Simultaneous Sustained Drug Delivery, Tracking, and On-Demand Photoactivation of DNA-Hydrogel Formulated from a Biomass-Derived DNA Nanoparticle.

Conversion of biomass into nanoparticles for meaningful biomedical applications is a formidable proposition with excellent prospects but fewer patrons. A lack of general methodology for upscaled production and limited versatility of those nanoparticles are the main drawbacks. Herein, we report the creation of a DNA nanoparticle (DNA Dots) from onion genomic DNA (gDNA), a plant biomass source, through controlled hydrothermal pyrolysis in water without any chemicals. The DNA Dots are further formulated into a stimuli-responsive hydrogel through hybridization-mediated self-assembly with untransformed precursor gDNA. The versatility of the DNA Dots is recognized through its crosslinking ability with gDNA through its dangling DNA strands on the surface resulting from incomplete carbonization during annealing without the need for any external organic, inorganic, or polymeric crosslinkers. The gDNA-DNA Dots hybrid hydrogel is shown to be an excellent drug delivery vehicle for sustained release trackable through the inherent fluorescence of the DNA Dots. Interestingly, the DNA Dots are photoexcited with normal visible light to generate on-demand reactive oxygen species, making them exciting candidates for combination therapeutics. Most importantly, the ease with which the hydrogel is internalized in fibroblast cells with minimal cytotoxicity should encourage the nanotization of biomass as a tool for interesting sustainable biomedical applications.

Targeting Ion Channels for the Treatment of Glioma.

BACKGROUND: Glioma refers to the most aggressive tumor in the central nervous system that starts from support cells or glial cells. The glial cell is the most common cell type in the CNS, and they insulate, surround, as well as feed, oxygen, and nutrition to the neurons. Seizures, headaches, irritability, vision difficulties, and weakness are some of the symptoms. Targeting ion channels is particularly helpful when it comes to glioma treatment because of their substantial activity in glioma genesis through multiple pathways. OBJECTIVE: In this study, we explore how distinct ion channels can be targeted for glioma treatment and summarize the pathogenic ion channels activity in gliomas. RESULTS: Current research found several side effects such as bone marrow suppression, alopecia, insomnia, and cognitive impairments for presently done chemotherapy. The involvement of research on ion channels in the regulation of cellular biology and towards improvements of glioma have expanded recognition of their innovative roles. CONCLUSION: Present review article has expanded knowledge of ion channels as therapeutic targets and detailed cellular mechanisms in the roles of ion channels in gliomas pathogenesis.

Chemobrain: A review on mechanistic insight, targets and treatments.

Chemo-brain refers to the thinking and memory problems that occur in cancer patients during and after chemotherapy. It is also known as cognitive dysfunction or chemo-fog. Risk factors include brain malignancies, either primary or metastatic, radiotherapy and chemotherapy, either systemic or brain targeted. There are various mechanisms by which chemo-brain occurs in patients post-chemotherapy, including inflammation of neurons, stress due to free radical generation, and alterations in normal neuronal cell process due to biochemical changes. While chemotherapy drugs that are non-brain targeted, usually fail to cross the blood-brain barrier (BBB), this is not the case for inflammatory cytokines that are released, which easily cross the BBB. These inflammatory neurotoxic agents may represent the primary mediators of chemobrain and include the pro-inflammatory cytokines such as interleukins 1 and 6 and tumor necrosis factor. The pronounced rise in oxidative stress due to continuous chemotherapy also leads to a reduction in neurogenesis and gliogenesis, loss of spine and dendritic cells, and a reduction in neurotransmitter release. Based on recent research, potential agents to prevent and treat chemo brain have been identified, which include Lithium, Fluoxetine, Metformin, Rolipram, Astaxanthin, and microglial inhibitors. However, more defined animal models for cognitive dysfunction are required to study in detail the mechanisms involved in chemo-brain; furthermore, well-defined clinical trials are required to identify drug targets and their therapeutic significance. With these focused approaches, the future for improved therapies is promising.

Correlation of Serum Homocysteine Levels and Hyperinsulinaemia with Body Mass Index in Polycystic Ovarian Syndrome.

Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting women in reproductive age group. The interrelationship of serum homocysteine, homoeostatic assessment of insulin resistance (HOMA-IR) and body mass index amongst overweight, obese and non-obese PCOS patients is not fully established. Aims: We aimed to study the correlation of serum homocysteine levels and hyperinsulinaemia with body mass index (BMI) in PCOS patients. Study Setting and Design: This was a case-control study in which 35 women with PCOS and 35 non-PCOS women acting as controls were enrolled. Materials and Methods: Cases were identified by Rotterdam's criteria. (IR) indices, HOMA determination and serum homocysteine levels were determined and their correlation with BMI was studied. Statistical Analysis Used: Student's t-test and analysis of variance test were used for statistical analysis. The Pearson correlation coefficient was then used to estimate the correlation. Results: On overall evaluation, a significant positive correlation of fasting insulin, HOMA-IR and serum homocysteine) was observed (P < 0.05), however, on evaluating the correlation of these markers independently in cases and controls, only fasting insulin and HOMA-IR showed a significant correlation. In a multivariate model where PCOS was considered a dependent variable with age, fasting glucose, HOMA-IR, serum homocysteine and body mass index as the independent variables, only serum homocysteine levels were found to be significantly associated with the dependent variable (odds ratio = 1.172; 95% confidence interval = 1.032-1.330). Conclusion: PCOS women had significantly higher mean fasting glucose, fasting insulin, HOMA-IR and homocysteine levels as compared to non-PCOS controls. Mean HOMA-IR, homocysteine and fasting insulin levels showed a significant incremental trend with increasing BMI category in overall evaluation as well as in cases and controls independently.

Interaction of bivalent ligand KDN21 with heterodimeric delta-kappa opioid receptors in human embryonic kidney 293 cells.

KDN21 is a bivalent ligand that contains delta and kappa opioid antagonist pharmacophores linked through a 21-atom spacer. It has been reported that KDN21 bridges delta and kappa receptors that are organized as heterodimers. We have shown previously that when using [(3)H]diprenorphine as radioligand, KDN21 displayed greatly enhanced affinity in this series for coexpressed delta and kappa opioid receptors (CDK). The present study used in vitro expression systems to investigate interactions of members of the KDN series with delta-kappa heterodimers through competition binding using selective ligands and the mitogen-activated protein kinase (MAPK) assay. In this regard, the use of the selective radioligands [(3)H]naltrindole and [(3)H]norbinaltorphimine (nor-BNI) in competition binding studies revealed that KDN21 has much higher affinity than other KDN members for CDK and bound to CDK more selectively relative to mixed delta and kappa opioid receptors or singly expressed delta and kappa opioid receptors. Other experiments revealed that the binding of naltrindole to delta opioid receptors could increase the binding of nor-BNI to kappa opioid receptors and vice versa, suggesting reciprocal allosteric modulation of receptors in the heterodimer. Regarding the selectivity of KDN21 for phenotypic delta and kappa opioid receptors, we investigated the effect of KDN21 on the activation of MAPKs [extracellular signal-regulated kinases 1 and 2 (ERK1/2)] by delta- or kappa-selective agonists. KDN21 inhibited the activation of ERK1/2 by [D-Pen(2),D-Pen(5)]-enkephalin (delta(1)) and bremazocine (kappa(2)) but had no effect on the activation by deltorphin II (delta(2)) and (+)-(5alpha,7alpha,8beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide (U69593, kappa(1)). 7-Benzylidenenaltrexone (delta(1)) and bremazocine (kappa(2)) significantly reduced the binding of KDN21 to CDK, whereas naltriben (delta(2)) and U69593 produced no such change. Taken together, these data support the idea that the organization of delta and kappa receptors as heterodimers gives rise to delta(1) and kappa(2) phenotypes.

A bivalent ligand (KDAN-18) containing delta-antagonist and kappa-agonist pharmacophores bridges delta2 and kappa1 opioid receptor phenotypes.

To characterize delta- and kappa-opioid receptor phenotypes, bivalent ligands (KDAN series) containing delta-antagonist (naltrindole) and kappa(1)-agonist (ICI-199,441) pharmacophores were synthesized and evaluated by the intrathecal route using the mouse tail-flick assay and binding studies. The data have suggested that KDAN-18 (2) bridges phenotypic delta(2)- and kappa(1)-receptors. A conceptual model is presented to explain the organizational differences between the opioid receptors that give rise to the phenotypes (delta(1), delta(2), kappa(1), kappa(2)).

A bivalent ligand (KDN-21) reveals spinal delta and kappa opioid receptors are organized as heterodimers that give rise to delta(1) and kappa(2) phenotypes. Selective targeting of delta-kappa heterodimers.

In view of recent pharmacological studies suggesting the existence of delta-kappa opioid receptor heterodimers/oligomers in the spinal cord, we have synthesized and evaluated (intrathecally in mice) a series of bivalent ligands (KDN series) containing kappa and delta antagonist pharmacophores. Pharmacological and binding data have provided evidence for the bridging of spinal delta-kappa receptor heterodimers by KDN-21 and for their identification as delta(1) and kappa(2). The selectivity profile of KDN-21 and the apparent absence of coupled delta(1)-kappa(2) phenotypes in the brain suggest a new approach for targeting receptors.

Synthesis of conformationally restricted 2',3'-exo-methylene carbocyclic nucleosides built on a bicyclo[3.1.0]hexane template.

A series of 2',3'-exo-methylene carbocyclic nucleosides was synthesized as potential antiviral agents. These compounds were built on a bicyclo[3.1.0]hexane template that exhibits a rigid pseudoboat conformation and is capable of maintaining an identical conformation in solid state and in solution. The structures of the synthesized compounds were elucidated by NMR and X-ray crystallography. All the compounds were tested as anti-HIV and anti-HSV agents. The chemically synthesized 5'-triphosphate analogue of 7 was evaluated directly as a reverse transcriptase inhibitor.