A Molecular Link Between Diabetes and Breast Cancer: Therapeutic Potential of Repurposing Incretin-based Therapies for Breast Cancer.

Female breast cancer recently surpassed lung cancer and became the most commonly diagnosed cancer worldwide. As per the recent data from WHO, breast cancer accounts for one out of every 8 cancer cases diagnosed among an estimated 2.3 million new cancer cases. Breast cancer is the most prevailing cancer type among women causing the highest number of cancer-related mortality. It has been estimated that in 2020, 68,5000 women died due to this disease. Breast cancers have varying degrees of molecular heterogeneity; therefore, they are divided into various molecular clinical sub types. Recent reports suggest that type 2 diabetes (one of the common chronic diseases worldwide) is linked to the higher incidence, accelerated progression, and aggressiveness of different cancers; especially breast cancer. Breast cancer is hormone-dependent in nature and has a cross-talk with metabolism. A number of antidiabetic therapies are known to exert beneficial effects on various types of cancers, including breast cancer. However, only a few reports are available on the role of incretin-based antidiabetic therapies in cancer as a whole and in breast cancer in particular. The present review sheds light on the potential of incretin based therapies on breast cancer and explores the plausible underlying mechanisms. Additionally, we have also discussed the sub types of breast cancer as well as the intricate relationship between diabetes and breast cancer.

Evaluation of a Peptide-Based Coassembled Nanofibrous and Thixotropic Hydrogel for Dermal Wound Healing.

The development of a peptide-based coassembled thixotropic hydrogel is a promising biomaterial, which could be used for dermal wound healing application. Cyclodextrins are widely used as biocompatible cyclic oligosaccharides that have hydrophilic exterior and hydrophobic interior for the formation of functional biomaterials. The current work presents a paradigm of a coassembled hydrogel with suitable mechanical strength that exhibits in vivo wound healing efficacy. In this report, we have designed and synthesized an Amoc (9-anthracenemethoxycarbonyl)-capped dipeptide, which self-assembles into a tough and robust hydrogel owing to participation of various noncovalent interactions. The mechanical strength of the self-assembling peptide-based hydrogel is tuned by incorporation of equimolar ß-cyclodextrin (CD), which leads to the formation of a coassembled hydrogel suitable for wound healing application. The coassembled hydrogel exhibits simple syringe injectability and is thixotropic in nature. The nanostructural morphology of the coassembled hydrogel reveals a highly cross-linked and entangled nanofibrillar network. Several spectroscopic data elucidate the presence of noncovalent interactions between CD and peptide, which could be the driving force for the formation of ordered nanostructures. The coassembled hydrogel shows potent antibacterial activity against Gram-positive pathogenic bacteria. In vitro biocompatibility of the coassembled hydrogel has been investigated with the human embryonic kidney (HEK293) and MCF-7 cell lines. Additionally, confocal laser scanning microscopic data show cellular uptake of the coassembled hydrogel with blue fluorescence. Moreover, the in vivo wound healing activity of the coassembled hydrogel has been investigated by the histopathology study. The biochemical parameters such as nitric oxide and collagen contents have been evaluated by Griess and hydroxy proline assays. All the results corroborate the wound healing efficacy of a nanofibrillar antibacterial coassembled hydrogel.

Investigations of Anti-Inflammatory Activity of a Peptide-Based Hydrogel Using Rat Air Pouch Model.

The growing area of biomaterial sciences has attracted broad attention in recent years in the development of peptide-based biocompatible materials with inherent therapeutic potentials. Here, we developed an Amoc (9-anthracenemethoxycarbonyl)-capped dipeptide-based biocompatible, injectable, thixotropic, and self-healable hydrogel. In vitro cytotoxicity of the hydrogel was investigated with the human embryonic kidney cell (HEK293) line. We observed that the synthesized peptide is noncytotoxic. The hydrogel showed an antibacterial efficacy against Gram-positive and Gram-negative bacteria. In vivo anti-inflammatory activity of the hydrogel was investigated using the rat air pouch model of acute inflammation. The major parameters considered for the anti-inflammatory study were exudate volume, total and differential white blood cell count, tissue histology, and lipid peroxidation assay. These experimental data suggest biocompatibility and potential therapeutic applications of peptide hydrogel in inflammation.

Investigations of Peptide-Based Biocompatible Injectable Shape-Memory Hydrogels: Differential Biological Effects on Bacterial and Human Blood Cells.

Here, we report the self-assembly of Amoc (9-anthracenemethoxycarbonyl)-capped dipeptides, which self-assemble to form injectable, self-healable, and shape-memory hydrogels with inherent antibacterial properties. Amoc-capped dipeptides self-assemble to form nanofibrillar networks, which are established by several spectroscopic and microscopic techniques. The inherent antibacterial properties of hydrogels are evaluated using two Gram-positive Staphylococcus aureus, Bacillus subtilis and three Gram-negative Escherichia coli, Pseudomonas aeruginosa, and Salmonella typhi bacteria. These hydrogels exhibit potent antibacterial efficacy against Gram-positive and Gram-negative bacteria. The minimum inhibitory concentrations (MIC50) for the hydrogels on Gram-positive bacteria are in the range of 10-200 µM hydrogelator concentrations. The biocompatibility and cytotoxicity of the hydrogels are evaluated using 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), hemolysis, and lipid peroxidation (LPO) assay on human blood cells. The hydrogels are hemocompatible and they decrease LPO values on human red blood cells probably via increased cellular stability against oxidative stress. Furthermore, MTT data show that the hydrogels are biocompatible and promote cell viability and proliferation on cultured human white blood cells. Taken together, these results may suggest that our designed injectable hydrogels could be useful to prevent localized bacterial infections.

Inhibition of Aβ(1-42)Oligomerization, Fibrillization and Acetylcholinesterase Activity by Some Anti-Inflammatory Drugs: An in vitro Study.

BACKGROUND: Number of contradictory reports are available on the effects of antiinflammatory drugs on Alzheimer's disease (AD) including beneficial, adverse and stage dependent effects. We provide insights of the effects exerted by some anti-inflammatory drugs on the chemistry of AD. METHODS: Three different doses of dexamethasone (0.015, 0.030, 0.060 µM), piroxicam (5, 7.5, 10 µM), indomethacin (1, 1.25, 1.50 µM), diclofenac (0.6, 0.8, 1.0 µM), aspirin (90, 120, 150 µM) and celecoxib (30, 45, 60 µM) were used. Rivastigmine, methylene blue and butylated hydroxyanisole were used as standard drug, oligomerization inhibitor and antioxidant, respectively. Oligomerization and fibrillization reactions were performed using Aß1-42 peptides. Results-Indomethacin and aspirin mainly inhibited oligomerization, while rivastigmine and piroxicam inhibited fibrillization. Diclofenac and celecoxib inhibited both oligomerization and fibrillization almost equally. Dexamethasone showed poor efficiency on both the processes, but exert comparably more inhibition of oligomerization than fibrillization. Inhibition of acetylcholinesterase activity was also potent and was in the following order: celecoxib> piroxicam> diclofenac> aspirin> indomethacin> dexamethasone. Strong radical scavenging (More than 50%) activity was showed by indomethacin and aspirin for NO radicals. CONCLUSION: Present study consistently revealed that anti-inflammatory drugs have potential to Modulate chemistry of AD progression. Inclusion of anti-inflammatory drugs in low doses along with routine therapies may provide therapeutically and economically more efficient therapies for AD. However, further studies are warranted, because the overall therapeutic effect seems to be the function of stage of disease, dose of drug, main underlying mechanism of action(s).

Lipase-catalyzed dissipative self-assembly of a thixotropic Peptide bolaamphiphile hydrogel for human umbilical cord stem-cell proliferation.

We report lipase-catalyzed inclusion of p-hydroxy benzylalcohol to peptide bolaamphiphiles. The lipase-catalyzed reactions of peptide bolaamphiphiles with p-hydroxy benzylalcohol generate dynamic combinatorial libraries (DCL) in aqueous medium that mimic the natural dissipative system. The peptide bolaamphiphile 1 (HO-WY-Suc-YW-OH) reacts with p-hydroxy benzylalcohol in the presence of lipase forming an activated diester building block. The activated diester building block self-assembles to produce nanofibrillar thixotropic hydrogel. The subsequent hydrolysis results in the dissipation of energy to form nonassembling bolaamphiphile 1 with collapsed nanofibers. The thixotropic DCL hydrogel matrix is used for 3D cell culture experiments for different periods of time, significantly supporting the cell survival and proliferation of human umbilical cord mesenchymal stem cells.

Self-programmed nanovesicle to nanofiber transformation of a dipeptide appended bolaamphiphile and its dose dependent cytotoxic behaviour.

Nanostructural transition of a small peptide bolaamphiphile via molecular self-assembly is a challenging task. Here, we report the self-programmed morphological transformation from nanovesicles to nanofibers of a smart peptide bolaamphiphile in its self-assembling hydrogel state. The nanostructural transition occurs based on the structural continuity of the ß-sheet structures. Spectroscopic studies confirmed the different molecular arrangements of the two different nanostructures. Furthermore, the smart bolaamphiphile shows a dose-dependent cytotoxicity and cell-proliferation behaviour.

Ovalbumin induced allergic rhinitis and development of prediabetes to rats: possible role of Th2 cytokines.

Diabetes is known to be regulated by cytokines secreted from Th1 cells, while allergic rhinitis (AR) is mainly regulated by Th2 cytokines. In recent past we have reported the development of diabetes in response to parthinium induced AR to rats. These results were contradictory to Th1/Th2 paradigm which suggests that Th1 and Th2 cells reciprocally counteract each other. Subsequently in silico interactome analysis further revealed that Th2 cytokines may signal to increase the level of Th1 along with the proteins involved in the development of diabetes. In present study we tried to understand the diabetogenic changes on the background of ovalbumin induced allergic rhinitis (OVA). Three groups of seven rats were considered; group I control (Ctrl); group II OVA and group III OVA+L-cetrizine (OVA+ D). The study continued for 48 days and the experiment was terminated on day 49, while L-cetrizine was administered for last 07 days (42-48 days). Group II showed increased levels of Th1 (IL-2) and Th2 cytokines, induction of allergic rhinitis and changes in the proteins involved in diabetes. In group III, most of the changes were reverted back towards normalcy. Induction of allergic rhinitis triggers Th2 cytokines that result increase IL-2 (Th1) and alterations in the metabolic parameters led to the condition of prediabetes.

The effect of aspirin on atherogenic diet-induced diabetes mellitus.

Exploration of atherogenic diet-induced diabetes mellitus and the evaluation of antidiabetic potential of aspirin were carried out in this study. Male albino Wistar rats were divided into three groups of seven each (1, 2 and 3). Animals of groups 2 and 3 received CCT diet (normal rat chow supplemented with 4% cholesterol, 1% cholic acid and 0.5%, 2-thiouracil), whereas the animals of group 1 received normal feed and served as control. In addition to CCT, animals of group 3 (CCT + Asp) also received aspirin (8 gm/kg), commencing from day 8 till the end of study (day 15). In another experiment (exp. 2), aspirin-supplemented normal rat chow (Asp) was fed to the animals for 7 days and compared with the normal rat chow-fed control group. In experiment 3, an in vitro nitric oxide radical-scavenging potential of aspirin at three different doses (25, 50 and 100 µg/ml) was evaluated. In response to CCT diet, a decrease in serum insulin, α-amylase activity, hepatic glycogen, pancreatic calcium with a concomitant increase in serum glucose, lipid profile (except high-density lipoprotein cholesterol (HDL-C)), pancreatic nitrite and lipid peroxidation and the size of adipocytes along with macrophages infiltration were observed. Aspirin administration to CCT diet-fed animals (CCT + Asp) reverted all the studied biochemical and histological changes towards normality. In experiment 2, aspirin administration decreased the serum glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C) and VLDL-C with concomitantly increased HDL-C and insulin; however, it increased hepatic glycogen and pancreatic calcium concentration with a decrease in pancreatic and adipose lipid peroxidation. In vitro assay revealed the nitric oxide radical-scavenging potential of aspirin in all the studied doses. It is concluded that CCT diet-induced diabetes mellitus might be the outcome of nitric oxide radical-induced oxidative stress in pancreatic tissue, as well as diminished insulin secretion because of decrease in pancreatic calcium release, obesity and inflammation. However, aspirin treatment reversed all the above-mentioned parameters to normality.