Combined effects of vitamin D3 and dioxopiperidinamide derivative on lipid homeostasis, inflammatory pathways, and redox imbalance in non-alcoholic fatty liver disease in vivo zebrafish model.

Liver damage and metabolic dysfunctions, the defining features of non-alcoholic fatty liver disease (NAFLD), are marked by inflammation, oxidative stress, and excessive hepatic fat accumulation. The current therapeutic approaches for NAFLD are limited, necessitating exploring novel treatment strategies. Dioxopiperidinamide derivatives, particularly DOPA-33, have shown effective anti-inflammatory and antioxidant properties, potentially offering therapeutic benefits against NAFLD. This study investigated the combined potential of vitamin D3 (Vit D3) and DOPA-33 in treating NAFLD. The network pharmacology analysis identified key NAFLD targets modulated by Vit D3 and DOPA-33, emphasizing their potential mechanisms of action. In NAFLD-induced zebrafish models, Vit D3 and DOPA-33 significantly reduced hepatic lipid accumulation, oxidative stress, and apoptosis, demonstrating superior efficacy over individual treatments. The treatment also lowered reactive oxygen species (ROS) levels, decreased liver damage, and enhanced antioxidant defense mechanisms. Moreover, behavioral analyses showed improved locomotion and reduced weight gain in treated zebrafish. Biochemical analyses revealed lower triglycerides (TG) and glucose levels with improved oxidative markers. Furthermore, histological analyses indicated reduced hepatic steatosis and inflammation, with decreased expression of lipogenesis-related genes and inflammatory mediators. Finally, high-performance liquid chromatography (HPLC) confirmed a significant reduction in hepatic cholesterol levels, indicating the effectiveness of the combination therapy in addressing key NAFLD-related dyslipidemias. These findings suggest that Vit D3 + DOPA-33 targets pathways involved in lipid metabolism, inflammation, and oxidative stress by offering a promising therapeutic approach for NAFLD.

Indole-3-acetic acid exposure leads to cardiovascular inflammation and fibrosis in chronic kidney disease rat model.

Indole-3-acetic acid (IAA), a protein-bound uremic toxin, has been linked to cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. This study explores the influence of IAA (125 mg/kg) on cardiovascular changes in adenine sulfate-induced CKD rats. HPLC analysis revealed that IAA-exposed CKD rats had lower excretion and increased circulation of IAA compared to both CKD and IAA control groups. Moreover, echocardiography indicated that CKD rats exposed to IAA exhibited heart enlargement, thickening of the myocardium, and cardiac hypertrophy in contrast to CKD or IAA control group. Biochemical analyses supported the finding that IAA-induced CKD rats had elevated serum levels of c-Tn-I, CK-MB, and LDH; there was also evidence of oxidative stress in cardiac tissues, with a significant decrease in SOD and CAT levels, as well as an increase in MDA levels. The gene expression analysis found significant increases in ANP, BNP, ß-MHC, TNF-α, IL-1ß, and NF-κB levels in IAA-exposed CKD groups in contrast to the CKD or IAA control group. In addition, higher cardiac fibrosis markers, including Col-I and Col-III. The findings of this study indicate that IAA could trigger cardiovascular inflammation and fibrosis in CKD conditions.

Antimigraine activity of Asarinin by OPRM1 pathway with multifaceted impacts through network analysis.

Migraine is a debilitating neurological disorder impacting millions worldwide. Calcitonin Gene-Related Peptide (CGRP) has emerged as a key player in migraine pathophysiology, leading to the development of targeted therapies. This study reviews novel CGRP-targeted treatments, including monoclonal antibodies small molecule inhibitors/nutraceuticals and introduces Asarinin as a potential modulator of the pathway. Asarinin, a natural compound found in various plants, is examined for its pharmacological potential in migraine management. Pharmacokinetic assessments, toxicological modelling, molecular property analysis, and network pharmacology were conducted. Molecular docking and dynamics studies with CGRP reveal potential interactions, providing a foundation for understanding Asarinin's therapeutic effects. Asarinin's favourable pharmacokinetics, safety profile, and bioactivity, supporting its candidacy as a therapeutic agent. In-depth molecular docking studies with the CGRP receptor (PDB: 6ZHO) demonstrate strong binding affinity (- 10.3kcal/mol), while molecular dynamics simulations unveil the dynamic behavior of the Asarinin-CGRP complex, (- 10.53 kcal/mol) for Atogepant-CGRP complex. Network analysis highlights key proteins in migraine pathology, indicating Asarinin's potential efficacy. The groundwork for future investigations, suggests Asarinin as a promising candidate for migraine management by targeting OPRM1 pathway. The integration of diverse assessments provides a comprehensive understanding of Asarinin's potential and paves the way for further preclinical and clinical research.

Co-occurrence of azorubine and bisphenol A in beverages increases the risk of developmental toxicity: A study in zebrafish model.

The prevalent use of Azorubine (E122) and the unintentional food additive, Bisphenol A (BPA), in ready-to-drink (RTD) beverages raises significant health concerns, especially for children. The combined impact on embryonic development must be explored despite individual safety assessments. Our investigation revealed that the combined exposure of E122 and BPA at beverage concentration significantly induces mortality and morphological deformities, including reduced growth, pericardial edema, and yolk sac edema. The co-exposure triggers oxidative stress, impairing antioxidant enzyme responses and resulting in lipid and cellular damage. Notably, apoptotic cells are observed in the neural tube and notochord of the co-exposed larvae. Critical genes related to the antioxidant response elements (nrf2, ho1, and nqo1), apoptosis activation (bcl2, bax, and p53), and pro/anti-inflammatory cytokines (nfkb, tnfa, il1b, tgfb, il10, and il12) displayed substantial changes, highlighting the molecular mechanisms. Behavior studies indicated hypo-locomotion with reduced thigmotaxis and touch response in co-exposed larvae, distinguishing it from individual exposures. These findings underscore the neurodevelopmental impacts of E122 and BPA at reported beverage concentrations, emphasizing the urgent need for comprehensive safety assessments, particularly for child consumption.

A role of NLRP3 and MMP9 in migraine progression: a systematic review of translational study.

Background: Migraines affect one billion individuals globally, with a higher occurrence among young adults and women. A significant survey in the United States indicated that 17.1% of women and 5.6% of men suffer from migraines. This study seeks to investigate the potential connection between NLRP3 and MMP9 in migraine pathology. Methods: The research involved searching databases such as PubMed, Scopus, Science Direct, Google Scholar, and Proquest, with the search concluding on March 31, 2024. Following PRISMA guidelines, PICO data were collected, focusing exclusively on animal models induced by Nitroglycerine (10 mg/kg), while excluding clinical studies. Results: The study, originally registered in Prospero Reg. No. CRD42022355893, conducted bias analysis using SYRCLE's RoB tool and evaluated author consensus using GraphPad v9.5.1. Out of 7,359 search results, 22 papers met the inclusion criteria. Inter-rater reliability among reviewers was assessed using Cohen's kappa statistics. Conclusion: This review summarizes 22 preclinical studies on Nitroglycerin (NTG), NLRP3, MMP9, and related biomarkers in migraine. They reveal that NTG, especially at 10 mg/kg, consistently induces migraine-like symptoms in rodents by activating NLRP3 inflammasome and stimulating proinflammatory molecule production. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, CRD42022355893.

Neuroprotective potential of pyrazole benzenesulfonamide derivative T1 in targeted intervention against PTZ-induced epilepsy-like condition in in vivo zebrafish model.

Epilepsy is a chronic neurological disease characterized by a persistent susceptibility to seizures. Pharmaco-resistant epilepsies, impacting around 30 % of patients, highlight the urgent need for improved treatments. Neuroinflammation, prevalent in epileptogenic brain regions, is a key player in epilepsy, prompting the search for new mechanistic therapies. Hence, in this study, we explored the anti-inflammatory potential of pyrazole benzenesulfonamide derivative (T1) against pentylenetetrazole (PTZ) induced epilepsy-like conditions in in-vivo zebrafish model. The results from the survival assay showed 79.97 ± 6.65 % at 150 µM of T1 compared to PTZ-group. The results from reactive oxygen species (ROS), apoptosis and histology analysis showed that T1 significantly reduces cellular damage due to oxidative stress in PTZ-exposed zebrafish. The gene expression analysis and neutral red assay results demonstrated a notable reduction in the inflammatory response in zebrafish pre-treated with T1. Subsequently, the open field test unveiled the anti-convulsant activity of T1, particularly at a concentration of 150 µM. Moreover, both RT-PCR and immunohistochemistry findings indicated a concentration-dependent potential of T1, which inhibited COX-2 in zebrafish exposed to PTZ. In summary, T1 protected zebrafish against PTZ-induced neuronal damage, and behavioural changes by mitigating the inflammatory response through the inhibition of COX-2.

Challenges and mitigation strategies associated with Burkholderia cepacia complex contamination in pharmaceutical manufacturing.

Burkholderia cepacia complex (BCC) is a Gram-negative, non-spore-forming bacterium with more than 20 opportunistic pathogenic species, most commonly found in soil and water. Due to their rapid mutation rates, these organisms are adaptable and possess high genomic plasticity. BCC can cause life-threatening infections in immunocompromised individuals, such as those with cystic fibrosis, chronic granulomatous disease, and neonates. BCC contamination is a significant concern in pharmaceutical manufacturing, frequently causing non-sterile product recalls. BCC has been found in purified water, cosmetics, household items, and even ultrasound gel used in veterinary practices. Pharmaceuticals, personal care products, and cleaning solutions have been implicated in numerous outbreaks worldwide, highlighting the risks associated with intrinsic manufacturing site contamination. Regulatory compliance, product safety, and human health protection depend on testing for BCC in pharmaceutical manufacturing. Identification challenges exist, with BCC often misidentified as other bacteria like non-lactose fermenting Escherichia coli or Pseudomonas spp., particularly in developing countries where reporting BCC in pharmaceuticals remains limited. This review comprehensively aims to address the organisms causing BCC contamination, genetic diversity, identification challenges, regulatory requirements, and mitigation strategies. Recommendations are proposed to aid pharmaceutical chemists in managing BCC-associated risks and implementing prevention strategies within manufacturing processes.

Indole-3 acetic acid induced cardiac hypertrophy in Wistar albino rats.

Indole-3-acetic acid (IAA) is the most widely utilized plant growth regulator. Despite its extensive usage, IAA is often overlooked as an environmental pollutant. Due to its protein-binding nature, it also functions as a uremic toxin, contributing to its association with chronic kidney disease (CKD). While in vitro and epidemiological research have demonstrated this association, the precise impact of IAA on cardiovascular disease in animal models is unknown. The main objective of this study is to conduct a mechanistic analysis of the cardiotoxic effects caused by IAA using male Wistar albino rats as the experimental model. Three different concentrations of IAA (125, 250, 500 mg/kg) were administered for 28 days. The circulating IAA concentration mimicked previously observed levels in CKD patients. The administration of IAA led to a notable augmentation in heart size and heart-to-body weight ratio, indicating cardiac hypertrophy. Echocardiographic assessments supported these observations, revealing myocardial thickening. Biochemical and gene expression analyses further corroborated the cardiotoxic effects of IAA. Dyslipidemia, increased serum c-Troponin-I levels, decreased SOD and CAT levels, and elevated lipid peroxidation in cardiac tissue were identified. Moreover, increased expression of cardiac inflammatory biomarkers, including ANP, BNP, ß-MHC, Col-III, TNF-α, and NF-κB, was also found in the IAA-treated animals. Histopathological analysis confirmed the cardiotoxic nature of IAA, providing additional evidence of its adverse effects on cardiovascular health. These results offer insights into the potential negative impact of IAA on cardiovascular function, and elucidating the underlying mechanisms of its cardiotoxicity.

Major Targets Involved in Clinical Management of Migraine.

BACKGROUND: There has been a protracted effort to identify reliable targets for migraine. It is believed that each year, hundreds of millions of individuals worldwide suffer from migraines, making this widespread neurological ailment the second leading cause of years of disability worldwide. The rationale of this study is to identify the major targets involved in migraine attacks. METHODS: For this review, specialized databases were searched, such as PubMed, EMBASE, DynaMed Plus, and Science Direct databases that included the pathophysiological mechanisms of migraine, focusing on in vitro and in vivo studies in the clinical management of migraine. RESULTS: Calcitonin gene-related peptide, Pituitary adenylate cyclase-activating polypeptide (PACAP), NOD-like receptor Protein (NLRP3), Serotonin, and some other neuroinflammatory biomarkers are collectively responsible for the cerebral blood vessel dilation and involved in the nociceptive pain which leads to migraine attack. CONCLUSION: Migraine biomarkers such as CGRP, PACAP, NLRP3, Nitric oxide synthase, MMP9, and Serotonin could be targets for developing drugs. Present marketed medications temporarily reduce symptoms and pain and have serious cardiovascular side effects. It is suggested that herbal treatment may help prevent migraine attacks without adverse effects. Natural biomolecules that may give better treatment than the present marketed medication and full fledge research should be carried out with natural biomarkers by the Network Pharmacological approach.