Abstract
Chronic exposure to pesticides is implicated in the etiopathogenesis of Parkinson’s disease (PD). Previously, we showed that dieldrin induces dopaminergic neurotoxicity by activating a ...cascade of apoptotic signaling pathways in experimental models of PD. Here, we systematically investigated endosulfan’s effect on the interplay between apoptosis and autophagy in dopaminergic neuronal cell models of PD. Exposing N27 dopaminergic neuronal cells to endosulfan rapidly induced autophagy, indicated by an increased number of autophagosomes and LC3-II accumulation. Prolonged endosulfan exposure (>9 h) triggered apoptotic signaling, including caspase-2 and -3 activation and protein kinase C delta (PKCδ) proteolytic activation, ultimately leading to cell death, thus demonstrating that autophagy precedes apoptosis during endosulfan neurotoxicity. Furthermore, inhibiting autophagy with wortmannin, a phosphoinositide 3-kinase inhibitor, potentiated endosulfan-induced apoptosis, suggesting that autophagy is an early protective response against endosulfan. Additionally, Beclin-1, a major regulator of autophagy, was cleaved during the initiation of apoptotic cell death, and the cleavage was predominantly mediated by caspase-2. Also, caspase-2 and caspase-3 inhibitors effectively blocked endosulfan-induced apoptotic cell death. CRISPR/Cas9-based stable knockdown of PKCδ significantly attenuated endosulfan-induced caspase-3 activation, indicating that the kinase serves as a regulatory switch for apoptosis. Additional studies in primary mesencephalic neuronal cultures confirmed endosulfan’s effect on autophagy and neuronal degeneration. Collectively, our results demonstrate that a functional interplay between autophagy and apoptosis dictate pesticide-induced neurodegenerative processes in dopaminergic neuronal cells. Our study provides insight into cell death mechanisms in environmentally linked neurodegenerative diseases.
Abstract
Dengue virus is an arthropod-borne virus, transmitted by Aedes aegypti among humans. In this review, we discussed the epidemiology of dengue hemorrhagic fever (DHF) as well as the disease's ...natural history, cycles of transmission, clinical diagnosis, aetiology, prevention, therapy, and management. A systematic literature search was done by databases such as PubMed and Google Scholar using search terms, ‘dengue fever’, ‘symptoms and causes of dengue fever’, ‘dengue virus transmission’, and ‘strategies to control dengue’. We reviewed relevant literature to identify hazards related to DHF and the most recent recommendations for its management and prevention. Clinical signs and symptoms of dengue infection range from mild dengue fever (DF) to potentially lethal conditions like DHF or dengue shock syndrome (DSS). Acute-onset high fever, muscle and joint pain, myalgia, a rash on the skin, hemorrhagic episodes, and circulatory shock are among the most common symptoms. An early diagnosis is vital to lower mortality. As dengue virus infections are self-limiting, but in tropical and subtropical areas, dengue infection has become a public health concern. Hence, developing and executing long-term control policies that can reduce the global burden of DHF is a major issue for public health specialists everywhere.
As a prevalent progressive neurodegenerative disorder, Parkinson’s disease (PD) is characterized by the neuropathological hallmark of the loss of nigrostriatal dopaminergic (DAergic) innervation and ...the appearance of Lewy bodies with aggregated α-synuclein. Although several familial forms of PD have been reported to be associated with several gene variants, most cases in nature are sporadic, triggered by a complex interplay of genetic and environmental risk factors. Numerous epidemiological studies during the past two decades have shown positive associations between PD and several environmental factors, including exposure to neurotoxic pesticides/herbicides and heavy metals as well as traumatic brain injury. Other environmental factors that have been implicated as potential risk factors for PD include industrial chemicals, wood pulp mills, farming, well-water consumption, and rural residence. In this review, we summarize the environmental toxicology of PD with the focus on the elaboration of chemical toxicity and the underlying pathogenic mechanisms associated with exposure to several neurotoxic chemicals, specifically 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, paraquat (PQ), dichloro-diphenyl-trichloroethane (DDT), dieldrin, manganese (Mn), and vanadium (V). Our overview of the current findings from cellular, animal, and human studies of PD provides information for possible intervention strategies aimed at halting the initiation and exacerbation of environmentally linked PD.
Fluorine is characterized by high electronegativity and small atomic size, which provide this molecule with the unique property of augmenting the potency, selectivity, metabolic stability, and ...pharmacokinetics of drugs. Fluorine (F) substitution has been extensively explored in drug research as a means of improving biological activity and enhancing chemical or metabolic stability. Selective F substitution onto a therapeutic or diagnostic drug candidate can enhance several pharmacokinetic and physicochemical properties such as metabolic stability and membrane permeation. The increased binding ability of fluorinated drug target proteins has also been reported in some cases. An emerging line of research on F substitution has been addressed by using 18F as a radiolabel tracer atom in the extremely sensitive methodology of positron emission tomography (PET) imaging. This review aims to report on the fluorinated drugs approved by the US Food and Drug Administration (FDA) from 2016 to 2022. It cites selected examples from a variety of therapeutic and diagnostic drugs. FDA-approved drugs in this period have a variety of heterocyclic cores, including pyrrole, pyrazole, imidazole, triazole, pyridine, pyridone, pyridazine, pyrazine, pyrimidine, triazine, purine, indole, benzimidazole, isoquinoline, and quinoline appended with either F-18 or F-19. Some fluorinated oligonucleotides were also authorized by the FDA between 2019 and 2022.
Cardiovascular diseases are becoming a leading cause of death in the world, and attention is being paid to develop natural drug-based treatment to cure heart diseases. Curcumin, ginger, and magnolol ...are pharmaceutically active in many ways, having properties including anticoagulation, antiproliferation, anti-inflammatory, and antioxidant, and may be used to synthesis coatings for drug-eluting stents to treat cardiovascular diseases. In the present investigation, a degradable polymer with varying molecular weights was used as a drug carrier to control the degradation of polymer; three different natural drugs such as curcumin, magnolol, and ginger were used owing to their reported pharmacological properties. The results of in vitro measurements of all three natural drugs released from drug-loaded polymeric films showed an initial burst release followed by a sustained release for up to 38 days of measurement. On the other hand, different levels of hemocompatibility were observed by varying concentrations of natural drugs in human erythrocytes. As per the ASTM F756 standard, ginger having low concentration showed optimum hemocompatibility with regard to the drug-eluting stent application as compared with magnolol and curcumin concentrations, which showed suboptimal hemocompatibility and fall in the range of mild-to-severe blood toxicity category. The structure of the coating films was characterized by Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM) with results suggesting that there was no chemical bonding between the polymer and drug. Thus, according to this study, it can be concluded that after more detailed in vitro testing such as hemocompatibility tests and platelet adhesion testing, ginger can be a better candidate as a drug-coating material for drug-eluting stent applications.
Background/Aim. Type 2 diabetes is the most common form of diabetes mellitus. The aim of this study was to develop and standardize the polyhedral formulation (granule) and check its efficacy with ...regard to type 2 diabetes. Methods. The alcoholic extract of each plant (H. antidysentrica, Prunus dulcis and Cicer arietinum) and oleic acid was mixed and then formulated by wet granulation method. FTIR was done to investigate the presence of active compounds. Physicochemical properties of granules were evaluated and antidiabetic potential was substantiated through inhibition of carbohydrate digestive enzyme (α-amylase and α-glucosidase), glucose uptake activity in yeast cells, and antioxidant activity. Results. IR spectra indicated the presence of active compounds by showing the characteristic peaks of phenols and amines. The FTIR results also showed no interaction between drug and excipients. The prepared granules exhibited excellent flow properties according to USP 30. The dissolution profile of active pharmaceutical ingredient (API) from granules showed 72–80% release in 2 hrs. Granules exhibited better inhibition of α-amylase and α-glucosidase as in comparison with the standard drug and found to be dose-dependent. The enhanced uptake of glucose was observed with a decrease in drug concentration. Moreover, the DPPH scavenging activity was high (98%) at 1 mg/ml. Conclusion. The stabilized formulation (granules) was formed and the presence of active compounds is responsible for better antidiabetic activity by inhibiting carbohydrate-digesting enzymes. Hence, it could lower the postprandial hyperglycemia and has the potential to be used for the treatment of type II diabetes after determining the dose regime.
In recent years, the use of accelerometer data in biosensors, which tracks physical activity levels and mobility, has gained more attention. Accelerometers offer enormous promise in the field of ...blood pressure measurement in addition to being utilized for physical activity monitoring. It is possible to utilize it as a sensor to measure ballistocardiograms (BCG) and seismocardiograms (SCG), which can be used to forecast blood pressure. Accelerated plethysmograms can also be monitored in real-time with accelerometer-based devices. More importantly, three-dimensional accelerometer data can provide physiological information and can therefore be used to forecast blood pressure. Other research claims to be able to measure pulse transit time (PTT) and, consequently, blood pressure using opto-accelerometers. The data produced by the accelerometer can be used as contextual information in blood pressure prediction models and is essential for preventing motion artifact in physiological signals. These appealing factors lead us to investigate the importance of accelerometer data in this field. This review intends to explore the significance of accelerometer data in blood pressure monitoring, emphasizing its possible effects on clinical practice and public health.
Background: Lung cancer is one of the most fatal cancers worldwide, and malignant tumors are characterized by the growth of abnormal cells in the tissues of lungs. Usually, symptoms of lung cancer do ...not appear until it is already at an advanced stage. The proper segmentation of cancerous lesions in CT images is the primary method of detection towards achieving a completely automated diagnostic system. Method: In this work, we developed an improved hybrid neural network via the fusion of two architectures, MobileNetV2 and UNET, for the semantic segmentation of malignant lung tumors from CT images. The transfer learning technique was employed and the pre-trained MobileNetV2 was utilized as an encoder of a conventional UNET model for feature extraction. The proposed network is an efficient segmentation approach that performs lightweight filtering to reduce computation and pointwise convolution for building more features. Skip connections were established with the Relu activation function for improving model convergence to connect the encoder layers of MobileNetv2 to decoder layers in UNET that allow the concatenation of feature maps with different resolutions from the encoder to decoder. Furthermore, the model was trained and fine-tuned on the training dataset acquired from the Medical Segmentation Decathlon (MSD) 2018 Challenge. Results: The proposed network was tested and evaluated on 25% of the dataset obtained from the MSD, and it achieved a dice score of 0.8793, recall of 0.8602 and precision of 0.93. It is pertinent to mention that our technique outperforms the current available networks, which have several phases of training and testing.
The prevalence of
is escalating in developing countries, exacerbated by unjustified antibiotic usage, which leads to increased resistance. This trend has been notably amplified since the COVID-19 ...pandemic. Consequently, the effectiveness of existing eradication regimens has been compromised. This study aimed to compare the efficacy of two weeks of vonoprazan-based quadruple sequential therapy and lansoprazole-based quadruple sequential therapy in treating
infection. Methods: A non-randomized clinical trial was conducted over 18 months at the Department of Gastroenterology, Lahore General Hospital, Lahore, Pakistan. It included patients presenting with dyspepsia, as defined by the Rome IV criteria, and who tested positive on the urea breath test. Patients were divided into two groups, i.e., Group A and Group B. Group A patients received lansoprazole 30 mg + amoxicillin + tinidazole + tab. colloidal bismuth subcitrate for the first seven days, followed by lansoprazole + levofloxacin + azithromycin + colloidal bismuth subcitrate. Group B patients received vonoprazan + amoxicillin + tinidazole + colloidal bismuth subcitrate for the first seven days, followed by vonoprazan + levofloxacin + azithromycin + colloidal bismuth subcitrate. Both regimes continued for 14 days. Four weeks after 14 days of the treatment, an early morning urea breath test was conducted to evaluate the efficacy of the treatment. Patients were scheduled for follow-up visits at seven and 14 days post-treatment initiation to record adverse events and assess compliance with the treatment regimen. Patients who lost the follow-up and remained non-compliant to the medications were excluded from the final data analysis as per standard protocols of the per-protocol analysis. Results: A total of 252 patients were included. In Group A and Group B, 6/126 (4.76%) and 8/126 (6.35%) of the patients were lost to follow-up, respectively. The non-compliance rate in Group A was 5/126 (3.97%), compared to Group B with 3/126 (2.38%). Finally, the per-protocol analysis of the results included 115 patients in each group. Baseline characteristics, including demographics, lifestyle, and clinical factors, were comparable between groups with p-values of 0.138 for age, 0.356 for gender, 0.126 for BMI, 0.495 for residence, 0.500 for water source, 0.866 for meal habit, 0.863 for smoking, 0.188 for nonsteroidal anti-inflammatory drug (NSAID) use, 0.145 for proton pump inhibitor (PPI) use, 0.213 for antibiotics, and 0.456 for treatment history. Both treatments effectively eradicated
, as determined by a negative urea breath test at four weeks post-treatment, with Group B showing a higher eradication rate of 96.5% compared to 92.2% in Group A, although the difference was not statistically significant (p = 0.153). There was no difference in adverse effects in both treatment groups (p-value > 0.05). Conclusion: The study found that while the vonoprazan-based regime exhibited a slightly higher eradication rate of
compared to lansoprazole, the difference was not statistically significant. It was concluded that both regimens demonstrated comparable efficacy and similar profiles of adverse effects in treating
infection.
Objectives This study aimed to identify the causes, clinical characteristics, and 28-day in-hospital mortality predictors in patients with acute-on-chronic liver failure (ACLF). Methods A ...cross-sectional study enrolled sixty-four patients aged 18-70 years with acute-on-chronic liver failure. The study was conducted at the Gastroenterology Department, Lahore General Hospital. The study classified ACLF according to the criteria of the European Association for the Study of the Liver - Chronic Liver Failure (EASL-CLIF). Patients were followed for 28 days for mortality outcomes. The outcomes between Survivor and Non-survivor groups were compared using the Chi-Square/Fisher's Exact Test for categorical variables and the Mann-Whitney U test for continuous variables. Results In this study, age and duration of chronic liver disease were not significantly different between survivors and non-survivors. The etiology of liver disease and ACLF causes had no impact on 28-day mortality. Non-survivors had lower mean arterial pressure, and higher mortality was linked with lower Glasgow Coma Scale scores, upper gastrointestinal bleeding, and Grade IV hepatic encephalopathy. Significant differences in bilirubin, serum creatinine, urea, and C-reactive protein levels were observed at 28 days. Survival rates were highest with single organ failure (35.94%) and decreased with multiple organ failures. The overall survival rate was 51.56%. Predictive validity for mortality was assessed using the Area Under the Curve (AUC), with Child-Turcotte-Pugh (CTP) at 0.679, Model for End-Stage Liver Disease (MELD) at 0.819, and Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) at 0.771. Conclusion This study concludes that in acute-on-chronic liver failure, factors like age, gender, and disease etiology do not significantly predict 28-day mortality. Key mortality indicators include clinical parameters such as lower Glasgow Coma Scale scores, hepatic encephalopathy Grade IV, and laboratory findings like elevated bilirubin and serum creatinine. The MELD score is the most compelling prognostic tool.
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