Tanshinone IIA from Salvia miltiorrhiza alleviates follicular maturation arrest symptoms in zebrafish via binding to the human androgen receptors and modulating Tox3 and Dennd1a.

Follicular maturation arrest is a prevalent endocrine disorder characterized by hormonal imbalance, ovarian dysfunction, and metabolic disturbances leading to Polycystic ovarian syndrome (PCOS). Tanshinone IIA (TIIA), a bioactive compound derived from Salvia miltiorrhiza, has shown promising therapeutic potential in various diseases, including cardiovascular diseases and cancer. However, its effects on reproductive health and gynecological disorders, particularly PCOS, remain poorly understood. In this study, we investigated the potential therapeutic effects of TIIA on ovarian function. Using a combination of experimental and computational approaches, we elucidated the molecular mechanisms underlying TIIA's pharmacological impact on ovarian function, follicular development, and androgen receptor signaling. Molecular docking and dynamics simulations revealed that TIIA interacts with the human androgen receptor (HAR), modulating its activity and downstream signaling pathways. Our results demonstrate that TIIA treatment alleviates PCOS-like symptoms in a zebrafish model, including improved follicular development, lowered GSI index, improved antioxidant status (SOD, CAT), decreased LDH levels, and enhanced AChE levels by regulating Tox3 and Dennd1a pathway. Our findings suggest that TIIA may hold promise as a novel therapeutic agent for the management of PCOS or ovulation induction.

Identification of novel CA IX inhibitor: Pharmacophore modeling, docking, DFT, and dynamic simulation.

Human Carbonic anhydrase IX (hCA IX) is found to be an essential biomarker for the treatment of hypoxic tumors in both the early and metastatic stages of cancer. Due to its active function in maintaining pH levels and overexpression in hypoxic conditions, hCA IX inhibitors can be a potential candidate specifically designed to target cancer development at various stages. In search of selective hCA IX inhibitors, we developed a pharmacophore model from the existing natural product inhibitors with IC50 values less than 50 nm. The identified hit molecules were then investigated on protein-ligand interactions using molecular docking experiments followed by molecular dynamics simulations. Among the zinc database 186 hits with an RMSD value less than 1 were obtained, indicating good contact with key residues HIS94, HIS96, HIS119, THR199, and ZN301 required for optimum activity. The top three compounds were subjected to molecular dynamics simulations for 100 ns to know the protein-ligand complex stability. Based on the obtained MD simulation results, binding free energies are calculated. Density Functional Theory (DFT) studies confirmed the energy variation between the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO). The current study has led to the discovery of lead compounds that show considerable promise as hCA IX inhibitors and suggests that three compounds with special molecular features are more likely to be better-inhibiting hCA IX. Compound S35, characterized by a higher stability margin and a smaller energy gap in quantum studies, is an ideal candidate for selective inhibition of CA IX.

Hues of risk: investigating genotoxicity and environmental impacts of azo textile dyes.

The textile industry, with its extensive use of dyes and chemicals, stands out as a significant source of water pollution. Exposure to certain textile dyes, such as azo dyes and their breakdown products like aromatic amines, has been associated with health concerns like skin sensitization, allergic reactions, and even cancer in humans. Annually, the worldwide production of synthetic dyes approximates 7 × 107 tons, of which the textile industry accounts for over 10,000 tons. Inefficient dyeing procedures result in the discharge of 15-50% of azo dyes, which do not adequately bind to fibers, into wastewater. This review delves into the genotoxic impact of azo dyes, prevalent in the textile industry, on aquatic ecosystems and human health. Examining different families of textile dye which contain azo group in their structure such as Sudan I and Sudan III Sudan IV, Basic Red 51, Basic Violet 14, Disperse Yellow 7, Congo Red, Acid Red 26, and Acid Blue 113 reveals their carcinogenic potential, which may affect both industrial workers and aquatic life. Genotoxic and carcinogenic characteristics, chromosomal abnormalities, induced physiological and neurobehavioral changes, and disruptions to spermatogenesis are evident, underscoring the harmful effects of these dyes. The review calls for comprehensive investigations into the toxic profile of azo dyes, providing essential insights to safeguard the aquatic ecosystem and human well-being. The importance of effective effluent treatment systems is underscored to mitigate adverse impacts on agricultural lands, water resources, and the environment, particularly in regions heavily reliant on wastewater irrigation for food production.

Dual Anti-Inflammatory and Anticancer Activity of Novel 1,5-Diaryl Pyrazole Derivatives: Molecular Modeling, Synthesis, In Vitro Activity, and Dynamics Study.

A series of novel 1,5-diaryl pyrazole derivatives targeting the COX enzyme were designed by combined ligand and structure-based approach. The designed molecules were then further subjected to ADMET and molecular docking studies. Out of 34 designed compounds, the top-10 molecules from the computation studies were synthesized, characterized, and evaluated for COX-2 inhibition and anti-cancer activity. Initially, the target compounds were screened for the protein denaturation assay. The results of the top-five molecules T2, T3, T5, T6, and T9 were further subjected to in vitro COX-2 enzymatic assay and anti-cancer activity. As far as COX-2 inhibitory activity is considered, two compounds, T3 and T5, exhibited the half maximum inhibitory concentration (IC50) at 0.781 µM and 0.781 µM respectively. Further, the two compounds T3 and T5, when evaluated for COX-1 inhibition, exhibited excellent inhibitory activity with T3 IC50 of 4.655µM and T5 with IC50 of 5.596 µM. The compound T5 showed more significant human COX-2 inhibition, with a selectivity index of 7.16, when compared with T3, which had a selectivity index of 5.96. Further, in vitro anti-cancer activity was screened against two cancer cell lines in which compounds T2 and T3 were active against A549 cell lines and T6 was active against the HepG2 cell line. Stronger binding energy was found by comparing MM-PBSA simulations with molecular docking, which suggests that compounds T3 and T5 have a better possibility of being effective compounds, in which T5 showed higher binding affinity. The results suggest that these compounds have the potential to develop effective COX-2 inhibitors as anti-cancer agents.

Mechanistic interplay of dual environmental stressors: Bisphenol-A and cadmium-induced ovarian follicular damage and hepatocyte dysfunction in vivo.

This study investigates the individual and combined toxic effects of Bisphenol A (BPA) and Cadmium (Cd) in zebrafish, recognizing the complex mixture of pollutants organisms encounter in their natural environment. Examining developmental, neurobehavioral, reproductive, and physiological aspects, the study reveals significant adverse effects, particularly in combined exposures. Zebrafish embryos exposed to BPA + Cd exhibit synergistically increased mortality, delayed hatching, and morphological abnormalities, emphasizing the heightened toxicity of the combination. Prolonged exposure until 10 days post-fertilization underscores enduring effects on embryonic development. BPA and Cd induce oxidative stress, as evidenced by increased production of reactive oxygen species and lipid peroxidation. This oxidative stress disrupts cellular functions, affecting lipid metabolism and immune response. Adult zebrafish exposed to BPA and Cd for 40 days display compromised neurobehavioral functions, altered antioxidant defenses, and increased oxidative stress, suggesting potential neurotoxicity. Additionally, disruptions in ovarian follicle maturation and skeletal abnormalities indicate reproductive and skeletal impacts. Histological analysis reveals significant liver damage, emphasizing the synergistic hepatotoxicity of BPA and Cd. Molecular assessments further demonstrate compromised cellular defense mechanisms, synaptic function, and elevated cellular stress and inflammation-related gene expression in response to combined exposures. Bioaccumulation analysis highlights differential tissue accumulation patterns. In conclusion, this study provides comprehensive insights into the multifaceted toxicological effects of BPA and Cd in zebrafish, raising concerns about potential adverse impacts on environmental ecosystems and human health.

Multifunctional curcumin mediated zinc oxide nanoparticle enhancing biofilm inhibition and targeting apoptotic specific pathway in oral squamous carcinoma cells.

BACKGROUND: Oral health remains a significant global concern with the prevalence of oral pathogens and the increasing incidence of oral cancer posing formidable challenges. Additionally, the emergence of antibiotic-resistant strains has complicated treatment strategies, emphasizing the urgent need for alternative therapeutic approaches. Recent research has explored the application of plant compounds mediated with nanotechnology in oral health, focusing on the antimicrobial and anticancer properties. METHODS: In this study, curcumin (Cu)-mediated zinc oxide nanoparticles (ZnO NPs) were synthesized and characterized using SEM, EDAX, UV spectroscopy, FTIR, and XRD to validate their composition and structural features. The antioxidant and antimicrobial activity of ZnO-CU NPs was investigated through DPPH, ABTS, and zone of inhibition assays. Apoptotic assays and gene expression analysis were performed in KB oral squamous carcinoma cells to identify their anticancer activity. RESULTS: ZnO-CU NPs showcased formidable antioxidant prowess in both DPPH and ABTS assays, signifying their potential as robust scavengers of free radicals. The determined minimal inhibitory concentration of 40 µg/mL against dental pathogens underscored the compelling antimicrobial attributes of ZnO-CU NPs. Furthermore, the interaction analysis revealed the superior binding affinity and intricate amino acid interactions of ZnO-CU NPs with receptors on dental pathogens. Moreover, in the realm of anticancer activity, ZnO-CU NPs exhibited a dose-dependent response against Human Oral Epidermal Carcinoma KB cells at concentrations of 10 µg/mL, 20 µg/mL, 40 µg/mL, and 80 µg/mL. Unraveling the intricate mechanism of apoptotic activity, ZnO-CU NPs orchestrated the upregulation of pivotal genes, including BCL2, BAX, and P53, within the KB cells. CONCLUSIONS: This multifaceted approach, addressing both antimicrobial and anticancer activity, positions ZnO-CU NPs as a compelling avenue for advancing oral health, offering a comprehensive strategy for tackling both oral infections and cancer.

Mitigating microplastic pollution: A critical review on the effects, remediation, and utilization strategies of microplastics.

Microplastics are found ubiquitous in the natural environment and are an increasing source of worry for global health. Rapid industrialization and inappropriate plastic waste management in our daily lives have resulted in an increase in the amount of microplastics in the ecosystem. Microplastics that are <150 µm in size could be easily ingested by living beings and cause considerable toxicity. Microplastics can aggregate in living organisms and cause acute, chronic, carcinogenic, developmental, and genotoxic damage. As a result, a sustainable approach to reducing, reusing, and recycling plastic waste is required to manage microplastic pollution in the environment. However, there is still a significant lack of effective methods for managing these pollutants. As a result, the purpose of this review is to convey information on microplastic toxicity and management practices that may aid in the reduction of microplastic pollution. This review further insights on how plastic trash could be converted as value-added products, reducing the load of accumulating plastic wastes in the environment, and leading to a beneficial endeavor for humanity.

Sustainable food packaging: Harnessing biowaste of Terminalia catappa L. for chitosan-based biodegradable active films for shrimp storage.

Shrimp, a globally consumed perishable food, faces rapid deterioration during storage and marketing, causing nutritional and economic losses. With a rising environmental consciousness regarding conventional plastic packaging, consumers seek sustainable options. Utilizing natural waste resources for packaging films strengthens the food industry. In this context, we aim to create chitosan-based active films by incorporating Terminalia catappa L. leaves extract (TCE) to enhance barrier properties and extend shrimp shelf life under refrigeration. Incorporation of TCE improves mechanical, microstructural, UV, and moisture barrier properties of the chitosan film due to cross-linking interactions, resulting in robust, foldable packaging film. Active TCE film exhibits high antioxidant property due to polyphenols. These films also exhibited low wettability and showed hydrophobicity than neat CH films which is essential for meat packaging. These biodegradable films offer an eco-friendly end-of-life option when buried in soil. TCE-loaded films effectively control spoilage organisms, prevent biochemical spoilage, and maintain shrimp freshness compared to neat CH films during refrigerated condition. The active TCE film retains sensory attributes better than neat chitosan, aligning with consumer preference. The developed edible and active film from waste sources might offer sustainable, alternative packaging material with a lower carbon footprint than petroleum-based sources.

Histone acetyltransferases derived RW20 protects and promotes rapid clearance of Pseudomonas aeruginosa in zebrafish larvae.

Pseudomonas is a group of bacteria that can cause a wide range of infections, particularly in people with weakened immune systems, such as those with cystic fibrosis or who are hospitalized. It can also cause infections in the skin and soft tissue, including cellulitis, abscesses and wound infections. Antimicrobial peptides (AMPS) are the alternative strategy due to their broad spectrum of activity and act as effective treatment against multi-drug resistance pathogens. In this study, we have used an AMP, RW20 (1RPVKRKKGWPKGVKRGPPKW20). RW20 peptide is derived from the histone acetyltransferases (HATs) of the freshwater teleost, Channa striatus. The antimicrobial prediction tool has been utilized to identify the RW20 sequence from the HATs sequence. We synthesized the peptide to explore its mechanism of action. In an in vitro assay, RW20 was challenged against P. aeruginosa and we showed that RW20 displayed antibacterial properties and damaged the cell membrane. The mechanism of action of RW20 against P. aeruginosa has been established via field emission scanning electron microscopy (FESEM) as well as fluorescence assisted cell sorter (FACS) analysis. Both these experiments established that RW20 caused bacterial membrane disruption and cell death. Moreover, the impact of RW20, in-vivo, was tested against P. aeruginosa-infected zebrafish larvae. In the infected larvae, RW20 showed protective effect against P. aeruginosa by increasing the larval antioxidant enzymes, reducing the excess oxidative stress and apoptosis. Thus, it is possible that HATs-derived RW20 can be an efficient antimicrobial molecule against P. aeruginosa.

Co-encapsulation and release of apigenin and ascorbic acid in polyelectrolyte multilayer capsules for targeted polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder in women of reproductive age, is linked to hormonal imbalances and oxidative stress. Our study investigates the regenerative potential of apigenin (AP, hydrophobic) and ascorbic acid (AC, hydrophilic) encapsulated within poly (allylamine hydrochloride) and dextran sulfate (PAH/DS) hollow microcapsules for PCOS. These microcapsules, constructed using a layer-by-layer (LbL) assembly, are found to be 4 ± 0.5 µm in size. Our research successfully demonstrates the co-encapsulation of AP and AC in a single PAH/DS system with high encapsulation efficiency followed by successful release at physiological conditions by CLSM investigations. In vitro tests with testosterone-treated CHO cells reveal that the dual-drug-loaded PAH/DS capsules effectively reduce intracellular ROS levels and apoptosis and offering protection. In an in-vivo zebrafish model, these capsules demonstrate active biodistribution to targeted ovaries and reduce testosterone levels through radical scavenging. Histopathological examinations show that the injected dual-drug-loaded PAH/DS microcapsules assist in the development of ovarian follicles in testosterone-treated zebrafish. Hence, this dual-drug-loaded system, capable of co-encapsulating two natural compounds, effectively interacts with ovarian cells, reducing cellular damage and normalizing PCOS conditions.

Osteoporosis in polycystic ovary syndrome (PCOS) and involved mechanisms.

Polycystic Ovary Syndrome (PCOS) and osteoporosis, though seemingly unrelated, exhibit intricate connections influenced by genetic and epigenetic factors. PCOS, characterized by elevated androgen levels, insulin resistance, and increased body weight, has historically been considered protective against bone fragility disorders. However, emerging research suggests that chronic inflammation, prevalent in PCOS, can adversely affect bone health. Studies have demonstrated variable bone mineral density loss in PCOS, often associated with leptin resistance and hyperinsulinemia. Key genes such as INS, IGF1, CTNNB1, AKT1, and STAT3 play pivotal roles in the complex interplay between PCOS and osteoporosis, influencing insulin signaling, oxidative stress, and inflammatory pathways. Oxidative stress, a prominent element in PCOS, can lead to osteoporosis through hormonal imbalances, chronic inflammation, insulin resistance, and lifestyle factors. The insulin signaling pathway also significantly impacts both conditions by contributing to hormonal imbalances and bone health alterations. This intricate network of genetic and epigenetic factors underscores the need for a deeper understanding of their interrelationships. Thus, this review elucidates the multifaceted genetic, epigenetic, and inflammatory connections between PCOS and osteoporosis, highlighting their implications for bone health management in individuals with PCOS.

Skeletal and neurological risks demonstrated in zebrafish due to second-hand cigarette smoke and the neutralization of luteolin.

BACKGROUND: Cigarette smoke exposure poses significant health risks, including oxidative stress, inflammation, tissue damage, and neurodegenerative diseases. Luteolin, a natural flavonoid known for its antioxidant and anti-inflammatory properties, is of interest in countering these effects. AIM: This study aims to assess luteolin's protective potential against cigarette smoke extract (CSE) in adult zebrafish. MATERIALS AND METHODS: Adult zebrafish were exposed to CSE for 15 days, inducing smoke-related damage. Subsequent luteolin treatment assessed its impact. Evaluations included antioxidant enzymes (SOD, CAT), nitric oxide (NO), LDH activity (cellular damage), tissue integrity, fibrosis, amyloid plaque accumulation, and CSE component analysis via HPLC. KEY FINDINGS: CSE exposure heightened oxidative stress, reducing SOD and CAT activity and elevating NO levels, leading to cellular damage and tissue disruption, notably fibrosis and amyloid plaque accumulation. Inflammatory markers TNF-α and IL-1ß also increased. Luteolin treatment restored SOD and CAT activity, reduced LDH and NO activity, counteracting oxidative damage. It also mitigated fibrosis and reduced amyloid plaque deposition, preserving tissue integrity. Luteolin reduced TNF-α and IL-1ß levels and CSE components, displaying anti-inflammatory effects. SIGNIFICANCE: This study underscores luteolin's potential as a protective agent against cigarette smoke-induced harm in a zebrafish model.

Aquatic Peptide: The Potential Anti-Cancer and Anti-Microbial Activity of GE18 Derived from Pathogenic Fungus Aphanomyces invadans.

Small molecules as well as peptide-based therapeutic approaches have attracted global interest due to their lower or no toxicity in nature, and their potential in addressing several health complications including immune diseases, cardiovascular diseases, metabolic disorders, osteoporosis and cancer. This study proposed a peptide, GE18 of subtilisin-like peptidase from the virulence factor of aquatic pathogenic fungus Aphanomyces invadans, which elicits anti-cancer and anti-microbial activities. To understand the potential GE18 peptide-induced biological effects, an in silico analysis, in vitro (L6 cells) and in vivo toxicity assays (using zebrafish embryo), in vitro anti-cancer assays and anti-microbial assays were performed. The outcomes of the in silico analyses demonstrated that the GE18 peptide has potent anti-cancer and anti-microbial activities. GE18 is non-toxic to in vitro non-cancerous cells and in vivo zebrafish larvae. However, the peptide showed significant anti-cancer properties against MCF-7 cells with an IC50 value of 35.34 µM, at 24 h. Besides the anti-proliferative effect on cancer cells, the peptide exposure does promote the ROS concentration, mitochondrial membrane potential and the subsequent upregulation of anti-cancer genes. On the other hand, GE18 elicits significant anti-microbial activity against P. aeruginosa, wherein GE18 significantly inhibits bacterial biofilm formation. Since the peptide has positively charged amino acid residues, it targets the cell membrane, as is evident in the FESEM analysis. Based on these outcomes, it is possible that the GE18 peptide is a significant anti-cancer and anti-microbial molecule.

Luteolin photo-protects zebrafish from environmental stressor ultraviolet radiation (UVB).

Ultraviolet B wavelength ray radiation (UVB) is an environmental stressor with detrimental effects to the aquatic and human systems but also enhances adverse effects when combined with several other environmental factors such as temperature and pollution. UV rays induce cellular oxidative damage and impair motility. This study aimed to examine the photo-protective activity of flavonoid luteolin against UV-B irradiation-induced oxidative stress and cellular damage using zebrafish. An in-vivo photoaging model was established using UV-B irradiation in zebrafish larvae exposed to 100 mJ/cm2. Data demonstrated that UV-B irradiation of swimming water enhanced production of ROS and superoxide anions as well as depleted total glutathione levels in zebrafish larvae. UV-B irradiation also triggered cellular damage and membrane rupture in zebra fish. Further, 100 mJ/cm2 of UV-B radiation exposure to adult-wild type zebrafish co-exposed with intraperitoneally (ip) injected luteolin upregulated the local neuroendocrine axes by activating vascular endothelial growth factor (VEGF) and elevating levels of pro-inflammatory cytokines IL-1ß and TNF-α. Histologically, UV-B irradiation induced skin lesions and locomotory defects with clumping and degeneration of brain glial cells. However, luteolin effectively inhibited the excess production of reactive oxygen species (ROS) and decreased superoxide anion levels induced by UV-B irradiation. Luteolin restored the depleted glutathione levels. In addition, luteolin blocked apoptosis and lipidperoxidation. Luteolin protected adult zebrafish by downregulating the pro-inflammatory cytokine protein expression levels and diminishing VEGF activation. Luteolin also alleviated locomotory defects by inhibiting activation of microglia and inflammatory responses by preventing accumulation of glial cells and vacuolation. Data demonstrate that luteolin may protect zebrafish from UV-B-induced photodamage through DNA-protective, antioxidant and anti-inflammatory responses.