Forced-Exercise Alleviates Neuropathic Pain in Experimental Diabetes: Effects on Voltage-Gated Calcium Channels

Exercise is now established as an integral adjunct to the management of diabetes. Diabetic polyneuropathy, a painful complication of diabetes, remains untreatable, emphasizing a critical need for improved therapeutic strategies. Recent evidence suggests that exercise may facilitate recovery of peripheral nerve function in diabetes. However, the mechanism by which exercise protects against diabetes-induced nerve dysfunction is unknown. In this dissertation we hypothesized that forced-exercise protects against experimental DPN by preventing glucose-associated alterations of voltage-gated calcium currents (VGCC) in small diameter dorsal root ganglion (DRG) neurons. Using behavioral, nerve-electrophysiology and patch-clamp methodology we examined the functional consequences of forced-exercise (treadmill, 5.4 km/week) on VGCC in dissociated small diameter DRG neurons from rats conferred diabetic by streptozotocin (STZ) treatment. Exercised-STZ rats in comparison to sedentary-STZ rats, demonstrated a 4 week delay in the onset of tactile hyperalgesia that was independent of changes in blood glucose levels. Interestingly, forced-exercise induced protection against diabetes-induced tactile hyperalgesia was reversed in a dose dependent manner by the opioid antagonist, naloxone. Forced-Exercise also prevented peripheral nerve conduction deficits in STZ-treated rats. Small diameter DRG neurons harvested from sedentary-STZ rats with demonstrated hyperalgesia exhibited 2-fold increase in peak high-voltage activated (HVA) Ca2+ current density and low-voltage activated (LVA) Ca2+ current component. The steady-state inactivation (SSI) (measure of channel availability) of LVA currents demonstrated a rightward shift in sedentary-STZ rats (+7.5 mV shift; V50 = -50.9 ± 0.6 mV; vehicle treated rats V50 = -58.4 ± 0.9 mV). Forced-exercise prevented the increase in both, peak HVA Ca2+ current density and LVA SSI shift (V50 = -58.2 ± 1.4 mV), but did not alter LVA current component. We conclude that forced-exercise delayed the onset of diabetic tactile hyperalgesia by preventing the alteration of VGCCs in small diameter DRG neurons, possibly by decreasing total calcium influx and dampening neuronal over-excitability

Efficacy versus Toxicity - The Ying and Yang in Translating Nanomedicines

Nanomedicine, as a relatively new offshoot of nanotechnology, has presented vast opportunities in biomedical research for developing novel strategies to treat diseases. In the past decade, there has been a significant increase in in vitro and preclinical studies addressing the benefits of nanomedicines. In this commentary, we focus specifically on the efficacy- and toxicity-related translational challenges of nanocarrier-mediated systems, and briefly discuss possible strategies for addressing such issues at in vitro and preclinical stages. We address questions related specifically to the balance between toxicity and efficacy, a balance that is expected to be substantially different for nanomedicines compared to that for a free drug. Using case studies, we propose a ratiometric assessment tool to quantify the overall benefit of nanomedicine as compared to free drugs in terms of efficacy and toxicity. The overall goal of this commentary is to emphasize the strategies that promote the translation of nanomedicines, especially by learning lessons from previous translational failures of other drugs and devices, and to apply these lessons to critically assess data at the basic stages of nanomedicinal research

Repeatable and adjustable on-demand sciatic nerve block with phototriggerable liposomes

Pain management would be greatly enhanced by a formulation that would provide local anesthesia at the time desired by patients and with the desired intensity and duration. To this end, we have developed near-infrared (NIR) light-triggered liposomes to provide on-demand adjustable local anesthesia. The liposomes contained tetrodotoxin (TTX), which has ultrapotent local anesthetic properties. They were made photo-labile by encapsulation of a NIR-triggerable photosensitizer; irradiation at 730 nm led to peroxidation of liposomal lipids, allowing drug release. In vitro, 5.6% of TTX was released upon NIR irradiation, which could be repeated a second time. The formulations were not cytotoxic in cell culture. In vivo, injection of liposomes containing TTX and the photosensitizer caused an initial nerve block lasting 13.5 ± 3.1 h. Additional periods of nerve block could be induced by irradiation at 730 nm. The timing, intensity, and duration of nerve blockade could be controlled by adjusting the timing, irradiance, and duration of irradiation. Tissue reaction to this formulation and the associated irradiation was benign.National Institutes of Health (U.S.) (GM073626

Antibacterial efficacy of Jackfruit rag extract against clinically important pathogens and validation of its antimicrobial activity in Shigella dysenteriae infected Drosophila melanogaster infection model

513-522Exploration of alternative sources of antibacterial compounds is an important and possibly an effective solution to the current challenges in antimicrobial therapy. Plant derived wastes may offer one such alternative. Here, we investigated the antibacterial property of extract derived from a part of the Jackfruit (Artocarpus heterophyllus Lam.) called ‘rag’, generally considered as fruit waste. Morpho-physical characterization of the Jackfruit rag extract (JFRE) was performed using Gas-chromatography, where peaks indicative of furfural; pentanoic acid; and hexadecanoic acid were observed. In vitro biocompatibility of JFRE was performed using the MTT assay, which showed comparable cellular viability between extract-treated and untreated mouse fibroblast cells. Agar well disc diffusion assay exhibited JFRE induced zones of inhibition for a wide variety of laboratory and clinical strains of Gram-positive and Gram-negative bacteria. Analysis of electron microscope images of bacterial cells suggests that JFRE induces cell death by disintegration of the bacterial cell wall and precipitating intracytoplasmic clumping. The antibacterial activity of the JFREs was further validated in vivo using Shigella dysenteriae infected fly model, where JFRE pre-fed flies infected with S. dysenteriae had significantly reduced mortality compared to controls. JFRE demonstrates broad antibacterial property, both in vitro and in vivo, possibly by its activity on bacterial cell wall

Hydrogel Scaffolds: Towards Restitution of Ischemic Stroke-Injured Brain

Chronic brain injury following cerebral ischemia is a severe debilitating neurological condition, where clinical intervention is well known to decrease morbidity and mortality. Despite the development of several therapeutic strategies, clinical outcome in the majority of patients could be better improved, since many still face life-long neurological deficits. Among the several strategic options that are currently being pursued, tissue engineering provides much promise for neural tissue salvage and regeneration in brain ischemia. Specifically, hydrogel biomaterials have been utilized to docket biomolecules, adhesion motifs, growth factors, and other proneural cues for stable stem cell encapsulation. Here, we provide an overview of therapeutic applications of hydrogels in stroke treatment. Special focus is given to design considerations for generation of efficient hydrogel systems for neurological applications. Therapeutic applications of hydrogels in stroke as conducive microenvironments for stem cell transplantation and drug delivery have been discussed. Finally, we present our perspectives on clinical translation of hydrogels for neural tissue regeneration

Forced Exercise Preconditioning Attenuates Experimental Autoimmune Neuritis by Altering T1 Lymphocyte Composition and Egress

A short-term exposure to moderately intense physical exercise affords a novel measure of protection against autoimmune-mediated peripheral nerve injury. Here, we investigated the mechanism by which forced exercise attenuates the development and progression of experimental autoimmune neuritis (EAN), an established animal model of Guillain–Barré syndrome. Adult male Lewis rats remained sedentary (control) or were preconditioned with forced exercise (1.2 km/day × 3 weeks) prior to P2-antigen induction of EAN. Sedentary rats developed a monophasic course of EAN beginning on postimmunization day 12.3 ± 0.2 and reaching peak severity on day 17.0 ± 0.3 ( N  = 12). By comparison, forced-exercise preconditioned rats exhibited a similar monophasic course but with significant ( p  < .05) reduction of disease severity. Analysis of popliteal lymph nodes revealed a protective effect of exercise preconditioning on leukocyte composition and egress. Compared with sedentary controls, forced exercise preconditioning promoted a sustained twofold retention of P2-antigen responsive leukocytes. The percentage distribution of pro-inflammatory (T h 1) lymphocytes retained in the nodes from sedentary EAN rats (5.1 ± 0.9%) was significantly greater than that present in nodes from forced-exercise preconditioned EAN rats (2.9 ± 0.6%) or from adjuvant controls (2.0 ± 0.3%). In contrast, the percentage of anti-inflammatory (T h 2) lymphocytes (7–10%) and that of cytotoxic T lymphocytes (∼20%) remained unaltered by forced exercise preconditioning. These data do not support an exercise-inducible shift in T h 1:T h 2 cell bias. Rather, preconditioning with forced exercise elicits a sustained attenuation of EAN severity, in part, by altering the composition and egress of autoreactive proinflammatory (T h 1) lymphocytes from draining lymph nodes

Cost effective natural photo-sensitizer from upcycled jackfruit rags for dye sensitized solar cells

Photo-sensitizers, usually organic dye molecules, are considered to be one of the most expensive components in dye sensitized solar cells (DSSCs). The present work demonstrates a cost effective and high throughput upcycling process on jackfruit rags to extract a natural photo-active dye and its application as a photo-sensitizing candidate on titanium dioxide (TiO2) in DSSCs. The jackfruit derived natural dye (JDND) exhibits a dominant photo-absorption in a spectral range of 350 nm–800 nm with an optical bandgap of ∼1.1 eV estimated from UV–visible absorption spectroscopic studies. The JDND in DSSCs as a major photo-absorbing candidate exhibits a photo-conversion efficiency of ∼1.1% with short circuit current density and open circuit voltage of 2.2 mA⋅cm−2 and 805 mV, respectively. Further, the results show that the concentration of JDND plays an influential role on the photovoltaic performance of the DSSCs due to the significant change in photo-absorption, exciton generation and electron injection into TiO2. The simple, high throughput method used to obtain JDND and the resulting DSSC performance can be considered as potential merits establishing a cost effective excitonic photovoltaic technology. Keywords: Solar cell, Dyes, Titanium dioxide, Photo-absorption, Charge transpor

Electrospun drug-eluting sutures for local anesthesia

We have developed a local anesthetic-eluting suture system which would combine the function and ubiquity of the suture for surgical repair with the controlled release properties of a biodegradable polymeric matrix. Drug-free and drug-loaded poly(lactic-co-glycolic acid) (PLGA) sutures were fabricated by electrospinning, with or without the local anesthetic bupivacaine. The tensile strength of the electrospun sutures decreased as drug content increased, but strains remained relatively similar across all groups. Sutures released their entire drug payload over the course of 12 days and maintained approximately 12% of their initial tensile strength after 14 days of incubation in vitro. In a rat skin wound model, local analgesia was achieved 1 day after surgery and lasted approximately 1 week in 90% of treated animals (n = 10, p < 0.05), and all wounds were able to heal normally without the need for further reinforcement. The sutures caused tissue reaction in vivo that was comparable to that seen with a commercially available suture composed of PLGA. Such sutures may enhance perioperative analgesia and mitigate the need for standard postoperative opioid analgesics

Electrospun Polymeric Core–sheath Yarns as Drug Eluting Surgical Sutures

Drug-coated sutures are widely used as delivery depots for antibiotics and anti-inflammatory drugs at surgical wound sites. Although drug-laden coating provides good localized drug concentration, variable loading efficiency and release kinetics limits its use. Alternatively, drug incorporation within suture matrices is hampered by the harsh fabrication conditions required for suture-strength enhancement. To circumvent these limitations, we fabricated mechanically robust electrospun core–sheath yarns as sutures, with a central poly-l-lactic acid core, and a drug-eluting poly-lactic-<i>co</i>-glycolic acid sheath. The electrospun sheath was incorporated with aceclofenac or insulin to demonstrate versatility of the suture in loading both chemical and biological class of drugs. Aceclofenac and insulin incorporated sutures exhibited 15% and 4% loading, and release for 10 and 7 days, respectively. Aceclofenac sutures demonstrated reduced epidermal hyperplasia and cellularity in skin-inflammation animal model, while insulin loaded sutures showed enhanced cellular migration in wound healing assay. In conclusion, we demonstrate an innovative strategy of producing mechanically strong, prolonged drug-release sutures loaded with different classes of drugs