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.

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.

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.

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.

Preclinical evaluation of Hibiscus cannabinus Linn. in the treatment of urolithiasis and cholelithiasis / 数字中医药（英文）

@#【Objective】  To investigate the therapeutic effect of Hibiscus cannabinus Linn. (H. cannabinus) leaves on cholelithiasis and urolithiasis. 【Methods】  The study evaluated the effect of aqueous leaf extract of H. cannabinus on thiouracil and cholesterol cholic acid diet induced cholelithiasis in BALB/c mice and ethylene glycol induced urolithiasis in Wistar rats. Three doses of aqueous extract (40, 80, and 160 mg/kg) were selected to evaluate the effectiveness in cholelithiasis in mice; another three doses of aqueous extract (400, 800, and 1 600 mg/kg) were administered for evaluating the effect on urolithiasis in rats. Biochemical parameters such as biliary cholesterol, biliary phospholipid, and bile acid were determined in cholelithiasis model. Similarly, 24-hour urine output, urinary parameters such as creatinine, uric acid, protein, urea, presence of calcium oxalate crystals, red blood cells (RBCs), and pyuria were determined in urolithiasis model. 【Results】  Statistically significant differences were noted in the biliary and urinary parameters after administrating three test doses of H. cannabinus aqueous extract (P < 0.05). 【Conclusion】 H. cannabinus was found to be effective against high fat lithogenic diet urolithiasis and cholelithiasis.

Preventive and therapeutic effects of Aerva lanata (L.) extract on ethylene glycol-induced nephrolithiasis in male Wistar albino rats / 数字中医药（英文）

@#Objective Nephrolithiasis is a common urological disease. This study aims to evaluate the preventive and therapeutic effects of hydro-alcoholic extract of Aerva lanata (L.) roots (HAEAL) on ethylene glycol-induced nephrolithiasis in rats. Methods Fifty grams of shade-dried coarsely powdered Aerva lanata (L.) root was successively extracted with organic solvents in increasing order of polarity [petroleum ether (60 −80 °C), chloroform, and ethanol] using a Soxhlet apparatus, and then concentrated. Physical tests including nature, color, odor, and texture were performed on the herbal suspension. In vitro nephrolithiasis assessment was performed by nucleation assay, aggregation assay, and crystal growth assay. Thirty adult male Wistar albino rats were randomly divided into five groups (six rats in each group). Group 1: negative control group without induction or treatment till day 28. Group 2: positive control group receiving a daily oral solution of 0.75% ethylene glycol till day 14, and mixed with distilled water till day 28. Group 3: standard group receiving a daily oral solution of 0.75% ethylene glycol till day 14 and Cystone (750 mg/kg) from day 15 to day 28. Group 4: low dose HAEAL group receiving a daily oral solution of 0.75% ethylene glycol till day 14, and 400 mg/kg HAEAL from day 15 to day 28 (1 mL per day). Group 5: high dose HAEAL group receiving a daily oral solution of 0.75% ethylene glycol till day 14, and 800 mg/kg HAEAL from day 15 to day 28 (1 mL per day). Urine (urine volume, pH value, appearance, odor, and turbidity) examination and serum test were performed. On day 29, the kidneys were dissected, and histopathology examination was performed to determine the degree of tubular injury. Results The suspension showed stability and aroma with no turbidity at room temperature. The suspension did not show changes in color and odor until day 3, indicating that the preparation was stable for 72 h. Body weight decreased in the positive control group indicating stone formation and changes in water intake. Both standard and HAEAL treatments restored the body weight to normal levels after treatment, indicating the beneficial effects of the treatment. Histopathological examination revealed no significant findings in the negative control group, whereas the positive control group showed inflammation in the kidney parenchyma. Compared with positive control group, there was increase in urine volume and excretion of urinary constituents such as calcium and oxalate (P < 0.01) as well as improved clearance rate (P < 0.05) in HAEAL treatment groups, in addition, the urine pH value of HAEAL groups was increased. Conclusion HAEAL reduced nephrolithiasis formation and had a diuretic effect, which could be used to promote the expulsion of stones. Further studies are needed to enhance the stability of the suspension for the production of better pharmaceutical formulations.