A Novel NOX Inhibitor Alleviates Parkinson's Disease Pathology in PFF-Injected Mice.

Oxidative stress-mediated damage is often a downstream result of Parkinson's disease (PD), which is marked by sharp decline in dopaminergic neurons within the nigrostriatal regions of the brain, accounting for the symptomatic motor deficits in patients. Regulating the level of oxidative stress may present a beneficial approach in preventing PD pathology. Here, we assessed the efficacy of a nicotinamide adenine phosphate (NADPH) oxidase (NOX) inhibitor, an exogenous reactive oxygen species (ROS) regulator synthesized by Aptabio therapeutics with the specificity to NOX-1, 2 and 4. Utilizing N27 rat dopaminergic cells and C57Bl/6 mice, we confirmed that the exposures of alpha-synuclein preformed fibrils (PFF) induced protein aggregation, a hallmark in PD pathology. In vitro assessment of the novel compound revealed an increase in cell viability and decreases in cytotoxicity, ROS, and protein aggregation (Thioflavin-T stain) against PFF exposure at the optimal concentration of 10 nM. Concomitantly, the oral treatment alleviated motor-deficits in behavioral tests, such as hindlimb clasping, rotarod, pole, nesting and grooming test, via reducing protein aggregation, based on rescued dopaminergic neuronal loss. The suppression of NOX-1, 2 and 4 within the striatum and ventral midbrain regions including Substantia Nigra compacta (SNc) contributed to neuroprotective/recovery effects, making it a potential therapeutic option for PD.

A Novel NOX Inhibitor Treatment Attenuates Parkinson's Disease-Related Pathology in Mouse Models.

Parkinson's disease (PD) is a progressive neurodegenerative motor disorder without an available therapeutic to halt the formation of Lewy bodies for preventing dopaminergic neuronal loss in the nigrostriatal pathway. Since oxidative-stress-mediated damage has been commonly reported as one of the main pathological mechanisms in PD, we assessed the efficacy of a novel NOX inhibitor from AptaBio Therapeutics (C-6) in dopaminergic cells and PD mouse models. The compound reduced the cytotoxicity and enhanced the cell viability at various concentrations against MPP+ and α-synuclein preformed fibrils (PFFs). Further, the levels of ROS and protein aggregation were significantly reduced at the optimal concentration (1 µM). Using two different mouse models, we gavaged C-6 at two different doses to the PD sign-displaying transgenic mice for 2 weeks and stereotaxically PFF-injected mice for 5 weeks. Our results demonstrated that both C-6-treated mouse models showed alleviated motor deficits in pole test, hindlimb clasping, crossbeam, rotarod, grooming, and nesting analyses. We also confirmed that the compound treatment reduced the levels of protein aggregation, along with phosphorylated-α-synuclein, in the striatum and ventral midbrain and further dopaminergic neuronal loss. Taken together, our results strongly suggest that NOX inhibition can be a potential therapeutic target for PD.

Entrainment of aperiodic and periodic oscillations in the Mercury Beating Heart system using external periodic forcing.

We report experimental results indicating entrainment of aperiodic and periodic oscillatory dynamics in the Mercury Beating Heart (MBH) system under the influence of superimposed periodic forcing. Aperiodic oscillations in MBH were controlled to generate stable topological modes, namely, circle, ellipse, and triangle, evolving in a periodic fashion at different parameters of the forcing signal. These periodic dynamics show 1:1 entrainment for circular and elliptical modes, and additionally the controlled system exhibits 1:2 entrainment for elliptical and triangular modes at a different set of parameters. The external periodic forcing of the periodic MBH system reveals the existence of domains of entrainment (1:1, 1:2, 1:3, and 1:4) represented in the Arnold tongue structures. Moreover, Devil's staircase is obtained when the amplitude-frequency space of parameters of the applied signal is scanned.

New therapeutic activity of metabolic enhancer piracetam in treatment of neurodegenerative disease: Participation of caspase independent death factors, oxidative stress, inflammatory responses and apoptosis.

Piracetam, a nootropic drug that has been clinically used for decades but remains enigmatic due to no distinct understanding of its mechanism of action. The present study aimed to investigate the role of caspase independent pathway in piracetam mediated neuroprotection. LPS administration caused significant alterations in oxidative stress related parameters like glutathione, glutathione reductase and increased lipid peroxidation. LPS administration also caused augmented expression of inflammatory cytokines and astrocytes activation. Piracetam treatment offered significant protection against LPS induced oxidative and inflammatory parameters and inhibited astrocytes activation. LPS administration caused augmented level of reactive oxygen species and depleted mitochondrial membrane potential which were attenuated with piracetam treatment. This study for the first time demonstrates the role of caspase independent death factors in piracetam induced neuroprotective effects in rat brain. Translocation of mitochondrial resident apoptosis inducing factor and endonuclease G to nucleus through cytosol after LPS administration was significantly blocked with piracetam treatment. Further, LPS induced DNA fragmentation along with up regulated Poly [ADP-ribose] polymerase 1 (PARP1) levels were also inhibited with piracetam treatment. Apoptotic death was confirmed by the cleavage of caspase 3 as well as histological alteration in rat brain regions. LPS administration caused significantly increased level of cleaved caspase 3, altered neuronal morphology and decreased neuronal density which were restored with piracetam treatment. Collectively our findings indicate that piracetam offered protection against LPS induced inflammatory responses and cellular death including its antioxidative antiapoptotic activity with its attenuation against mitochondria mediated caspase independent pathway.

Kuramoto transition in an ensemble of mercury beating heart systems.

We have studied, experimentally, the collective behavior of the electrically coupled autonomous Mercury Beating Heart (MBH) systems exhibiting the breathing mode, by varying both the coupling strength and the population size (from N = 3 to N = 16). For a fixed N, the electrical and the mechanical activities of the MBH systems achieve complete synchronization at different coupling strengths. The electrical activity of each MBH system is measured by the corresponding electrode potential (Ei = Vi). Additionally, the mechanical activity of each MBH oscillator is visually observed (snapshots and video clips). Subsequently, this activity is quantified by calculating the temporal variation in the area (Ai) of the Hg drop. As a result, the synchronization of the electrical (Ei = Vi) and the mechanical (Ai) activities can be measured. The extent of synchronization was quantified by employing the order parameter (r). Our experimental results are found to be in agreement with the Kuramoto theory.

Synchronization in autonomous mercury beating heart systems.

The ability of the mercury beating heart (MBH) system to exhibit sustained mechanical and electrochemical activities simultaneously without any external agent (fluctuating or constant), has attracted researchers for decades. The interplay of these activities could mimic the biological phenomena such as a pulsating heart that occurs due to the coupled tissues exhibiting mechanical as well as electrical dynamics. In the present work, we have studied experimentally the dynamics of electrically coupled two and three autonomous MBH systems. A dynamical triangular (heart) shape, in the traditional watch glass geometry, has been chosen for the experiments. It is found that the redox potentials (electrical behavior) of the quasi-identical (due to the inherent heterogeneities in the setup) MBH systems get synchronized at the intermediate coupling strengths whereas coherence in their mechanical activities occur only at large coupling strengths. To the best of our knowledge, this synchronization phenomenon involving two distinct activities (electrical and mechanical) and different coupling thresholds has not been reported, so far. The coherent mechanical activities means the simultaneous occurrence of compressions and expansions in the coupled Hg drops, which are shown using snapshots. In addition to this, the redox time series have also been provided to demonstrate the synchronization in the electrical behavior of MBH systems. Moreover, a mathematical framework considering only electrical and mechanical components of the MBH systems is presented to validate the experimental findings that the strong synchrony in the redox potentials of the MBH systems is a prerequisite for the synchrony in their mechanical activities.

Severe acute respiratory syndrome Coronavirus-2 GenoAnalyzer and mutagenic anomaly detector using FCMFI and NSCE.

In order to deepen our understanding of the virus and help guide the creation of efficient therapies, this study uses artificial intelligence tools to thoroughly explore the genetic sequences of the SARS-CoV-2 virus. The process starts by using the Fuzzy Closure Miner for Frequent Itemsets (FCMFI) on a large corpus of SARS-CoV-2 genomic sequences to reveal hidden patterns, including nucleotides base sequences, repeating motifs, and corresponding interchanges. Then, using the Nucleotide Sequence Comprehension Engine (NSCE) technique, we were able to precisely define the genomic areas for mutation analysis. Structured and unstructured proteins are both strongly impacted by virus mutations, with spike proteins that are linked to the severity of COVID-19 pneumonia being particularly affected. Notably, the Mutagenic Anomaly Detector shows a 65 % efficiency boost in computing genome mutation rates compared to conventional point mutation analysis, while GenoAnalyzer offers a remarkable 93.33 % improvement over existing approaches in recognizing common genomic sequence patterns. These results highlight the potential of FCMFI to reveal complex genomic patterns and significant insights in COVID-19 genetic sequences when combined with mutation analysis. The Mutagenic Anomaly Detector and GenoAnalyzer show promise for revealing hidden genomic patterns and precisely estimating the SARS-CoV-2 mutation rate.

Throat packing via nasopharyngeal airway for severe trismus cases requiring surgical intervention under general anesthesia: A simplified and innovative approach.

Throat packing is essential in oral and maxillofacial surgeries to prevent blood and tissue debris aspiration, reducing postoperative complications. Traditional oral route methods are often inadequate, especially in severe trismus cases like Oral Submucous Fibrosis (OSMF), TMJ Ankylosis, and post-traumatic conditions due to limited mouth opening. This study introduces a novel technique using a nasopharyngeal airway (NPA) for throat packing. The method involves inserting a hemostatic dressing through an NPA, ensuring minimal invasiveness and effective airway management. Proper positioning is confirmed with a laryngoscope or fiberoptic scope, and the dressing is secured to prevent dislodgement. This technique is easy, reproducible, and less injurious compared to traditional methods. At our center, throat packing via NPA was performed on 35 patients undergoing surgery under general anesthesia, resulting in high satisfaction and no reported complications.

Shielding against breast tumor relapse with an autologous chemo-photo-immune active Nano-Micro-Sera based fibrin implant.

Local recurrence post-surgery in early-stage triple-negative breast cancer is a major challenge. To control the regrowth of a residual tumor, we have developed an autologous therapeutic hybrid fibrin glue for intra-operative implantation. Using autologous serum proteins as stabilizers, we have optimized high drug-loaded lapatinib-NanoSera (Lap-NS; ∼66% L.C.) and imiquimod-MicroSera (IMQ-MS; ∼92% L.C). Additionally, plasmonic nanosera (PNS) with an ∼67% photothermal conversion efficiency under 980 nm laser irradiation was also developed. While localized monotherapy with either Lap-NS or PNS reduced the tumor regrowth rate, their combination with IMQ-MS amplified the effect of immunogenic cell death with a high level of tumor infiltration by immune cells at the surgical site. The localized combination immunotherapy with a Nano-MicroSera based hybrid fibrin implant showed superior tumor inhibition and survival with significant promise for clinical translation.

Potential-dependent topological modes in the mercury beating heart system.

We study the dynamics of the mercury beating heart (MBH) system in an acidic solution in the absence of a strong oxidant. Furthermore, the system is subjected to an external square wave potential. It was observed that different shapes (circular, elliptical, triangular, and multilobed stars) of the mercury drop could be stabilized as the frequency of the external potential and the volume of the mercury were varied. The redox potential time series for this forced MBH system, corresponding to the different stabilized topological configurations, were also recorded, and their power spectra were analyzed. The obtained results, involving the different topological modes, were fairly reproducible and sustainable. A possible oxidation-reduction mechanism for these experimental observations is provided.

Can Amoxicillin and Clavulanic Acid Impregnated Plaster of Paris Beads Serve as an Effective Alternative to Systemic Antibiotics for Third Molar Surgeries? A Split Mouth Randomized Clinical Trial.

Purpose: The present work was a pilot study undertaken to evaluate the effectiveness of amoxicillin and clavulanic acid impregnated plaster of paris beads for prevention of infection of third molar extraction sockets. Materials and Methods: This was a prospective, randomized, split mouth clinical trial done on 16 patients (32 sites) who required surgical extraction of mandibular third molars. Control arm patients were given Tab. amoxicillin 500 mg with clavulanic acid 125 mg (Tab. Klavimed 625 mg, Indomed, India), thrice daily for 3 days after extraction, whereas test arm patients received Antibiotic Impregnated Microbeads (AIM), containing Amoxicillin 500 mg and Clavulanic Acid 100 mg placed in situ in the extraction socket. The primary outcome parameter was infection and the secondary outcome parameters were pain, trismus, swelling and wound healing. Results: None of the patients in either group had post operative infection. There was no significant difference in pain intensity between the two groups (1st day p = 0.41; 3rd day p = 0.38, 7th day p = 0.37). Both the groups were also similar with respect to swelling (p = 0.596, 0.146, 0.871, 0.820 on 1st, 3rd, 7th, 15th post-op day ,respectively). Conclusion: Amoxycillin with clavulanic acid impregnated PoP beads appears to be as effective as oral 3 day amoxicillin with clavulanic acid regime for prevention of 3 M socket infection.

Applications of artificial intelligence and machine learning in orthognathic surgery: A scoping review.

Over the recent years, Artificial Intelligence (AI) has been progressing rapidly with its ability to mimic human cognitive functions. The potential applications of AI technology in diagnosis, treatment planning, and prognosis prediction have been demonstrated in various studies. The present scoping review aimed to provide an overview of AI and Machine Learning (ML) algorithms and their applications in orthognathic surgery. A comprehensive search was conducted in databases including PubMed, Embase, Scopus, Web of Science and OVID Medline until November 2021. This scoping review was conducted following the PRISMA-ScR guidelines. After applying the inclusion and exclusion criteria, a total of 19 studies were included for final review. AI has profoundly impacted the diagnosis and prediction of orthognathic surgeries with a clinically acceptable accuracy range. Furthermore, AI reduces the work burden of the clinician by eliminating the tedious registration procedures, thereby helping in efficient and automated planning. However, focussing on the research gaps, there is a need to foster the AI models/algorithms to contemporize their efficiency in clinical decision making, diagnosis and surgical planning in future studies.

A retrospective study on factors affecting the dropout rate among temporomandibular joint internal disc derangement patients in India - A single-institution experience.

Introduction: Patients suffering temporomandibular joint internal disc derangement (IDD) ignore appointments after the first examination or after the first or second sessions of initial treatment. The dropout rate for these patients varies from 36% to 78% as per literature. Unfortunately, very few studies have investigated the dropout rate of these patients. Hence, the present study was undertaken to find out the dropout rate among these kinds of patients. Material and Methods: A retrospective study was done from June 2008 to December 2017 by collecting the records of the patients who were diagnosed to have IDD. Outcome variables included were age, sex, distance traveled, occupation, and education. Results: Out of 1021 patients 766 patients were included in the study after fulfilling the inclusion and exclusion criteria. The data were analyzed using Chi-square test. The level of significance was set at <0.05. In this study, there is slight male predominance (52.8%) and 63.1% (21-40 years) were among young adults and the patients in the age group of 21-30 years had shown good compliance, Postgraduate has shown the highest follow-up rate when compared with graduates and school level and the difference was found to be statistically significant. People in the job had shown good compliance when compared with business class and retired people and the patients within 50 km had shown the maximum follow-up with a statistically significant difference (P < 0.01). Conclusion: This study has shown that the dropout rate of treatment in temporomandibular joint disorder is affected by age, sex, distance traveled, occupation, and education.

Alpha-Synuclein Preformed Fibrils Induce Cellular Senescence in Parkinson's Disease Models.

Emerging evidence indicates that cellular senescence could be a critical inducing factor for aging-associated neurodegenerative disorders. However, the involvement of cellular senescence remains unclear in Parkinson's disease (PD). To determine this, we assessed the effects of α-synuclein preformed fibrils (α-syn PFF) or 1-methyl-4-phenylpyridinium (MPP+) on changes in cellular senescence markers, employing α-syn PFF treated-dopaminergic N27 cells, primary cortical neurons, astrocytes and microglia and α-syn PFF-injected mouse brain tissues, as well as human PD patient brains. Our results demonstrate that α-syn PFF-induced toxicity reduces the levels of Lamin B1 and HMGB1, both established markers of cellular senescence, in correlation with an increase in the levels of p21, a cell cycle-arrester and senescence marker, in both reactive astrocytes and microglia in mouse brains. Using Western blot and immunohistochemistry, we found these cellular senescence markers in reactive astrocytes as indicated by enlarged cell bodies within GFAP-positive cells and Iba1-positive activated microglia in α-syn PFF injected mouse brains. These results indicate that PFF-induced pathology could lead to astrocyte and/or microglia senescence in PD brains, which may contribute to neuropathology in this model. Targeting senescent cells using senolytics could therefore constitute a viable therapeutic option for the treatment of PD.

Synergistic Tribo-Activity of Nanohybrids of Zirconia/Cerium-Doped Zirconia Nanoparticles with Nano Lamellar Reduced Graphene Oxide and Molybdenum Disulfide.

Zirconia and 10%, 20%, and 30% cerium-doped zirconia nanoparticles (ZCO), ZCO-1, ZCO-2, and ZCO-3, respectively, were prepared using auto-combustion method. Binary nanohybrids, ZrO2@rGO and ZCO-2@rGO (rGO = reduced graphene oxide), and ternary nanohybrids, ZrO2@rGO@MoS2 and ZCO-2@rGO@MoS2, have been prepared with an anticipation of a fruitful synergic effect of rGO, MoS2, and cerium-doped zirconia on the tribo-activity. Tribo-activity of these additives in paraffin oil (PO) has been assessed by a four-ball lubricant tester at the optimized concentration, 0.125% w/v. The tribo-performance follows the order: ZCO-2@rGO@MoS2 > ZrO2@rGO@MoS2 > ZCO-2@rGO > ZrO2@rGO > MoS2 > ZrO2 > rGO > PO. The nanoparticles acting as spacers control restacking of the nanosheets provided structural augmentation while nanosheets, in turn, prevent agglomeration of the nanoparticles. Doped nanoparticles upgraded the activity by forming defects. Thus, the results acknowledge the synergic effect of cerium-doped zirconia and lamellar nanosheets of rGO and MoS2. There is noncovalent interaction among all the individuals. Analysis of the morphological features of wear-track carried out by scanning electron microscopy (SEM) and atomic force microscopy (AFM) in PO and its formulations with various additives is consistent with the above sequence. The energy dispersive X-ray (EDX) spectrum of ZCO-2@rGO@MoS2 indicates the existence of zirconium, cerium, molybdenum, and sulfur on the wear-track, confirming, thereby, the active role played by these elements during tribofilm formation. The X-ray photoelectron spectroscopy (XPS) studies of worn surface reveal that the tribofilm is made up of rGO, zirconia, ceria, and MoS2 along with Fe2O3, MoO3, and SO42- as the outcome of the tribo-chemical reaction.

The SUMO Conjugase Ubc9 Protects Dopaminergic Cells from Cytotoxicity and Enhances the Stability of α-Synuclein in Parkinson's Disease Models.

Small ubiquitin-like modifier (SUMO) is a widespread regulatory mechanism of post-translational modification (PTM) that induces rapid and reversible changes in protein function and stability. Using SUMO conjugase Ubc9-overexpressing or knock-down cells in Parkinson's disease (PD) models, we demonstrate that SUMOylation protects dopaminergic cells against MPP+ or preformed fibrils (PFFs) of α-synuclein (α-syn)-induced toxicities in cell viability and cytotoxicity assays. In the mechanism of protection, Ubc9 overexpression significantly suppressed the MPP+ or PFF-induced reactive oxygen species (ROS) generation, while Ubc9-RNAi enhanced the toxicity-induced ROS production. Further, PFF-mediated protein aggregation was exacerbated by Ubc9-RNAi in thioflavin T staining, compared with NC1 controls. In cycloheximide (Chx)-based protein stability assays, higher protein level of α-syn was identified in Ubc9-enhanced green fluorescent protein (EGFP) than in EGFP cells. Since there was no difference in endogenous mRNA levels of α-syn between Ubc9 and EGFP cells in quantitative real-time PCR (qRT-PCR), we assessed the mechanisms of SUMO-mediated delayed α-syn degradation via MG132, proteasomal inhibitor, and PMA, lysosomal degradation inducer. Ubc9-mediated SUMOylated α-syn avoided PMA-induced lysosomal degradation because of its high solubility. Our results suggest that Ubc9 enhances the levels of SUMO1 and ubiquitin on α-syn and interrupts SUMO1 removal from α-syn. In immunohistochemistry, dopaminergic axon tips in the striatum and cell bodies in the substantia nigra from Ubc9-overexpressing transgenic mice were protected from MPTP toxicities compared with wild-type (WT) siblings. Our results support that SUMOylation can be a regulatory target to protect dopaminergic neurons from oxidative stress and protein aggregation, with the implication that high levels of SUMOylation in dopaminergic neurons can prevent the pathologic progression of PD.

Gap Arthroplasty or Interpositional Arthroplasty for the Management of TMJ Ankylosis? A Prospective Randomized Comparative Multicenter Clinical Trial.

AIM: The main aim of this study is to compare the gap arthroplasty with interpositional gap arthroplasty for the management of TMJ ankylosis. METHODOLOGY: A prospective randomized multicenter clinical trial had been performed, on 60 patients diagnosed with TMJ ankylosis from August 2005 to June 2015. Patients were equally divided into two groups: Group I patients were treated with gap arthroplasty, while patients in Group II were treated with interpositional arthroplasty. RESULTS: The mean age in Group I was 27.9 years and in Group II was 25.6 years. Trauma was the common etiological factor in both the groups. The mean postoperative mouth opening after 1 month, 6 months and 24 months was found to better in Group II. Open bite after 24 months was present in six patients in Group I and in one case in Group II. Permanent facial nerve palsy was present in one patient in both the groups. Frey's syndrome was present in one patient from Group I and none from Group II. Reoccurrence occurred in eight cases from Group I (26.6%) and none from Group II. CONCLUSION: This study concluded that interpositional arthroplasty is better than gap arthroplasty in terms of mouth opening and reankylosis.

Control of Postoperative Nausea and Vomiting in Oral and Maxillofacial Surgery Patients with Isopropyl Alcohol: A Prospective Randomized Clinical Trial.

PURPOSE: The present study was undertaken to evaluate the effectiveness of inhaled 70% isopropyl alcohol (IPA) in controlling postoperative nausea and vomiting (PONV) in oral and maxillofacial surgery patients undergoing surgery under general anesthesia (GA). MATERIALS AND METHODS: This was a prospective, randomized, case-controlled study done on 208 maxillofacial surgery patients operated under GA. Patient's demographic data, APFEL score for risk of PONV, duration of surgery and duration of anesthesia were recorded preoperatively. The test arm of the study received inhalation of 70% IPA every half an hour in the postoperative period for 8 h along with ondansetron 4 mg i.v. every 6 h. The control arm received only ondansetron 4 mg i.v. every 6 h. Both the groups followed the same preoperative and postoperative instruction and drug protocol except the test drug. PONV was recorded using the simplified PONV intensity score and VAS. The scores were analyzed with Mann-Whitney test with < 0.05 considered significant. RESULTS: The groups were similar with regard to age (p = 0.083), BMI (p = 0.1.00), sex (p = 0.379), type of surgery (p = 0.504), duration of anesthesia (p = 0.621), duration of surgery (p = 0.515) and APFEL score (p = 0.687). IPA inhalation group achieved significantly better simplified PONV scores and VAS scores at 4 h (p = 0.000), 6 h (p = 0.000) and 8 h (p = 0.000). PONV control at 2 h was similar to the control group. CONCLUSION: Inhalation of 70% IPA every half an hour was associated with significant PONV control in maxillofacial surgery patients undergoing surgery under GA.

Metabolic Enhancer Piracetam Attenuates the Translocation of Mitochondrion-Specific Proteins of Caspase-Independent Pathway, Poly [ADP-Ribose] Polymerase 1 Up-regulation and Oxidative DNA Fragmentation.

Piracetam, a nootropic drug, has been clinically used for decades; however, its mechanism of action still remains enigmatic. The present study was undertaken to evaluate the role of mitochondrion-specific factors of caspase-independent pathway like apoptotic-inducing factor (AIF) and endonuclease-G (endo-G) in piracetam-induced neuroprotection. N2A cells treated with lipopolysaccharide (LPS) exhibited significant cytotoxicity, impaired mitochondrial activity, and reactive oxygen species generation which was significantly attenuated with piracetam co-treatment. Cells co-treated with LPS and piracetam exhibited significant uptake of piracetam in comparison to only piracetam-treated cells as estimated by liquid chromatography-mass spectrometry (LC-MSMS). LPS treatment caused significant translocation of AIF and endonuclease-G in neuronal N2A cells which were significantly attenuated with piracetam co-treatment. Significant over-expression of proinflammatory cytokines was also observed after treatment of LPS to cells which was inhibited with piracetam co-treatment demonstrating its anti-inflammatory property. LPS-treated cells exhibited significant oxidative DNA fragmentation and poly [ADP-ribose] polymerase-1 (PARP-1) up-regulation in nucleus, both of which were attenuated with piracetam treatment. Antioxidant melatonin but not z-VAD offered the inhibited LPS-induced DNA fragmentation indicating the involvement of oxidative DNA fragmentation. Further, we did not observe the altered caspase-3 level after LPS treatment initially while at a later time point, significantly augmented level of caspase-3 was observed which was not inhibited with piracetam treatment. In total, our findings indicate the interference of piracetam in mitochondrion-mediated caspase-independent pathway, as well as its anti-inflammatory and antioxidative properties. Graphical Abstract Graphical abstract indicating the novel interference of metabolic enhancer piracetam (P) in neuronal death mechanisms.

Involvement of glucose related energy crisis and endoplasmic reticulum stress: Insinuation of streptozotocin induced Alzheimer's like pathology.

The present study was conducted to correlate the cellular and molecular alterations in Alzheimer's pathology employing streptozotocin (STZ) induced experimental rat model. The STZ was administered in rat brain bilaterally by intracerebroventricular route using stereotaxic surgery followed by donepezil dosing. The Alzheimer's related pathological marker like acetylcholinesterase (AChE) activity, tau phosphorylation and amyloid aggregation were observed after STZ administration. STZ treatment showed decreased glucose and glucose transporters (GLUT) level along with augmented level of calcium in both cortical and hippocampal regions of rat brain. Increased calcium level may correlate with endoplasmic reticulum (ER) stress and significantly increased expression of ER stress markers like GRP78, GADD and caspase-12 were observed in STZ treated rat brain. Cellular communication was also affected by STZ administration as observed by increased expression connexin 43. With this view the activation of astrocytes and microglia was also assessed and observed by augmented GFAP and cd11b expression which were partially inhibited with donepezil treatment. The significantly increased level of degenerating neurons, caspase-3 and DNA fragmentation was also observed in rat brain regions which were not inhibited with donepezil treatment and validating the clinical observations. In conclusion, study indicated the STZ induced occurrence of Alzheimer's pathology. Further, STZ administration also caused depleted glucose level, inhibited mitochondrial activity, augmented calcium levels, ER stress, altered cellular communication and neuronal death which were partially attenuated with donepezil treatment.