Parental (F0) exposure to Cadmium and Ketoprofen induces developmental deformities in offspring (F1): A transgenerational toxicity assessment in zebrafish model.

In the aquatic environment, the primary pollutants of heavy metals and pharmaceuticals always occur in coexisting forms, and the research about combined impacts remains unclear, especially transgenerational effects. Cadmium (Cd) is a heavy metal that can damage the endocrine reproduction systems and cause thyroid dysfunction in fish. Meanwhile, ketoprofen (KPF) is a nonsteroidal anti-inflammatory drug (NSAID) that can cause neurobehavioral damage and physiological impairment. However, to our knowledge, the combined exposure of Cd and KPF in transgenerational studies has not been reported. In this investigation, sexually mature zebrafish were subjected to isolated exposure and combined exposure to Cd (10 µg/L) and KPF (10 and 100 µg/L) at environmentally relevant concentrations for 42 days. In this background, breeding capacity, chemical accumulation rate in gonads, and tissue morphologies are investigated in parental fish. This is followed by examining the malformation rate, inflammation rate, and gene transcription in the F1 offspring. Our results indicate that combined exposure of Cd and KPF to the parental fish could increase the chemical accumulation rate and tissue damage in the gonads of fish and significantly reduce the breeding ability. Furthermore, these negative impacts were transmitted to its produced F1 embryos, reflected by hatching rate, body deformities, and thyroid axis-related gene transcription. These findings provide further insights into the harm posed by Cd in the presence of KPF to the aquatic ecosystems.

Cadmium and ketoprofen accumulation influences aquatic ecosystem demonstrated using in-vivo zebrafish model.

The growing concern about pollution and toxicity in aquatic as well as terrestrial organisms is predominantly caused due to waterborne exposure and poses a risk to environmental systems and human health. This study addresses the co-toxic effects of cadmium (Cd) and ketoprofen (KPF), representing heavy metal and pharmaceutical discharge pollutants, respectively, in aquatic ecosystems. A 96-h acute toxicity assessment was conducted using zebrafish embryos. The results indicated that high dosages of KPF (10, 15, and 100 µg/mL) and Cd (10 and 15 µg/mL) reduced survivability and caused concentration-dependent deformities such as scoliosis and yolk sac edema. These findings highlight the potential defects in development and metabolism, as evidenced by hemolysis tests demonstrating dose-dependent effects on blood cell integrity. Furthermore, this study employs adult zebrafish for a 42-day chronic exposure to Cd and KPF (10 and 100 µg/L) alone or combined (10 + 10 and 100 + 100 µg/L) to assess organ-specific Cd and KPF accumulation in tissue samples. Organ-specific accumulation patterns underscore complex interactions impacting respiratory, metabolic, and detoxification functions. Prolonged exposure induces reactive oxygen species formation, compromising antioxidant defense systems. Histological examinations reveal structural changes in gills, gastrointestinal, kidney, and liver tissues, suggesting impairments in respiratory, osmoregulatory, nutritional, and immune functions. This study emphasizes the importance of conducting extensive research on co-toxic effects to assist with environmental risk assessments and safeguard human health and aquatic ecosystems.

Role and mechanistic actions of protein kinase inhibitors as an effective drug target for cancer and COVID.

Kinases can be grouped into 20 families which play a vital role as a regulator of neoplasia, metastasis, and cytokine suppression. Human genome sequencing has discovered more than 500 kinases. Mutations of the kinase itself or the pathway regulated by kinases leads to the progression of diseases such as Alzheimer's, viral infections, and cancers. Cancer chemotherapy has made significant leaps in recent years. The utilization of chemotherapeutic agents for treating cancers has become difficult due to their unpredictable nature and their toxicity toward the host cells. Therefore, targeted therapy as a therapeutic option against cancer-specific cells and toward the signaling pathways is a valuable avenue of research. SARS-CoV-2 is a member of the Betacoronavirus genus that is responsible for causing the COVID pandemic. Kinase family provides a valuable source of biological targets against cancers and for recent COVID infections. Kinases such as tyrosine kinases, Rho kinase, Bruton tyrosine kinase, ABL kinases, and NAK kinases play an important role in the modulation of signaling pathways involved in both cancers and viral infections such as COVID. These kinase inhibitors consist of multiple protein targets such as the viral replication machinery and specific molecules targeting signaling pathways for cancer. Thus, kinase inhibitors can be used for their anti-inflammatory, anti-fibrotic activity along with cytokine suppression in cases of COVID. The main goal of this review is to focus on the pharmacology of kinase inhibitors for cancer and COVID, as well as ideas for future development.

Molecular insights into benzene sulphonamide substituted diarylpyrazoles as cyclooxygenase-2 inhibitor and its structural modifications.

Quantitative Structure Activity Relationship (QSAR) is one of the realistic and most successful methods for drug design in optimizing a lead. A series of forty-four molecules from diarylpyrazole benzene sulphonamide derivatives with their cyclooxygenase-2 inhibitory activity were subjected to qsar studies using QSARINS software. The significant two descriptor qsar model generated showed correlation coefficient of cross validation leave one out (Q2LOO)=0.5565, coefficient of determination (R2)=0.6530, (R2ext)=0.8225, cross validation leave many out (Q2LMO)=0.5201, Concordance Correlation Coefficient (CCCcv)=0.7262, CCCtr=0.7901, and CCCext=0.8930. The descriptor 3D Molecular Representations of Structures based on Electronic diffraction (3D-MoRSEC-6) weighted by atomic charges, where 6 is scattering parameter and Geary Autocorrelation-lag3/weighted by atomic Sanderson electronegativities (GATSe3) revealed that the atomic charges and spatial autocorrelation play a key role in Cyclooxygenase-2 inhibitory (COX-2) activity. New lead molecules were designed based on key structural findings and predicted for their COX-2 inhibitory activity using the developed two-descriptor model. Molecular docking studies were carried out for the best-designed molecules using Autodock 4.2.6 along with supportive in silico absorption, distribution, metabolism, excretion, and toxicity predictions. Both the hydrophilic as well as hydrophobic parts of the residues of active site regions interacted with best predicted active compounds. The study suggests crucial properties and key interactions that are essential for potent enzyme inhibition and finds this series as a promising lead for further development as novel cyclooxygenase agents. Communicated by Ramaswamy H. Sarma.

Mycothiol: a promising antitubercular target.

Tuberculosis (TB) is the world's second commonest cause of death next to HIV/AIDS. The increasing emergence of multi drug resistance and the recalcitrant nature of persistent infections pose an additional challenge for the treatment of TB. Due to the development of resistance to conventional antibiotics there is a need for new therapeutic strategies to combat M. tuberculosis. One such target is Mycothiol (MSH), a major low molecular-mass thiol in mycobacteria, an important cellular anti-oxidant. MSH is present only in actinomycetes and hence is a good target. This review explores mycothiol as a potential target against tuberculosis and various research ongoing worldwide.