Degradable Polymer-Based Nanoassemblies for Precise Targeting and Drug Delivery to Breast Cancer Cells without Affecting Normal Healthy Cells.

Stimuli-responsive amphiphilic polymers are known to be precursors to forming promising nanoarchitectonics with tunable properties for application in biomedical sciences. Currently, self-immolative polymers are widely recognized as an emerging class of responsive materials with excellent degradability, which is one of the crucial criteria for designing a robust drug delivery vehicle. Here, we design an amphiphilic polyurethane endowed with a redox-responsive self-immolative linker and a pH-responsive tertiary amine on the backbone, which forms entropy-driven nanoscale supramolecular assemblies (average hydrodynamic diameter ∼110 nm) and is programmed to disassemble in a redox environment (GSH) due to the degradation of the polymer in a self-immolative fashion. The nanoassembly shows efficient drug sequestration and release in a controlled manner in response to glutathione (10 mM). The tertiary amine residing on the surface of the nanoassembly becomes protonated in the tumor microenvironment (pH ∼ 6.4-6.8) and generates positively charged nanoassembly (ζ-potential = +36 mV), which enhances the cancer cell-selective cellular uptake. The biological evaluation of the drug-loaded nanoassembly revealed triple-negative breast cancer (MDAMB-231) selective internalization and cell death while shielding normal cells (RBCs or PBMCs) from off-targeting toxicity. We envision that polyurethane with a redox-responsive self-immolative linker might open up new opportunities for a completely degradable polyurethane-based nanocarrier for drug delivery and diagnosis applications.

Protective effects of red grape (Vitis vinifera) juice through restoration of antioxidant defense, endocrine swing and Hsf1, Hsp72 levels in heat stress induced testicular dysregulation of Wister rat.

Ability of red grape juice (RGJ), a known antioxidant, on testis of adult Wister rat to protect from oxidative stress induced damages by heat stress has been investigated in this study. Heat stress was induced maintaining body and testicular temperature at 43°C for 30min/day for 15 days using a hyperthermia induction chamber. Four groups of rats (n=6 per group) comprising of Group-I (control) -kept at 32°C, Group-II -exposed to heat stress alone, Group-III received RGJ (0.8ml/rat/day) alone and Group-IV -exposed to heat stress and received RGJ at same dose. Analysis of blood and testicular tissue exhibited significant reduction in serum testosterone, testicular superoxide dismutase, testicular catalase and testicular glutathione (all p < 0.001); whereas, significant rise in the level of serum corticosteroid, testicular lipid peroxidase and the apoptotic enzyme caspase-3 of testis (all p < 0.001) were observed along with substantial increase in testicular Hsp72 and Hsf-1, and decrease in 17ß-HSD3 were noted in heat stressed rats compared to controls. In Group-IV rats, RGJ administration could restore these parameters to normal levels. The signs of retention were clear in Group-IV rats and found to be significantly different as compared to that of the Group-II rats. In testicular histology of rats exposed to heat stress alone revealed remarkable germ cell degeneration and tubular deformations which were prevented by RGJ treatment (Group-IV). The reduced number of sperm level in Group-II also restored in RGJ treatment (Group-IV). The above results indicate that consumption of RGJ may substantially protect testis from heat stress induce dysfunctions.

Poly-ß-thioester-Based Cross-Linked Nanocarrier for Cancer Cell Selectivity over Normal Cells and Cellular Apoptosis by Triggered Release of Parthenolide, an Anticancer Drug.

Breast cancer is the most prevalent and aggressive type of cancer, causing high mortality rates in women globally. Many drawbacks and side effects of the current chemotherapy force us to develop a robust chemotherapeutic system that can deal with off-target hazards and selectively combat cancer growth, invasiveness, and cancer-initiating cells. Here, a pH-responsive cross-linked nanocarrier (140-160 nm) endowed with poly-ß-thioester functionality (CBAPTL) has been sketched and fabricated for noncovalent firm encapsulation of anticancer drug, parthenolide (PTL) at physiological pH (7.4), which enables sustain release of PTL at relevant endosomal pH (∼5.0-5.3). For this, a bolaamphiphilic molecule integrated with ß-thioester and acrylate functionality was synthesized to fabricate the pH-responsive poly-ß-thioester-based cross-linked nanocarrier via Michael addition click reactions in water. The poly-ß-thioester functionality of CBAPTL hydrolyzes at endosomal acidic conditions, thus leading to the selective release of PTL inside the cancer cell. Cross-linked nanocarriers exhibit high serum stability, dilution insensitivity, and targeted cellular uptake at tumor microenvironment (TME), contrasting normal cells. In vitro study using human MCF-7 breast cancer cells demonstrated that CBAPTL exhibited selective cytotoxicity, reduced clonogenic potential, increased reactive oxygen species (ROS) generation, and arrested the progression of the cell cycle at the G0/G1 phase efficiently. CBAPTL induced apoptosis via downregulating pro-proliferative protein Bcl-2 and upregulating proapoptotic proteins p53, BAD, p21, and cleaved PARP-1. CBAPTL inhibited proliferating signaling by suppressing AKT phosphorylation and p38 expression. CBAPTL also blocked the invasion and migration of MCF-7 cells. CBAPTL effectively inhibits primary and secondary mammosphere formation, thereby preventing cancer-initiating cells' growth. Conversely, CBAPTL has negligible effect on human red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs). These findings highlight the superior efficacy of CBAPTL compared to PTL alone in suppressing cancer cell growth, inducing apoptosis, and preventing invasiveness of MCF-7 cells. Thus, CBAPTL could be considered a possible selective chemotherapeutic cargo against breast cancer without affecting normal cells.

Evaluation of socio-demographic profile and basic risk factors of tuberculosis patients in South 24 Parganas district of West Bengal, India: a hospital-based study.

Aim: To study and analyse the socio-demographic profile and basic risk factors of tuberculosis(TB) patients and their relation with the current epidemiological status of TB registered under the RNTEP program in the study area. Subjects and Methods: This prospective study was conducted on 1743 newly registered tuberculosis patients at TB-DOT center of South 24 Parganas, West Bengal, India from 2011-2014. Socio-demographic variables and baseline characteristics of the participants were noted by a semi-structured questionnaire. Results: Our study results indicate that more than 95% of the TB patients were from lower socioeconomic class, and had poor literacy status and tuberculosis was observed highest in non-agricultural labour and cultivators. Among the young adult's majority of the affected population were females from the lower/upper-lower socioeconomic class. Our analysis revealed that, in successful tuberculosis therapy, men were more defaulters than women. Conclusion: Our study provides a socioeconomic profile and the risk factors of tuberculosis in patients such as the status of therapeutic intervention, involvement of other chronic diseases, age, sex and malnutrition. The findings of this study can be used to plan future studies with specific risk factors of the region and also for implementing the intervention and evaluating its effectiveness.

Prognostic value of circulating mitochondrial DNA in prostate cancer and underlying mechanism.

Circulating DNAs are considered as degraded DNA fragments of approximately 50-200 bp, found in blood plasma, consisting of cell-free mitochondrial and nuclear DNA. Such cell-free DNAs in the blood are found to be altered in different pathological conditions including lupus, heart disease, and malignancies. While nuclear DNAs are being used and being developed as a powerful clinical biomarker in liquid biopsies, mitochondrial DNAs (mtDNAs) are associated with inflammatory conditions including cancer progression. Patients with cancer including prostate cancer are found to have measurable concentrations of mitochondrial DNA in circulation in comparison with healthy controls. The plasma content of mitochondrial DNA is dramatically elevated in both prostate cancer patients and mouse models treated with the chemotherapeutic drug. Cell-free mtDNA, in its oxidized form, induced a pro-inflammatory condition and activates NLRP3-mediated inflammasome formation which causes IL-1ß-mediated activation of growth factors. On the other hand, interacting with TLR9, mtDNAs trigger NF-κB-mediated complement C3a positive feedback paracrine loop and activate pro-proliferating signaling through upregulating AKT, ERK, and Bcl2 in the prostate tumor microenvironment. In this review, we discuss the growing evidence supporting cell-free mitochondrial DNA copy number, size, and mutations in mtDNA genes as potential prognostic biomarkers in different cancers and targetable prostate cancer therapeutic candidates impacting stromal-epithelial interactions essential for chemotherapy response.

Multifaceted entrancing role of glucose and its analogue, 2-deoxy-D-glucose in cancer cell proliferation, inflammation, and virus infection.

Chronic exposure to high glucose inside the human body helps in the progression of cancer by activating various signaling pathways including PI3K, Akt, mTOR, Ras, Raf, MAPK, and PKC. Hyperglycemia induces ROS and AGE production and decreases the functional activities of the cellular antioxidant system. By downregulating the prolyl hydroxylase, it stabilizes HIF-α leading to EMT-induced cancer progression and inhibition of apoptosis. High glucose level increases inflammation by creating a pro-inflammatory environment through the production of certain pro-inflammatory mediators (cytokines, chemokines, leukotrienes), and by influencing the recruitment of immune cells, leukocytes in the inflamed region. High glucose impairs the immune response and dysregulates ROS formation through the alteration in ETC and glutaminolysis which makes hyperglycemic patients more susceptible to viral infection. 2-DG is a modified form of D-glucose, that shows anticancer, anti-inflammatory, and anti-viral effects. It enters the cells through GLUT transporters and is converted into 2-deoxy-D-glucose-6-phosphate with the help of hexokinase. It inhibits the glycolysis, the TCA cycle, and the pentose phosphate pathway leading to ATP depletion. By downregulating glucose uptake and energy (ATP) production it halts various pathways responsible for cancer progression. It promotes the formation of anti-inflammatory mediators, and macrophage polarization, and also modulates immune function, which decreases inflammation. 2-DG inhibits PI3K/Akt/mTOR and upregulates the AMPK pathway, causing activation of the SIRT-4 gene that reduces lipogenesis, glucose uptake, nucleotide formation, and alters viral replication thus reducing the chances of infection.

Advancements in Adjuvanticity of Bioactive Inorganic and Organic Compounds.

BACKGROUND: Regardless of the enormous success of vaccines over decades, the formulation of biocompatible and highly effective vaccines is still insufficient for combating new pathogens. DISCUSSION: The degree of effectiveness of any vaccine largely depends on the choice of appropriate adjuvant. Along with the optimum biocompatibility, an ideal adjuvant must be biodegradable, economical and easy to manufacture. To date, various organic and inorganic substances have been used as an adjuvant to augment the effectiveness of the vaccine. Immunological adjuvants are essential for strong and long-term effects against various pathogens. However, a very limited number of licensed adjuvants are available for the formulation of a successful vaccine. This leads to a challenging situation in medical science. CONCLUSION: The present review concisely summarizes the mechanism of action of various bioactive organic and inorganic immunological adjuvants, their limitations and future perspectives for their appropriate modification. Current trends of anticancer therapies using immunological adjuvants have also been highlighted in this review.

Rapid Green Synthesis of Biogenic Silver Nanoparticles Using Cinnamomum tamala Leaf Extract and its Potential Antimicrobial Application Against Clinically Isolated Multidrug-Resistant Bacterial Strains.

Cinnamomum tamala is Indian bay leaves also known as Tej patta commonly used in the preparation of delicious food for its sweet aroma and tremendous medicinal values. In this study, the significant concentration-dependent free radical scavenging and antioxidant efficacy of the aqueous extracts of bay leaves has been determined using DPPH (2, 2-diphenyl-l-picrylhydrazyl) radical scavenging, ferric ion-reducing power assay, and hydrogen peroxide radical scavenging assay. The leaf extract has also been utilized in the rapid synthesis of silver nanoparticles (AgNPs) under mild conditions (30 min reaction time at 70 °C) without the addition of extra stabilizing or capping agents. Mostly spherical shaped particles were formed with diameter ranging from 10 to 12 nm as evident by HRTEM imaging. The silver nanoparticles were also characterized using FTIR, XRD, and UV-visible spectroscopic techniques. The antibacterial effect of the synthesized AgNPs was studied against three clinically isolated multidrug-resistant bacterial strains (Escherichia coli (EC-1), Klebsiella pneumonia (KP-1), and Staphylococcus aureus (SA-1)). The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of AgNPs against EC-1 were 12.5 and 15 µg/mL and in SA-1 were 10 and 50 µg/mL, and in the case of KP-1, both values were 12.5 µg/mL. It was also noted that 8 h treatment duration using AgNPs was sufficient to eliminate all types of bacterial growth as evidenced by time-dependent killing kinetic assays. The biocompatibilities of AgNPs were also tested against human health RBCs, and it was observed that it did not show any significant toxicity up to 50 µg/mL concentration.

Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity.

Chronic exposure of glucose rich environment creates several physiological and pathophysiological changes. There are several pathways by which hyperglycemia exacerbate its toxic effect on cells, tissues and organ systems. Hyperglycemia can induce oxidative stress, upsurge polyol pathway, activate protein kinase C (PKC), enhance hexosamine biosynthetic pathway (HBP), promote the formation of advanced glycation end-products (AGEs) and finally alters gene expressions. Prolonged hyperglycemic condition leads to severe diabetic condition by damaging the pancreatic ß-cell and inducing insulin resistance. Numerous complications have been associated with diabetes, thus it has become a major health issue in the 21st century and has received serious attention. Dysregulation in the cardiovascular and reproductive systems along with nephropathy, retinopathy, neuropathy, diabetic foot ulcer may arise in the advanced stages of diabetes. High glucose level also encourages proliferation of cancer cells, development of osteoarthritis and potentiates a suitable environment for infections. This review culminates how elevated glucose level carries out its toxicity in cells, metabolic distortion along with organ dysfunction and elucidates the complications associated with chronic hyperglycemia.

Molecular modeling of NK-CT1, from Indian monocellate cobra (Naja kaouthia) and its docking interaction with human DNA topoisomerase II alpha.

A 6.76 kDa molecular weight cardio and cytotoxic protein of 60 amino acids in length called NK-CT1, was purified from the venom of Indian monocellate cobra (Naja kaouthia) by ion-exchange chromatography and HPLC as described in our earlier report. Therefore it is of interest to utlize the sequence of NK-CT1 for further functional inference using molecular modeling and docking. Thus homology model of NK-CT1 is described in this report. The anti-proliferative activity of the protein, binding with human DNA topoisomerase-II alpha was demonstrated using docking data with AUTODOCK and AUTODOCK MGL tools. Data shows that M26, V27 and S28 of NK-CT1 is in close contact with the nucleotides of the oligonucleotide, bound with topoisomerase-II alpha complex.