Heparin Biofunctionalized Selenium Nanoparticles as Potential Antiangiogenic-Chemotherapeutic Agents for Targeted Doxorubicin Delivery.

Combining antiangiogenic and chemotherapeutic agents has shown promising clinical benefits in cancer cures when the therapeutic intervention takes into account the tissue and molecular targets. Moreover, the risk of induced drug resistance is minimized when multiple pathways are involved in the treatment regimen, yielding a better therapeutic outcome. Nanodrug delivery systems have proven to be a prudent approach to treating complex disease pathologies. As such, combining antiangiogenic and chemotherapeutic drugs within multimodal nanocarriers synergistically augments the clinical efficiency of the drugs. This study reports the combinatorial efficacy of heparin (Hep), selenium NPs (SeNPs), and doxorubicin (Dox) to inhibit tumor growth and progression. Both Se@Hep-NPs and Se@Hep-Dox-NPs with excellent water dispersity having a size and charge in the range of 250 ± 5 and 253 ± 5 nm and -53 ± 0.4 and -48.4 ± 6.4 mV, respectively, showed strong anticancer potential assessed through in vitro assays like cell viability, specificity, colony formation, and wound scratch in MCF7 cells. Strong synergistic interactions among SeNPs, Hep, and Dox in Se@Hep-Dox-NPs render it to be an antiangiogenic and proapoptotic cancer cell death inducers. In vivo imaging highlights the dual-mode attributes of Se@Hep-NPs with desirable passive tumor targeting and biomedical imaging ability when tagged with Cy7.5, while Se@Hep-Dox-NPs significantly reduce the tumor burden and prolong the longevity of subcutaneous EAC-bearing mice. Histopathology studies reveal no signs of toxicity in major organs. Collectively, these results qualify Se@Hep-Dox-NPs as a plausible clinical therapeutic candidate.

Control Release of Adenosine Potentiate Osteogenic Differentiation within a Bone Integrative EGCG-g-NOCC/Collagen Composite Scaffold toward Guided Bone Regeneration in a Critical-Sized Calvarial Defect.

The regeneration of critical-sized bone defects with biomimetic scaffolds remains clinically challenging due to avascular necrosis, chronic inflammation, and altered osteogenic activity. Two confounding mechanisms, efficacy manipulation, and temporal regulation dictate the scaffold's bone regenerative ability. Equally critical is the priming of the mesenchymal stromal cells (MSCs) toward lineage-specific differentiation into bone-forming osteoblast, which particularly depends on varied mechanochemical and biological cues during bone tissue regeneration. This study sought to design and develop an optimized osteogenic scaffold, adenosine/epigallocatechin gallate-N,O-carboxymethyl chitosan/collagen type I (AD/EGCG-g-NOCC@clgn I), having osteoinductive components toward swift bone regeneration in a calvarial defect BALB/c mice model. The ex vivo findings distinctly establish the pro-osteogenic potential of adenosine and EGCG, stimulating MSCs toward osteoblast differentiation with significantly increased expression of alkaline phosphatase, calcium deposits, and enhanced osteocalcin expression. Moreover, the 3D matrix recapitulates extracellular matrix (ECM) properties, provides a favorable microenvironment, structural support against mechanical stress, and acts as a reservoir for sustained release of osteoinductive molecules for cell differentiation, proliferation, and migration during matrix osteointegration observed. Evidence from in vivo experiments, micro-CT analyses, histology, and histomorphometry signify accelerated osteogenesis both qualitatively and quantitatively: effectual bone union with enhanced bone formation and new ossified tissue in 4 mm sized defects. Our results suggest that the optimized scaffold serves as an adjuvant to guide bone tissue regeneration in critical-sized calvarial defects with promising therapeutic efficacy.

Relationship of serum ferritin level and tic severity in children with Tourette syndrome.

PURPOSE: Tics can be considered hyperkinetic movements akin to restless leg syndrome (RLS). Drawing the analogy of iron deficiency as an etiology of RLS, it is conceivable that iron deficiency may underlie or worsen tics in Tourette syndrome (TS). The purpose of this study was to evaluate the relationship between serum ferritin levels and tic severity, as well as consequent impact on life, in children with TS. METHODS: Children <18 years, diagnosed with TS during 2009-2015, were reviewed. Only those with serum ferritin testing were included. The following data were collected: tic severity, impact on life, medication, comorbidities, blood count, and serum ferritin at diagnosis and follow-up. RESULTS: In fifty-seven patients, M:F = 2:1, serum ferritin was 48.0 ± 33.28 ng/mL, tic severity score 2.3 ± 0.80, impact on life score 2.2 ± 0.93, and composite score 4.57 ± 1.6. Serum ferritin was not influenced by comorbid obsessive compulsive disorder (OCD), attention deficit hyperactive disorder (ADHD), or anxiety (P > 0.16). Thirty-eight percent with low serum ferritin (≤50 ng/mL) (n = 37) had severe tics (>5 composite score), compared with 25% in normal ferritin group (n = 20). Over 6-12 months, tic severity score improved in both iron treated groups, deficient (2.70 to 1.90) and sufficient (2.40 to 1.95), whereas tics worsened or remained the same when not treated with iron. CONCLUSIONS: Our data suggest iron deficiency may be associated with more severe tics with higher impact on TS children, independent of the presence of OCD, ADHD, or anxiety. Iron supplementation showed a trend towards improvement of tic severity upon follow-up. We suggest a double-blind, placebo-controlled prospective study to reach a definite conclusion.

Modulation of Neuronal Activity in the Motor Thalamus during GPi-DBS in the MPTP Nonhuman Primate Model of Parkinson's Disease.

BACKGROUND: The motor thalamus is a key nodal point in the pallidothalamocortical "motor" circuit, which has been implicated in the pathogenesis of Parkinson's disease (PD) and other movement disorders. Although a critical structure in the motor circuit, the role of the motor thalamus in mediating the therapeutic effects of deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) is not fully understood. OBJECTIVE: To characterize the changes in neuronal activity in the pallidal (ventralis lateralis pars oralis (VLo) and ventralis anterior (VA)) and cerebellar (ventralis posterior lateralis pars oralis (VPLo)) receiving areas of the motor thalamus during therapeutic GPi DBS. METHODS: Neuronal activity from the VA/VLo (n = 134) and VPLo (n = 129) was recorded from two non-human primates made parkinsonian using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. For each isolated unit, one minute of data was recorded before, during and after DBS; a pulse width of 90 µs and a frequency of 135 Hz were used for DBS to replicate commonly used clinical settings. Stimulation amplitude was determined based on the parameters required to improve motor signs. Severity of motor signs was assessed using the UPDRS modified for nonhuman primates. Discharge rate, presence and characteristics of bursts, and oscillatory activity were computed and compared across conditions (pre-, during, and post-stimulation). RESULTS: Neurons in both the pallidal and cerebellar receiving areas demonstrated significant changes in their pattern of activity during therapeutic GPi DBS. A majority of the neurons in each nucleus were inhibited during DBS (VA/VLo: 47% and VPLo: 49%), while a smaller subset was excited (VA/VLo: 21% and VPLo: 17%). Bursts changed in structure, becoming longer in duration and both intra-burst and inter-spike intervals and variability were increased in both subnuclei. High frequency oscillatory activity was significantly increased during stimulation with 33% of VA/VLo (likelihood ratio: p < 0.0001) and 34% of VPLo (p < 0.0001) neurons entrained to the stimulation pulse train. CONCLUSIONS: Therapeutic GPi DBS produced a significant change in neuronal activity in both pallidal and cerebellar receiving areas of the motor thalamus. DBS suppressed activity in the majority of neurons, changed the structure of bursting activity and locked the neuronal response of one-third of cells to the stimulation pulse, leading to an increase in the power of gamma oscillations. These data support the hypothesis that stimulation activates output from the stimulated structure and that GPi DBS produces network-wide changes in neuronal activity that includes both the pallidal and cerebellar thalamo-cortical circuits.

Zinc Oxide Nanoparticle Induces Microglial Death by NADPH-Oxidase-Independent Reactive Oxygen Species as well as Energy Depletion.

Zinc oxide nanoparticle (ZnO-NP) is one of the most widely used engineered nanoparticles. Upon exposure, nanoparticle can eventually reach the brain through various routes, interact with different brain cells, and alter their activity. Microglia is the fastest glial cell to respond to any toxic insult. Nanoparticle exposure can activate microglia and induce neuroinflammation. Simultaneous to activation, microglial death can exacerbate the scenario. Therefore, we focused on studying the effect of ZnO-NP on microglia and finding out the pathway involved in the microglial death. The present study showed that the 24 h inhibitory concentration 50 (IC50) of ZnO-NP for microglia is 6.6 µg/ml. Early events following ZnO-NP exposure involved increase in intracellular calcium level as well as reactive oxygen species (ROS). Neither of NADPH oxidase inhibitors, apocynin, (APO) and diphenyleneiodonium chloride (DPIC) were able to reduce the ROS level and rescue microglia from ZnO-NP toxicity. In contrary, N-acetyl cysteine (NAC) showed opposite effect. Exogenous supplementation of superoxide dismutase (SOD) reduced ROS significantly even beyond control level but partially rescued microglial viability. Interestingly, pyruvate supplementation rescued microglia near to control level. Following 10 h of ZnO-NP exposure, intracellular ATP level was measured to be almost 50 % to the control. ZnO-NP-induced ROS as well as ATP depletion both disturbed mitochondrial membrane potential and subsequently triggered the apoptotic pathway. The level of apoptosis-inducing proteins was measured by western blot analysis and found to be upregulated. Taken together, we have deciphered that ZnO-NP induced microglial apoptosis by NADPH oxidase-independent ROS as well as ATP depletion.

Hijacking microglial glutathione by inorganic arsenic impels bystander death of immature neurons through extracellular cystine/glutamate imbalance.

Arsenic-induced altered microglial activity leads to neuronal death, but the causative mechanism remains unclear. The present study showed, arsenic-exposed (10 µM) microglial (N9) culture supernatant induced bystander death of neuro-2a (N2a), which was further validated with primary microglia and immature neuronal cultures. Results indicated that arsenic-induced GSH synthesis by N9 unfavorably modified the extracellular milieu for N2a by lowering cystine and increasing glutamate concentration. Similar result was observed in N9-N2a co-culture. Co-exposure of arsenic and 250 µM glutamate, less than the level (265 µM) detected in arsenic-exposed N9 culture supernatant, compromised N2a viability which was rescued by cystine supplementation. Therefore, microglia executes bystander N2a death by competitive inhibition of system Xc(-) (xCT) through extracellular cystine/glutamate imbalance. We confirmed the role of xCT in mediating bystander N2a death by siRNA inhibition studies. Ex-vivo primary microglia culture supernatant from gestationally exposed mice measured to contain lower cystine and higher glutamate compared to control and N-acetyl cysteine co-treated group. Immunofluorescence staining of brain cryosections from treated group showed more dead immature neurons with no such effect on microglia. Collectively, we showed, in presence of arsenic microglia alters cystine/glutamate balance through xCT in extracellular milieu leading to bystander death of immature neurons.

Investigation on the long-term storage and fate of arsenic obtained as a treatment residual: a case study.

In several places in India, activated alumina is used for effective removal of arsenic from contaminated ground water used for drinking purposes. Once exhausted, activated alumina is regenerated and reused for number of cycles. Regeneration of activated alumina generates treatment residuals containing arsenic, disposal of which needs care so as to avoid further pollution of the neighbouring environment. In the present study, a suitable stabilization and disposal method for the treatment residuals inside a well aerated coarse sand filter bed has been developed. Standard leaching tests carried out with the stabilized treatment residual indicated that the leaching of arsenic from the stabilized treatment residual was minimum, and was within the regulatory limit. Water quality data of all the wells located within 100 m from the sand filter were monitored for nearly four years and no adverse impact of disposal of arsenic-laden treatment residuals in the sand filter was observed.

Essential tremor after ipsilateral cerebellar hemispherectomy: support for the thalamus as the central oscillator.

Essential tremor is a long-recognized and common movement disorder, yet controversy still surrounds its pathophysiology. The olivo-cerebello-thalamo-cortical pathway has been implicated in the genesis of essential tremor, and the inferior olive has been considered the central oscillator driving the peripheral tremor. We present the case of a patient who developed essential tremor ipsilateral to cerebellar hemispherectomy and propose that the central oscillator in patients with essential tremor may not be the inferior olive in all cases, but rather the nucleus ventralis intermedius of the thalamus.