Impact of food additives on neurodevelopmental processes in zebrafish (Danio rerio): Exploring circadian clock genes and dopamine system.

Assessing the impact of food additives on neurodevelopmental processes extends beyond traditional acute toxicity evaluations to address subtler, long-term effects. This study investigates the impact of common food additives (tartrazine, sunset yellow, sodium benzoate, and aspartame) on neurodevelopment in zebrafish embryos, observed from 18 hours postfertilization (hpf) to 91 days postfertilization (dpf). Results show reduced 96 hpf locomotor activity after aspartame exposure, with elevated additives correlating with decreased heart rates and induced neurodegenerative phenotypes, including bent tails and abnormal pigmentation. Although locomotor activity decreases at 7 days postexposure, a gradual recovery is observed. Transcriptome analysis indicates alterations in clock genes (Cry2 and Per2) and dopamine-related genes (NURR1 and tyrosine hydroxylase) in zebrafish larvae. Dietary additive exposure during embryonic development impacts clock genes, influencing dopamine activity and resulting in neurobehavioral changes. This study underscores potential risks associated with dietary additive exposure during critical developmental stages, warranting reconsideration of consumption guidelines, especially for expectant mothers. Observed neurodevelopmental toxicity, even below recommended levels, emphasizes the importance of safeguarding neurodevelopmental health in early life. Our findings contribute to understanding the neurotoxic effects of dietary additives, emphasizing the necessity of protecting neurodevelopment during vulnerable periods. This study is the first to demonstrate a direct correlation between food additives and the dysregulation of key circadian rhythm and dopaminergic genes in zebrafish, providing new insights into the neurodevelopmental impacts of dietary additives. These findings pave the way for further research into the molecular mechanisms and potential implications for human health.

Small-Molecule-Targeted Therapies for Gastrointestinal Cancer: Successes and Failures.

The genomic era witnessed the deciphering of molecular mechanisms underlying human gastric cancer (GC) that paved the way to specifically target key molecules or proteins involved in disease progression. A multifactorial disease, GC has a host of other factors that influence its initiation and progression such as age, gender, severe exposure to several environmental pressures, and inadequate diet. These aspects lead to changes at the molecular level that reflect at the protein level, thereby contributing to cancer. Targeting such specific proteins, widely referred to as targeted therapy (TT), is actively sought because it promises treatment precision. Several clinical trials are underway with candidate drugs and in combination with other lines of treatment such as chemotherapy and radiation therapy, for which results are varied. This review summarizes strategies that are involved in GC treatment, delving deeply into TT approaches (based on small molecules) that have already reached the clinic or are currently in clinical trials.

Circulating Biomarkers for the Early Diagnosis of Gastrointestinal Cancers.

Gastrointestinal (GI) cancer is a particularly sobering disease because it carries a high mortality rate. The characteristic tendency of GI cancers to reveal symptoms only in the malignant phase is the major contributing factor to its poor patient outcomes. Hence, it is critical to actively work towards identifying methods to diagnose this type of cancer in its early stages. Over the last decade, there has been robust research into identifying methods to detect GI cancers in their early stages with a particular emphasis on circulating biomarkers for this purpose. The present report is a review compounded from over 140 research papers on the emerging influence of circulating biomarkers in this regard. Circulating biomarker-based diagnosis via liquid biopsy offers several advantages over traditional diagnostic methods, such as colonoscopy, because the method is noninvasive; it can be used to monitor tumor load with respect to medication; and it can be used to predict recurrence. This review is largely divided into two relevant subtopics: biomarkers to diagnose gastrointestinal neuroendocrine tumors and genetic biomarkers used to diagnose common GI cancers. We focus on DNA-based biomarkers and the associated epigenetic dysregulation seen in these cancer types. Research into this area is urgently needed, and through this review chapter, the reader will gain a broad understanding of the various current uses of circulating biomarkers for both early diagnosis and prognosis of GI cancers.

Enhancement of antimicrobial activity by liposomal oleic acid-loaded antibiotics for the treatment of multidrug-resistant Pseudomonas aeruginosa.

In this study, we examined the efficacy of liposomal oleic acid-based antibiotic formulations on 32 strains of multidrug-resistant Pseudomonas aeruginosa (MDRPa). The average size of liposomes were 93.12 ± 2.3 nm holding a negative zeta potential at -57.3 ± 0.89. Liposomal antibiotic formulations were tested against 32 MDRPa strains isolated from burn wounds and urine samples, which exhibited an MIC of ≤8 µg/mL, whereas MIC of free antibiotics ranged from 32 to >1024 µg/mL. The results clearly indicate that the liposomes composed of naturally occurring oleic acid, could be used therapeutically either alone or in combination with antibiotics to effectively treat P. aeruginosa infections.

Novel pyochelin-based PEGylated liposomes for enhanced delivery of antibiotics against resistant clinical isolates of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a problematic human pathogen resistant to almost all available antibiotics. The important prerequisite for these drugs to target this bacterium is an efficient delivery system. Siderophore-mediated drug delivery system is a promising approach to carry out antibiotics to the cells. Pyochelin, a siderophore of P. aeruginosa, was successfully synthesized in a five-step procedure. PEGylated liposomal pyochelin-antibiotic (L-Pch-Ab) carrier was fabricated by thin-film hydration method. L-Pch-Ab had an average size of 90.31 ± 0.11 nm holding a negative zeta potential at -54.12 ± 0.03 mV (PDI <2). The MIC determined by broth dilution method against three clinical strains isolated from burn wounds showed that L-Pch-Ab significantly reduced (≤16 µg/ml) the MIC values than those of free antibiotics. In the time kill assay, L-Pch-Ab was bactericidal against all strains at most time intervals at 2 × and 4 × MIC up to 24 h. TEM observations revealed that L-Pch-Ab was actively taken up by P. aeruginosa and exhibited membrane deformation within 2 h. Developed L-Pch-Ab fused intimately with the outer membrane of MDRPa and exhibited effective antibacterial activity than free Ab. Furthermore, L-Pch-Ab kills MDRPa within infected HaCaT keratinocytes without any cytotoxic effects at 4× MIC concentrations after 72 h. Thus, the specific targeting of L-Pch-Ab with its higher efficacy to deliver drug by limiting the toxicity will be a novel approach to fight infections caused by P. aeruginosa.

Identification of NURR1 (Exon 4) and FOXA1 (Exon 3) Haplotypes Associated with mRNA Expression Levels in Peripheral Blood Lymphocytes of Parkinson's Patients in Small Indian Population.

Here, we study the expression of NURR1 and FOXA1 mRNA in peripheral blood lymphocytes and its haplotypes in coding region in a small Chennai population of India. Thirty cases of Parkinson's patients (PD) with anti-PD medications (20 males aged 65.85 ± 1.19 and 10 females aged 65.7 ± 1.202) and 30 age matched healthy people (20 males aged 68.45 ± 1.282 and 10 females aged 65.8 ± 1.133) were included. The expression of NURR1 and FOXA1 in PBL was detected by Q-PCR and haplotypes were identified by PCR-SSCP. In the 30 PD cases examined, NURR1 and FOXA1 expression was significantly reduced in both male and female PD patients. However, NURR1 (57.631% reduced in males; 28.93% in females) and FOXA1 (64.42% in males; 55.76% in females) mRNA expression did differ greatly between male and female PD patients. Polymorphisms were identified at exon 4 of the NURR1 and at exon 3 of the FOXA1, respectively, in both male and female patients. A near significant difference in SSCP patterns between genders of control and PD population was analyzed suggesting that further investigations of more patients, more molecular markers, and coding regions should be performed. Such studies could potentially reveal peripheral molecular marker of early PD and different significance to the respective genders.

Paraquat exposure induces behavioral deficits in larval zebrafish during the window of dopamine neurogenesis.

Exposure to environmental risk factors such as herbicides in early life has been proposed to play important roles in the development of neurodegenerative disorders in adult life. To test this hypothesis, we used a zebrafish model to link the herbicide paraquat (PQ) to disease etiology. Strikingly, treatment of 18 hpf embryonic zebrafish with low-dose PQ treatment (0.04 ppm, lower than the accepted human daily exposure) resulted in 50% display of neurodegenerative phenotypes and motor deficits at various developmental stages (segmentation to larval stage). Wide arrays of biomarkers have been employed to delineate the toxic responses which include lipid peroxidation, glutathione (GSH) and apoptosis studies. A decrease in the GSH levels, increase in lipid peroxidation and apoptosis, respectively, were observed at various developmental stages. Unexpectedly, we show that the exposure to paraquat during the window of dopamine neurogenesis causes Parkinsonian like motor defects in later life by perturbing cholinergic system due to oxidative stress.

Bacopa monnieri Phytochemicals Mediated Synthesis of Platinum Nanoparticles and Its Neurorescue Effect on 1-Methyl 4-Phenyl 1,2,3,6 Tetrahydropyridine-Induced Experimental Parkinsonism in Zebrafish.

Current discovery demonstrates the rapid formation of platinum nanoparticles using leaf extract of a neurobeneficial plant, Bacopa monnieri (BmE). The nanoparticles (BmE-PtNPs) were stabilized and then coated with varied phytochemicals present within the leaf extract. These nanoparticles demonstrated the same activity of Complex I, as that of oxidizing NADH to NAD(+) using a spectrophotometric method. This suggests that BmE-PtNPs are a potential medicinal substance for oxidative stress mediated disease with suppressed mitochondrial complex I, namely, Parkinson's disease (PD). Hence, the neuroprotective potentials of the phytochemical coated nanoparticle were explored in 1-methyl 4-phenyl 1,2,3,6 tetrahydropyridine- (MPTP-)induced experimental Parkinsonism in zebrafish model. BmE-PtNPs pretreatment significantly reversed toxic effects of MPTP by increasing the levels of dopamine, its metabolites, GSH and activities of GPx, catalase, SOD and complex I, and reducing levels of MDA along with enhanced locomotor activity. Taken together, these findings suggest that BmE-PtNPs have protective effect in MPTP-induced neurotoxicity in this model of Parkinson's disease via their dual functions as mitochondrial complex I and antioxidant activity.

Synthesis and characterization of chitosan and grape polyphenols stabilized palladium nanoparticles and their antibacterial activity.

Based on enhanced effectiveness, the new age drugs are nanoparticles of polymers, metals or ceramics, which can combat conditions like cancer and fight human pathogens like bacteria. In this present study we aimed for a green approach to synthesize palladium nanoparticles by reducing palladium chloride salts with nontoxic and biodegradable polymeric chitosan and grape polyphenols and confirmed by FTIR, TEM, SEM and UV-spectroscopy. We also extended our study to show the efficacy of the grape and chitosan impregnated palladium nanoparticles as an antibacterial agent against Escherichia coli. Antibacterial assays were carried out with a representative gram-negative bacterium, E. coli and a gram-positive bacterium, Staphylococcus aureus. Commendable efforts have been made to explore this property using electron microscopy, which has revealed size dependent interaction of palladium nanoparticles conjugates with bacteria by disrupting cell membranes and the leakage of cytoplasm. Therefore, the observed results imply that grape and chitosan-based nano palladium conjugates prepared in our present system are promising candidates for a wide range of biomedical and general applications.

Facile synthesis of biocompatible gold nanoparticles from Vites vinefera and its cellular internalization against HBL-100 cells.

The remarkable health benefits of the chemical cocktails occluded within Vites vinefera (grapes) have been broadly used as dietary supplements and as natural pharmaceuticals in the treatment of various diseases including human cancer. Current discovery demonstrates the rapid formation of gold nanoparticles with the phytochemicals present in grapes, which serve a dual role as synergistic reducing agents to reduce gold salts into gold nanoparticles and also as stabilizers to provide a robust coating on the gold nanoparticles in a single step. Furthermore, the grape-generated gold nanoparticles (GAuNPs), have demonstrated remarkable in vitro stability on specific functionalization with peptides (GSH) and thiol-containing compounds (lipoic acid) followed by the induction of cell-specific response. In addition, the grape-generated gold nanoparticles (GAuNPs, GSH-GAuNPs, LA-GAuNPs) have demonstrated remarkable affinity towards human breast cancer cells (HBL-100) in the present study. These studies thus signified the cellular internalization of GAuNPs and its conjugates by transmission electron microscopy through endocytosis into cancer cells. Notably, at higher concentration of gold nanoparticles conjugate, there was an asymmetric accumulation of gold nanoparticles in the periphery of the cell nucleus of the HBL-100 cells which was confirmed by fluorescence microscopy. Other than gold salts, no "manmade" chemicals are used in this truly biogenic, green nanotechnological process which thereby paves the way for outstanding opening for their application in molecular imaging and cancer therapy.