Therapeutic Implications of Targeting AKT Signaling in Melanoma

Identification of key enzymes regulating melanoma progression and drug resistance has the potential to lead to the development of novel, more effective targeted agents for inhibiting this deadly form of skin cancer. The Akt3, also known as protein kinase B gamma, pathway enzymes regulate diverse cellular processes including proliferation, survival, and invasion thereby promoting the development of melanoma. Accumulating preclinical evidence demonstrates that therapeutic agents targeting these kinases alone or in combination with other pathway members could be effective for the long-term treatment of advanced-stage disease. However, currently, no selective and effective therapeutic agent targeting these kinases has been identified for clinical use. This paper provides an overview of the key enzymes of the PI3K pathway with emphasis placed on Akt3 and the negative regulator of this kinase called PTEN (phosphatase and tensin homolog deleted on chromosome 10). Mechanisms regulating these enzymes, their substrates and therapeutic implications of targeting these proteins to treat melanoma are also discussed. Finally, key issues that remain to be answered and future directions for interested researchers pertaining to this signaling cascade are highlighted

A comparative evaluation of Advanced Platelet-Rich Fibrin (A-PRF) and Platelet-Rich Fibrin (PRF) as a Scaffold in Regenerative Endodontic Treatment of Traumatized Immature Non-vital permanent anterior teeth : a prospective clinical study

Regenerative endodontic treatment (RET) is a promising treatment alternative for traumatized immature non-vital teeth. Advanced platelet-rich fibrin (A-PRF) contains significantly more growth factors than Platelet-rich fibrin (PRF) and has not been evalu

Evaluation of anti-tumor activity of ethanolic extract of Glycyrrhiza glabra against Ehrlich ascites carcinoma in swiss albino mice

Background: Cancer is one of the most life threatening diseases which is in need of newer drug development. The use of plant products with potent antioxidant and cytotoxic activity is upcoming Studies reveal that herbal product have increased efficacy as well as decreased side effects, with this in mind the present study was undertaken to assess the antitumor activity of extracts of Glycyrrhiza glabra (GG) against ehrlich ascites carcinoma in swiss albino mice.Methods: The extracts of roots of GG was collected and acute toxicity study was done following which the antitumor effect of extracts of GG was assessed by change in the body weight, mean survival time (MST), and percentage increased life span (% ILS). MST of each group containing six mice was monitored by recording the mortality daily for 6 weeks and % ILS was calculated. The hematological parameters and biochemical assays were also measured.Results: Extracts of GG showed a significant reduction in % increase in tumor induced body weight of the mice. The % increase in life span was also significant in the higher dose of GG (500 mg/kg). The combination of GG with standard drug cisplatin had better efficacy in terms of % ILS, hematological and biochemical parameters. The results obtained were statistically significant.Conclusions: The antitumor activity studies measuring the viability of cancer cells when exposed to the ethanolic extract of Glycyrrhiza glabra showed a potent cell-killing effect, indicating the presence of anti-cancer principles in the preparation

THE ANTI-PROLIFERATIVE AND ANTIOXIDANT ACTIVITY OF FOUR INDIGENOUS SOUTH AFRICAN PLANTS.

Background: Cancer is a major cause of death worldwide. Limitations of current cancer therapies necessitate the search for new anticancer drugs. Plants represent an immeasurable source of bioactive compounds for drug discovery. The objective of this study was to assess the anti-proliferative and antioxidant potential of four indigenous South African plants commonly used in traditional medicine. Materials and Methods: The anti-proliferative activity of the plant extracts were assessed by the 2,3-Bis-(2-Methoxy-4- Nitro-5-Sulfophenyl)-2H-Tetrazolium-5-Carboxanilide (XTT) assay on A431; HaCat; HeLa; MCF-7 and UCT-Mel 1 cells and sulforhodamine-B (SRB) assay on HCT-116 and HCT-15 cell lines. Antioxidant activity was determined using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and superoxide scavenging assays. Results: Three of the plant extracts (Combretum mollefruit, Euclea crispa subsp. crispa leaves and stems and Sideroxylon inerme leaves and stems showed anti-proliferative activity on the A431 cells with IC50values ranging between 26.9 - 46.7 μg/ml. The Euclea crispa subsp. crispa extract also showed anti-proliferative activity on the MCF-7 cell line (45.7 μg/ml). All of the plant extracts (Combretum molle leaves and fruit, Euclea crispa subsp. crispa leaves and stems, Sideroxylon inerme leaves and stems and Terminalia prunioides leaves and stems) showed DPPH scavenging activity with IC50 values ranging from 1.8 μg/ml to 11.5 μg/ml. Conclusion: These results indicate that the active extracts of Combretum molle, Euclea crispa subsp. Crispa and Sideroxylon inerme warrants further investigation to determine the mechanism of anti-proliferative activity against cancerous cells. These plant extracts also show potential for further evaluation in the prevention and treatment of cancer

Treatment With Naringenin Elevates the Activity of Transcription Factor Nrf2 to Protect Pancreatic β-Cells From Streptozotocin-Induced Diabetes in vitro and in vivo

Chronic hyperglycemia and unusually high oxidative stress are the key contributors for diabetes in humans. Since nuclear factor E2-related factor 2 (Nrf2) controls the expression of antioxidant- and detoxification genes, it is hypothesized that targeted activation of Nrf2 using phytochemicals is likely to protect pancreatic β-cells, from oxidative damage, thereby mitigates the complications of diabetes. Naringenin is one such activator of Nrf2. However, it is currently not known whether the protective effect of naringenin against streptozotocin (STZ) induced damage is mediated by Nrf2 activation. Hence, the potential of naringenin to activate Nrf2 and protect pancreatic β-cells from STZ-induced damage in MIN6 cells is studied. In MIN6 cells, naringenin could activate Nrf2 and its target genes GST and NQO1, thereby inhibit cellular apoptosis. In animals, administration of 50 mg/kg body weight naringenin, for 45 days, significantly decreased STZ-induced blood glucose levels, normalized the lipid profile, and augmented the levels of antioxidants in pancreatic tissues. Immunohistochemical analysis measuring the number of insulin-positive cells in pancreas showed restoration of insulin expression similar to control animals. Furthermore, naringenin promoted glycolysis while inhibiting gluconeogenesis. In conclusion, naringenin could be a good anti-diabetic agent, which works by promoting Nrf2 levels and by decreasing cellular oxidative stress

Quercetin activates vitamin D receptor and ameliorates breast cancer induced hepatic inflammation and fibrosis

AimsTo explore the hepatoprotective role of quercetin and its novel molecular mechanism of action on breast cancer associated hepatic inflammation and fibrosis via Vitamin D receptor (VDR).Main methodsWe used Ehrlich Ascites Carcinoma (mouse mammary carcinoma) model for our in-vivo experiments and human breast cancer cell lines for in-vitro assays. We inoculated 1.5 × 106 Ehrlich ascites carcinoma cells into female Swiss albino mice. Quercetin (50 mg/kg) was administered intraperitoneally for 15 days. Liver enzymes activity was determined using a spectrophotometric assay. The hallmarks of inflammation and fibrosis were determined using Immunohistochemistry. The effect of quercetin on tumor formation was elucidated using human breast cancer cell lines and chick chorioallantoic membrane assay. Docking study was performed to explore the binding mode of quercetin with VDR.Key findingsIn EAC tumor-bearing mice, cell numbers, tumor volume, body weight and liver weight were dramatically increased, while they significantly decreased in mice treated with quercetin. Additionally, the peritoneal neo-angiogenesis was also significantly suppressed in the quercetin-treated mice, compared to the control. In addition, quercetin treated EAC tumor bearing mice had lower levels of liver enzymes, decreased hepatic inflammation and fibrosis compared with EAC tumor bearing mice. Docking study confirmed VDR-quercetin interaction. Furthermore, in-vitro assays and chick chorioallantoic membrane assay revealed the Vitamin D mimicking effect of quercetin.SignificanceDietary flavonoid, quercetin could act as a promising therapeutic drug to suppress the breast cancer induced tumor angiogenesis, hepatic inflammation, and fibrosis possibly via activation of VDR

COVID-19: Diabetes Perspective—Pathophysiology and Management

Recent evidence relating to the impact of COVID-19 on people with diabetes is limited but continues to emerge. COVID-19 pneumonia is a newly identified illness spreading rapidly throughout the world and causes many disabilities and fatal deaths. Over the ensuing 2 years, the indirect effects of the pandemic on healthcare delivery have become prominent, along with the lingering effects of the virus on those directly infected. Diabetes is a commonly identified risk factor that contributes not only to the severity and mortality of COVID-19 patients, but also to the associated complications, including acute respiratory distress syndrome (ARDS) and multi-organ failure. Diabetic patients are highly affected due to increased viral entry into the cells and decreased immunity. Several hypotheses to explain the increased incidence and severity of COVID-19 infection in people with diabetes have been proposed and explained in detail recently. On the other hand, 20–50% of COVID-19 patients reported new-onset hyperglycemia without diabetes and new-onset diabetes, suggesting the two-way interactions between COVID-19 and diabetes. A systematic review is required to confirm diabetes as a complication in those patients diagnosed with COVID-19. Diabetes and diabetes-related complications in COVID-19 patients are primarily due to the acute illness caused during the SARS-CoV-2 infection followed by the release of glucocorticoids, catecholamines, and pro-inflammatory cytokines, which have been shown to drive hyperglycemia positively. This review provides brief insights into the potential mechanisms linking COVID-19 and diabetes, and presents clinical management recommendations for better handling of the disease