascioliasis is one among common public health problems worldwide. It caused a great economic loss for the human race. Control of snail population below a certain threshold level is one of the important methods in the campaign to reduce the incidence of fascioliasis. The life cycle of the parasite can be interrupted by killing the snail or Fasciola larva redia and cercaria inside of the snail Lymnaea acuminata. In vitro toxicity of different binary combinations (1:1 ratio) of plant-derived larvicidal active components such as citral, ferulic acid, umbelliferone, azadirachtin and allicin against Fasciola redia and cercaria were tested. The mortality of larvae was observed at 2h, 4h, 6h and 8h of treatment. In in vitro condition azadirachtin + allicin (1:1 ratio) was highly toxic against redia and cercaria (8h LC50 0.006 and 0.005 mg/L). Toxicity of citral + ferulic acid was lowest against redia and cercaria larvae. .

RESUMO A infecção alimentar pelo trematóide da fasciolíase é uma dentre os mais comuns problemas de saúde pública mundiais, causando grande prejuízo econômico para a humanidade. Controle da população de caramujos abaixo de determinado nível é um dos métodos no campo mais importantes para a redução da incidência da fasciolíase. O ciclo de vida do parasita pode ser interrompido pela morte do caramujo ou da larva redia e cercária da Fasciola dentro da Lymnaea acuminata. Foi testada a toxicidade in vitro das diferentes combinações binárias (relação 1:1) entre os vários componentes larvicidas ativos da planta tais como citral, ácido ferúlico, umbeliferone, azadiractina, e alicina contra a Fasciola redia e a cercária. A mortalidade das larvas foi observada após duas, quatro, seis e oito horas de tratamento. A condição in vitro azadiractina + alicina (relação 1:1) foi altamente tóxica contra redia e cercária (8h LC50 0,006 e 0,005 mg/L). Toxicidade do citral + ácido ferúlico foi a mais baixa contra redia e larvas de cercária. .