Autophagy and UPS pathway contribute to nicotine-induced protection effect in Parkinson's disease.

The gradual nature of age-related neurodegeneration causes Parkinson's disease (PD) and impairs movement, memory, intellectual ability, and social interaction. One of the most prevalent neurodegenerative conditions affecting the central nervous system (CNS) among the elderly is PD. PD affects both motor and cognitive functions. Degeneration of dopaminergic (DA) neurons and buildup of the protein α-synuclein (α-Syn) in the substantia nigra pars compacta (SNpc) are two major causes of this disorder. Both UPS and ALS systems serve to eliminate α-Syn. Autophagy and UPS deficits, shortened life duration, and lipofuscin buildup accelerate PD. This sickness has no cure. Innovative therapies are halting PD progression. Bioactive phytochemicals may provide older individuals with a natural substitute to help delay the onset of neurodegenerative illnesses. This study examines whether nicotine helps transgenic C. elegans PD models. According to numerous studies, nicotine enhances synaptic plasticity and dopaminergic neuronal survival. Upgrades UPS pathways, increases autophagy, and decreases oxidative stress and mitochondrial dysfunction. At 100, 150, and 200 µM nicotine levels, worms showed reduced α-Syn aggregation, repaired DA neurotoxicity after 6-OHDA intoxication, increased lifetime, and reduced lipofuscin accumulation. Furthermore, nicotine triggered autophagy and UPS. We revealed nicotine's potential as a UPS and autophagy activator to prevent PD and other neurodegenerative diseases.

Role of electroanatomical mapping-guided superior vena cava isolation in paroxysmal atrial fibrillation patients without provoked superior vena cava triggers: a randomized controlled study.

AIMS: Data about whether empirical superior vena cava (SVC) isolation (SVCI) improves the success rate of paroxysmal atrial fibrillation (PAF) are conflicting. This study sought to first investigate the characteristics of SVC-triggered atrial fibrillation and secondly investigate the impact of electroanatomical mapping-guided SVCI, in addition to circumferential pulmonary vein isolation (CPVI), on the outcome of PAF ablation in the absence of provoked SVC triggers. METHODS AND RESULTS: A total of 130 patients undergoing PAF ablation underwent electrophysiological studies before ablation. In patients for whom SVC triggers were identified, SVCI was performed in addition to CPVI. Patients without provoked SVC triggers were randomized in a 1:1 ratio to CPVI plus SVCI or CPVI only. The primary endpoint was freedom from any documented atrial tachyarrhythmias lasting over 30 s after a 3-month blanking period without anti-arrhythmic drugs at 12 months after ablation. Superior vena cava triggers were identified in 30 (23.1%) patients with PAF. At 12 months, 93.3% of those with provoked SVC triggers who underwent CPVI plus SVCI were free from atrial tachyarrhythmias. In patients without provoked SVC triggers, SVCI, in addition to CPVI, did not increase freedom from atrial tachyarrhythmias (87.9 vs. 79.6%, log-rank P = 0.28). CONCLUSION: Electroanatomical mapping-guided SVCI, in addition to CPVI, did not increase the success rate of PAF ablation in patients who had no identifiable SVC triggers. REGISTRATION: ChineseClinicalTrials.gov: ChiCTR2000034532.

Biological role and regulation of circular RNA as an emerging biomarker and potential therapeutic target for cancer.

Circular RNAs (circRNAs) are a unique family of endogenous RNAs devoid of 3' poly-A tails and 5' end caps. These single-stranded circRNAs, found in the cytoplasm, are synthesized via back-splicing mechanisms, merging introns, exons, or both, resulting in covalently closed circular loops. They are profusely expressed across the eukaryotic transcriptome and offer heightened stability against exonuclease RNase R compared to linear RNA counterparts. This review endeavors to provide a comprehensive overview of circRNAs' characteristics, biogenesis, and mechanisms of action. Furthermore, aimed to shed light on the potential of circRNAs as significant biomarkers in various cancer types. It has been performed an exhaustive literature review, drawing on recent studies and findings related to circRNA characteristics, synthesis, function, evaluation techniques, and their associations with oncogenesis. CircRNAs are intricately associated with tumor progression and development. Their multifaceted roles encompass gene regulation through the sponging of proteins and microRNAs, controlling transcription and splicing, interacting with RNA binding proteins (RBPs), and facilitating gene translation. Due to these varied roles, circRNAs have become a focal point in tumor pathology investigations, given their promising potential as both biomarkers and therapeutic agents. CircRNAs, due to their unique biogenesis and multifunctionality, hold immense promise in the realm of oncology. Their stability, widespread expression, and intricate involvement in gene regulation underscore their prospective utility as reliable biomarkers and therapeutic targets in cancer. As our understanding of circRNAs deepens, advanced techniques for their detection, evaluation, and manipulation will likely emerge. These advancements might catalyze the translation of circRNA-based diagnostics and therapeutics into clinical practice, potentially revolutionizing cancer care and prognosis.

Impact of hemodialysis on efficacies of the antiplatelet agents in coronary artery disease patients complicated with end-stage renal disease.

It is controversial whether hemodialysis affects the efficacy of the antiplatelet agents. We aimed to investigate the impact of hemodialysis on efficacies of the antiplatelet agents in coronary artery disease (CAD) patients complicated with end-stage renal disease (ESRD). 86 CAD patients complicated with ESRD requiring hemodialysis were consecutively enrolled. After 5-day treatment with aspirin and clopidogrel or ticagrelor, the platelet aggregations induced by arachidonic acid (PLAA) or adenosine diphosphate (PLADP), and the P2Y12 reaction unit (PRU) were measured before and after hemodialysis. The propensity matching score method was adopted to generate a control group with normal renal function from 2439 CAD patients. In patients taking aspirin, the PLAA remained unchanged after hemodialysis. In patients taking clopidogrel, the PLADP (37.26 ± 17.04 vs. 31.77 ± 16.09, p = 0.029) and corresponding clopidogrel resistance (CR) rate (23 [48.9%] vs. 14 [29.8%], p = 0.022) significantly decreased after hemodialysis, though PRU remained unchanged. Subgroup analysis indicated that PLADP significantly decreased while using polysulfone membrane (36.8 ± 17.9 vs. 31.1 ± 14.5, p = 0.024). In patients taking ticagrelor, PLADP, and PRU remained unchanged after hemodialysis. ESRD patients had higher incidences of aspirin resistance (AR) and CR compared to those with normal renal function (AR: 16.1% vs. 0%, p = 0.001; CR: 48.4% vs. 24.8%, p = 0.024). Hemodialysis does not have negative effect on the efficacies of aspirin, clopidogrel and ticagrelor in ESRD patients with CAD. ESRD patients have higher incidences of AR and CR compared with those with normal renal function.Trial registration ClinicalTrials.gov Identifier: NCT03330223, first registered January 4, 2018.

Novel and experimental therapeutics for the management of motor and non-motor Parkinsonian symptoms.

BACKGROUND  : Both motor and non-motor symptoms of Parkinson's disease (PD) have a substantial detrimental influence on the patient's quality of life. The most effective treatment remains oral levodopa. All currently known treatments just address the symptoms; they do not completely reverse the condition. METHODOLOGY: In order to find literature on the creation of novel treatment agents and their efficacy for PD patients, we searched PubMed, Google Scholar, and other online libraries. RESULTS: According to the most recent study on Parkinson's disease (PD), a great deal of work has been done in both the clinical and laboratory domains, and some current scientists have even been successful in developing novel therapies for PD patients. CONCLUSION: The quality of life for PD patients has increased as a result of recent research, and numerous innovative medications are being developed for PD therapy. In the near future, we will see positive outcomes regarding PD treatment.

Apolipoprotein E Gene Variation in Pakistani Subjects with Type 2 Diabetes with and without Cardiovascular Complications.

Background: Apolipoprotein E (APOE) gene polymorphism has been implicated in the pathogenesis of various metabolic disorders, including type 2 diabetes mellitus (T2DM). Type 2 diabetes mellitus (T2DM) is a major public health concern worldwide, including in Pakistan. Cardiovascular problems linked with T2DM have a significant impact on individuals and society. The goal of this study is to investigate the relationship between Apolipoprotein E (ApoE) genotypes, dyslipidemia, and cardiovascular complications such as ischemic heart disease (IHD) and stroke. Methods: This study was carried out on 260 subjects divided into controls and diabetics. The diabetics were further divided into four subgroups such as D1: diabetics without cardiovascular issues, D2: diabetics with heart disease, D3: diabetics with stroke, and D4: diabetics with both heart disease and stroke. Anthropometric parameters (age, BMI) and risk factors (smoking, diabetes duration, hypertension) were assessed in all groups. Serum levels of TC, TG, LDL, HDL, VLDL, creatinine, BSF, and HbA1c were also measured. Apolipoprotein E gene polymorphism was determined using PCR-RFLP. Results: Hypertension, BMI, and dyslipidemia are defined as elevated levels of total cholesterol, triglycerides, LDL, and VLDL, and decreased levels of HDL. Uncontrolled hyperglycemia (elevated fasting blood sugar and glycated hemoglobin) in T2DM was linked to vascular complications such as IHD and stroke. Hypertension was prevalent in 79.3% of the population. Stage 2 hypertension was more prevalent in all age groups. It was also noted that common genotypes in the Pakistani population are 3/3, 4/4, 2/3, and 3/4. The frequency of genotypes 3/4 and 2/3 is highest in diabetics with stroke. Genotype 3/3 is present frequently in diabetics with IHD/stroke and patients with both these complications. However, genotype 4/4 is most frequently found in diabetics with IHD. Conclusions: It is concluded that BMI, hypertension, hyperglycemia, atherosclerosis, and dyslipidemia are linked with cardiovascular complications of type 2 diabetes. Apolipoprotein E gene polymorphism is associated with cardiovascular disease in patients with diabetes by affecting the lipid profile.

A novel homozygous missense substitution p.Thr313Ile in the PDE6B gene underlies autosomal recessive retinitis pigmentosa in a consanguineous Pakistani family.

BACKGROUND: Retinitis pigmentosa (RP) is one of the most frequent hereditary retinal diseases that often starts with night blindness and eventually leads to legal blindness. Our study aimed to identify the underlying genetic cause of autosomal recessive retinitis pigmentosa (arRP) in a consanguineous Pakistani family. METHODS: Following a detailed ophthalmological examination of the patients by an ophthalmologist, whole-exome sequencing was performed on the proband's DNA to delineate the genetic cause of RP in the family. In-depth computational methods, in-silico analysis, and familial co-segregation study were performed for variant detection and validation. RESULTS: We studied an inbred Pakistani family with two siblings affected by retinitis pigmentosa. The proband, a 32 years old female, was clinically diagnosed with RP at the age of 6 years. A classical night blindness symptom was reported in the proband since her early childhood. OCT report showed a major reduction in the outer nuclear layer and the ellipsoid zone width, leading to the progression of the disease. Exome sequencing revealed a novel homozygous missense mutation (c.938C > T;p.Thr313Ile) in exon 12 of the PDE6B gene. The mutation p.Thr313Ile co-segregated with RP phenotype in the family. The altered residue (p.Thr313) was super conserved evolutionarily across different vertebrate species, and all available in silico tools classified the mutation as highly pathogenic. CONCLUSION: We present a novel homozygous pathogenic mutation in the PDE6B gene as the underlying cause of arRP in a consanguineous Pakistani family. Our findings highlight the importance of missense mutations in the PDE6B gene and expand the known mutational repertoire of PDE6B-related RP.

Multiscale Feature-Learning with a Unified Model for Hyperspectral Image Classification.

In the realm of hyperspectral image classification, the pursuit of heightened accuracy and comprehensive feature extraction has led to the formulation of an advance architectural paradigm. This study proposed a model encapsulated within the framework of a unified model, which synergistically leverages the capabilities of three distinct branches: the swin transformer, convolutional neural network, and encoder-decoder. The main objective was to facilitate multiscale feature learning, a pivotal facet in hyperspectral image classification, with each branch specializing in unique facets of multiscale feature extraction. The swin transformer, recognized for its competence in distilling long-range dependencies, captures structural features across different scales; simultaneously, convolutional neural networks undertake localized feature extraction, engendering nuanced spatial information preservation. The encoder-decoder branch undertakes comprehensive analysis and reconstruction, fostering the assimilation of both multiscale spectral and spatial intricacies. To evaluate our approach, we conducted experiments on publicly available datasets and compared the results with state-of-the-art methods. Our proposed model obtains the best classification result compared to others. Specifically, overall accuracies of 96.87%, 98.48%, and 98.62% were obtained on the Xuzhou, Salinas, and LK datasets.

Advancements in Neighboring-Based Energy-Efficient Routing Protocol (NBEER) for Underwater Wireless Sensor Networks.

Underwater wireless sensor networks (UWSNs) have gained prominence in wireless sensor technology, featuring resource-limited sensor nodes deployed in challenging underwater environments. To address challenges like power consumption, network lifetime, node deployment, topology, and propagation delays, cooperative transmission protocols like co-operative (Co-UWSN) and co-operative energy-efficient routing (CEER) have been proposed. These protocols utilize broadcast capabilities and neighbor head node (NHN) selection for cooperative routing. This research introduces NBEER, a novel neighbor-based energy-efficient routing protocol tailored for UWSNs. NBEER aims to surpass the limitations of Co-UWSN and CEER by optimizing NHNS and cooperative mechanisms to achieve load balancing and enhance network performance. Through comprehensive MATLAB simulations, we evaluated NBEER against Co-UWSN and CEER, demonstrating its superior performance across various metrics. NBEER significantly maximizes end-to-end delay, reduces energy consumption, improves packet delivery ratio, extends network lifetime, and enhances total received packets analysis compared to the existing protocols.

Intensified antiplatelet therapy in patients after percutaneous coronary intervention with high on-treatment platelet reactivity: the OPTImal Management of Antithrombotic Agents (OPTIMA)-2 Trial.

High on-treatment platelet reactivity (HOPR) is associated with increased risk of cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). We randomised post-PCI patients with HOPR after 5 days of standard dual antiplatelet therapy (DAPT) to intensified therapy with aspirin 100 mg once daily in combination with either clopidogrel 150 mg once daily, clopidogrel 75 mg once daily plus cilostazol 100 mg twice daily, ticagrelor 90 mg twice daily, or standard therapy with clopidogrel 75 mg once daily (STD) for 1 month, after which all patients were switched to standard DAPT for a further 11 months. The primary outcome was residual HOPR rate at 1 month. We screened 1724 patients with light transmission aggregation studies and randomised 434 with HOPR. At 1 month the proportion of patients with persistent HOPR was significantly lower in the intensified therapy groups compared with STD group. Compared to the group receiving STD therapy, those receiving intensified therapy had significantly lower rate of major adverse cardiovascular events (MACE) at both 1 month and 12 months with no significant increase in bleeding. In patients with post-PCI HOPR, 1 month of intensified antiplatelet therapy provides greater platelet inhibition and improves outcomes without increasing bleeding. Clinical Trial Registration URL: http://www.clinicaltrials.gov; Unique Identifier: NCT01955200.

IGWO-IVNet3: DL-Based Automatic Diagnosis of Lung Nodules Using an Improved Gray Wolf Optimization and InceptionNet-V3.

Artificial intelligence plays an essential role in diagnosing lung cancer. Lung cancer is notoriously difficult to diagnose until it has progressed to a late stage, making it a leading cause of cancer-related mortality. Lung cancer is fatal if not treated early, making this a significant issue. Initial diagnosis of malignant nodules is often made using chest radiography (X-ray) and computed tomography (CT) scans; nevertheless, the possibility of benign nodules leads to wrong choices. In their first phases, benign and malignant nodules seem very similar. Additionally, radiologists have a hard time viewing and categorizing lung abnormalities. Lung cancer screenings performed by radiologists are often performed with the use of computer-aided diagnostic technologies. Computer scientists have presented many methods for identifying lung cancer in recent years. Low-quality images compromise the segmentation process, rendering traditional lung cancer prediction algorithms inaccurate. This article suggests a highly effective strategy for identifying and categorizing lung cancer. Noise in the pictures was reduced using a weighted filter, and the improved Gray Wolf Optimization method was performed before segmentation with watershed modification and dilation operations. We used InceptionNet-V3 to classify lung cancer into three groups, and it performed well compared to prior studies: 98.96% accuracy, 94.74% specificity, as well as 100% sensitivity.

AWANet: Attentive-Aware Wide-Kernels Asymmetrical Network with Blended Contour Information for Salient Object Detection.

Although deep learning-based techniques for salient object detection have considerably improved over recent years, estimated saliency maps still exhibit imprecise predictions owing to the internal complexity and indefinite boundaries of salient objects of varying sizes. Existing methods emphasize the design of an exemplary structure to integrate multi-level features by employing multi-scale features and attention modules to filter salient regions from cluttered scenarios. We propose a saliency detection network based on three novel contributions. First, we use a dense feature extraction unit (DFEU) by introducing large kernels of asymmetric and grouped-wise convolutions with channel reshuffling. The DFEU extracts semantically enriched features with large receptive fields and reduces the gridding problem and parameter sizes for subsequent operations. Second, we suggest a cross-feature integration unit (CFIU) that extracts semantically enriched features from their high resolutions using dense short connections and sub-samples the integrated information into different attentional branches based on the inputs received for each stage of the backbone. The embedded independent attentional branches can observe the importance of the sub-regions for a salient object. With the constraint-wise growth of the sub-attentional branches at various stages, the CFIU can efficiently avoid global and local feature dilution effects by extracting semantically enriched features via dense short-connections from high and low levels. Finally, a contour-aware saliency refinement unit (CSRU) was devised by blending the contour and contextual features in a progressive dense connected fashion to assist the model toward obtaining more accurate saliency maps with precise boundaries in complex and perplexing scenarios. Our proposed model was analyzed with ResNet-50 and VGG-16 and outperforms most contemporary techniques with fewer parameters.

Early-Stage Alzheimer's Disease Categorization Using PET Neuroimaging Modality and Convolutional Neural Networks in the 2D and 3D Domains.

Alzheimer's Disease (AD) is a health apprehension of significant proportions that is negatively impacting the ageing population globally. It is characterized by neuronal loss and the formation of structures such as neurofibrillary tangles and amyloid plaques in the early as well as later stages of the disease. Neuroimaging modalities are routinely used in clinical practice to capture brain alterations associated with AD. On the other hand, deep learning methods are routinely used to recognize patterns in underlying data distributions effectively. This work uses Convolutional Neural Network (CNN) architectures in both 2D and 3D domains to classify the initial stages of AD into AD, Mild Cognitive Impairment (MCI) and Normal Control (NC) classes using the positron emission tomography neuroimaging modality deploying data augmentation in a random zoomed in/out scheme. We used novel concepts such as the blurring before subsampling principle and distant domain transfer learning to build 2D CNN architectures. We performed three binaries, that is, AD/NC, AD/MCI, MCI/NC and one multiclass classification task AD/NC/MCI. The statistical comparison revealed that 3D-CNN architecture performed the best achieving an accuracy of 89.21% on AD/NC, 71.70% on AD/MCI, 62.25% on NC/MCI and 59.73% on AD/NC/MCI classification tasks using a five-fold cross-validation hyperparameter selection approach. Data augmentation helps in achieving superior performance on the multiclass classification task. The obtained results support the application of deep learning models towards early recognition of AD.

Genes and Longevity of Lifespan.

Aging is a complex process indicated by low energy levels, declined physiological activity, stress induced loss of homeostasis leading to the risk of diseases and mortality. Recent developments in medical sciences and an increased availability of nutritional requirements has significantly increased the average human lifespan worldwide. Several environmental and physiological factors contribute to the aging process. However, about 40% human life expectancy is inherited among generations, many lifespan associated genes, genetic mechanisms and pathways have been demonstrated during last decades. In the present review, we have evaluated many human genes and their non-human orthologs established for their role in the regulation of lifespan. The study has included more than fifty genes reported in the literature for their contributions to the longevity of life. Intact genomic DNA is essential for the life activities at the level of cell, tissue, and organ. Nucleic acids are vulnerable to oxidative stress, chemotherapies, and exposure to radiations. Efficient DNA repair mechanisms are essential for the maintenance of genomic integrity, damaged DNA is not replicated and transferred to next generations rather the presence of deleterious DNA initiates signaling cascades leading to the cell cycle arrest or apoptosis. DNA modifications, DNA methylation, histone methylation, histone acetylation and DNA damage can eventually lead towards apoptosis. The importance of calorie restriction therapy in the extension of lifespan has also been discussed. The role of pathways involved in the regulation of lifespan such as DAF-16/FOXO (forkhead box protein O1), TOR and JNK pathways has also been particularized. The study provides an updated account of genetic factors associated with the extended lifespan and their interactive contributory role with cellular pathways.

Theranostic Interpolation of Genomic Instability in Breast Cancer.

Breast cancer is a diverse disease caused by mutations in multiple genes accompanying epigenetic aberrations of hazardous genes and protein pathways, which distress tumor-suppressor genes and the expression of oncogenes. Alteration in any of the several physiological mechanisms such as cell cycle checkpoints, DNA repair machinery, mitotic checkpoints, and telomere maintenance results in genomic instability. Theranostic has the potential to foretell and estimate therapy response, contributing a valuable opportunity to modify the ongoing treatments and has developed new treatment strategies in a personalized manner. "Omics" technologies play a key role while studying genomic instability in breast cancer, and broadly include various aspects of proteomics, genomics, metabolomics, and tumor grading. Certain computational techniques have been designed to facilitate the early diagnosis of cancer and predict disease-specific therapies, which can produce many effective results. Several diverse tools are used to investigate genomic instability and underlying mechanisms. The current review aimed to explore the genomic landscape, tumor heterogeneity, and possible mechanisms of genomic instability involved in initiating breast cancer. We also discuss the implications of computational biology regarding mutational and pathway analyses, identification of prognostic markers, and the development of strategies for precision medicine. We also review different technologies required for the investigation of genomic instability in breast cancer cells, including recent therapeutic and preventive advances in breast cancer.

mTOR as a Potential Target for the Treatment of Microbial Infections, Inflammatory Bowel Diseases, and Colorectal Cancer.

The mammalian target of rapamycin (mTOR) is the major controller of a number of important cellular activities, including protein synthesis, cell expansion, multiplication, autophagy, lysosomal function, and cellular metabolism. When mTOR interacts with specific adaptor proteins, it forms two complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The mTOR signaling system regulates gene transcription and protein manufacturing to control proliferation of cell, differentiation of immune cell, and tumor metabolism. Due to its vital role in case of microbial infections, inflammations and cancer development and progression, mTOR has been considered as a key therapeutic target for the development of targeted medication. As autophagy dysfunction is linked to changes in both innate and adaptive immune responses, bacterial clearance defects, and goblet and Paneth cell malfunction, all of these changes are linked to inflammatory bowel diseases (IBD) and colorectal cancer (CRC) pathogenesis. Preclinical and clinical data have shown that the inhibition and induction of autophagy have significant potential to be translated into the clinical applications. In IBD and several CRC models, mTORC1 inhibitors have been found effective. In the recent years, a number of novel mTOR inhibitors have been investigated in clinical trials, and a number of drugs have shown considerably enhanced efficacy when combined with mTOR inhibitors. The future developments in the mTOR targeting medications can benefit patients in individualized therapy. Advanced and innovative medicines that are more effective and have lower drug resistance are still in high demand. New findings could be relevant in medicine development, pharmacological modification, or future mTOR inhibitor research. Therefore, the goal of this review is to present a comprehensive account of current developments on the mTOR pathway and its inhibitors, with an emphasis on the management of microbial infections, the treatment of inflammatory bowel disease, and the management of colon cancer.

Phytochemicals Mediated Synthesis of AuNPs from Citrullus colocynthis and Their Characterization.

Engineered nanoparticles that have distinctive targeted characteristics with high potency are modernistic technological innovations. In the modern era of research, nanotechnology has assumed critical importance due to its vast applications in all fields of science. Biologically synthesized nanoparticles using plants are an alternative to conventional methods. In the present study, Citrullus colocynthis (bitter apple) was used for the synthesis of gold nanoparticles (AuNPs). UV-Vis's spectroscopy, XRD, SEM and FTIR were performed to confirm the formation of AuNPs. UV-Vis's spectra showed a characteristic peak at the range of 531.5-541.5 nm. XRD peaks at 2 θ = 38°, 44°, 64° and 77°, corresponding to 111, 200, 220 and 311 planes, confirmed the crystalline nature of AuNPs. Spherical AuNPs ranged mostly between 7 and 33 nm, and were measured using SEM. The FTIR analysis confirmed the presence of phytochemicals on the surface of AuNPs. Successful synthesis of AuNPs by seed extract of Citrullus colocynthis (bitter apple) as a capping and reducing agent represents the novelty of the present study.

In Vivo Assessment of the Ameliorative Impact of Some Medicinal Plant Extracts on Lipopolysaccharide-Induced Multiple Sclerosis in Wistar Rats.

Multiple sclerosis is a chronic autoimmune disorder that leads to the demyelination of nerve fibers, which is the major cause of non-traumatic disability all around the world. Herbal plants Nepeta hindustana L., Vitex negundo L., and Argemone albiflora L., in addition to anti-inflammatory and anti-oxidative effects, have shown great potential as neuroprotective agents. The study was aimed to develop a neuroprotective model to study the effectiveness of herbal plants (N. hindustana, V. negundo, and A. albiflora) against multiple sclerosis. The in vivo neuroprotective effects of ethanolic extracts isolated from N. hindustana, V. negundo, and A. albiflora were evaluated in lipopolysaccharides (LPS) induced multiple sclerosis Wistar rat model. The rat models were categorized into seven groups including group A as normal, B as LPS induced diseased group, while C, D, E, F, and G were designed as treatment groups. Histopathological evaluation and biochemical markers including stress and inflammatory (MMP-6, MDA, TNF-α, AOPPs, AGEs, NO, IL-17 and IL-2), antioxidant (SOD, GSH, CAT, GPx), DNA damage (Isop-2α, 8OHdG) as well as molecular biomarkers (RAGE, Caspase-8, p38) along with glutamate, homocysteine, acetylcholinesterase, and myelin binding protein (MBP) were investigated. The obtained data were analyzed using SPSS version 21 and GraphPad Prism 8.0. The different extract treated groups (C, D, E, F, G) displayed a substantial neuroprotective effect regarding remyelination of axonal terminals and oligodendrocytes migration, reduced lymphocytic infiltrations, and reduced necrosis of Purkinje cells. The levels of stress, inflammatory, and DNA damage markers were observed high in the diseased group B, which were reduced after treatments with plant extracts. The antioxidant activity was significantly reduced in diseased induced group B, however, their levels were raised after treatment with plant extract. Group F (a mélange of all the extracts) showed the most significant change among all other treatment groups (C, D, E, G). The communal dose of selected plant extracts regulates neurodegeneration at the cellular level resulting in restoration and remyelination of axonal neurons. Moreover, 400 mg/kg dose of three plants in conjugation (Group F) were found to be more effective in restoring the normal activities of all measured parameters than independent doses (Group C, D, E) and is comparable with standard drug nimodipine (Group G) clinically used for the treatment of multiple sclerosis. The present study, for the first time, reported the clinical evidence of N. hindustana, V. negundo, and A. albiflora against multiple sclerosis and concludes that all three plants showed remyelination as well neuroprotective effects which may be used as a potential natural neurotherapeutic agent against multiple sclerosis.

Increased Expression of Circulating Stress Markers, Inflammatory Cytokines and Decreased Antioxidant Level in Diabetic Nephropathy.

Background and Objectives: The main objective of the present study was to determine the role of oxidative markers (glutathione (GSH), advanced oxidation protein products (AOPP), advanced glycation end products (AGEs), and malondialdehyde (MDA)) and inflammatory biomarkers (interleukin-6 IL-6, tumor necrosis factor α (TNF-α), myeloperoxide (MPO)) in the development of diabetic nephropathy along with routinely used biochemical parameters. Materials and Method: This was a case control study. All the selected patients were screened and enrolled by convenient non-probability sampling technique at the Jinnah hospital in Lahore. Informed consent was obtained before enrollment of the study subjects. A total of 450 patients enrolled in the study, and they were divided into three groups, 150 subjects with type 2 diabetes and 150 diagnosed diabetic nephropathy (DN) vs. 150 healthy individuals as a control group. Five mL of venous blood sample was taken from the antecubital vein of each participant. Statistical analysis was performed by SPSS. The results of all variables were evaluated by using one way ANOVA. Results: The mean value of biochemical parameters (WBCs, platelets, prothrombin time, HbA1c, glucose, urinary albumin-to creatinine ratio (UACR), triglycerides, LDL, HDL, serum creatinine, urinary albumin (creatinine)) were increased and Hb (g/dL), red blood cells (RBCs), hematocrit (Hct), free serum insulin levels, and estimated glomerular filtration rate (eGFR) were decreased in the nephropathy group compared to the control and type 2 diabetes groups. The mean values of MDA, AGE, and AOPPs in type 2 diabetes and diabetic nephropathy were significantly increased compared to the control group. GSH level was decreased in type 2 diabetics and DN patients as compared to the control group. In addition, IL-6, TNFα, and MPO levels were also increased in case of diabetes nephropathy compared to controls. Conclusions: ROS mediated injuries can be prevented by the restoration of an antioxidant defense system, through the administration of antioxidant agents. Moreover, increased levels of inflammatory mediators are responsible for enhancing inflammation in patients with diabetic nephropathy.

An optimal window of platelet reactivity by LTA assay for patients undergoing percutaneous coronary intervention.

OBJECTIVE: This study was aimed to determine how platelet reactivity (PR) on dual antiplatelet therapy predicts ischemic and bleeding events in patients underwent percutaneous coronary intervention (PCI). DESIGN: A total of 2768 patients who had received coronary stent implantation and had taken aspirin 100 mg in combination with clopidogrel 75 mg daily for > 5 days were consecutively screened and 1885 were enrolled. The recruited patients were followed-up for 12 months. The primary end-point was the net adverse clinical events (NACE) of cardiovascular death, nonfatal myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis (ST) and any bleeding. RESULT: 1709 patients completed the clinical follow-up. By using the receiver operating characteristic (ROC) curve analysis, the optimal cut-off values were found to be 37.5 and 25.5% respectively in predicting ischemic and bleeding events. Patients were classified into 2 groups according to PR: inside the window group (IW) [adenosine diphosphate (ADP) induced platelet aggregation (PLADP) 25.5-37.4%)] and outside the window group (OW) (PLADP < 25.5% or ≥ 37.5%). The incidence of NACE was 16.8 and 23.1% respectively in the IW and OW group. The hazard ratio of NACE in IW group was significantly lower [0.69 (95% CI, 0.54-0.89, P = 0.004)] than that in the OW group during 12-month follow-up. CONCLUSION: An optimal therapeutic window of 25.5-37.4% for PLADP predicts the lowest risk of NACE, which could be referred for tailored antiplatelet treatment while using LTA assay. TRIAL REGISTRATION: Trial registration number: ClinicalTrials.gov NCT01968499 . Registered 18 October 2013 - Retrospectively registered.