Ligand-based designing of DPP-4 inhibitors via hybridization; synthesis, docking, and biological evaluation of pyridazine-acetohydrazides.

A series of novel pyridazine-acetohydrazide hybrids were designed, synthesized, and evaluated for their in vitro and in vivo antihyperglycemic activity. In this context, pyridazine-acetohydrazides (6a-6p) were synthesized by coupling substituted aldehyde with 2-(5-cyano-6-oxo-3,4-diphenylpyridazine-1-6H-yl) acetohydrazide, which was prepared via the reaction of pyridazine ester with hydrazine hydrate. The molecular docking study was carried out to examine the binding affinities and interaction of designed compounds against the DPP-4 enzyme. Compounds 6e, 6f, 6l, and 6n exhibited interaction with active residue. In silico ADMET properties, and toxicity studies corroborated that compounds were found to have good bioavailability and less toxic. The synthesized compounds were further estimated for in vitro DPP-4 activity. Compounds 6e and 6l were found as the most effective DPP-4 inhibitor in this series with IC50 values (6.48, 8.22 nM) when compared with sitagliptin (13.02 nM). According to the toxicity assay compound, 6l showed very less toxicity at a higher concentration so further selected for the in vivo antihyperglycemic activity.

In silico and in vivo assessment of developmental toxicity, oxidative stress response & Na+/K+-ATPase activity in zebrafish embryos exposed to cypermethrin.

Cypermethrin (CYP), a synthetic type II pyrethroid pesticide, is extensively used to control pests in industrial, domestic, and agricultural environments. However, its indiscriminate use leads to a potential threat to aquatic organisms. Although several reports focussed on developmental toxicity effects, a concise study combining cardiotoxicity along with Na+/K+-ATPase activity and molecular docking of developmental proteins with CYP was lacking. This present study was designed to address this gap to comprehend the impact of CYP exposure (0, 25, 100 and 200 µg/L) on embryonic zebrafish. As a result, CYP delayed the hatching rate, reduced heart rate, increased mortality rate and induced numerous morphological abnormalities. Subsequently, CYP induced oxidative stress in treated zebrafish embryos with the concomitant increase in antioxidant enzymes (SOD and CAT) and malondialdehyde production. In addition, an alteration in AChE, NO content and Na+/K+-ATPase activity was observed, suggesting a disruption in cardiac development and ion regulation. Furthermore, AO staining showed notable apoptotic cells which are supported by alteration in apoptosis-related gene expressions. Moreover, to explore the putative targets of CYP, computational docking with developmental proteins (WNT3A, WNT8A, GATA-4, Nkx 2-5 and ZHE1) showed strong interactions and binding. Taken together, our findings provide a better understanding of assessing the ecotoxicological risk information and the mode of action underlying the development of teleost fishes following CYP exposure. Meanwhile, the pioneering nature of this study is to emphasize the future use of Na+/K+-ATPase activity as a potential toxicity biomarker and in silico molecular docking studies to complement developmental toxicity findings.

Homeopathic Medicines in Second Wave of COVID-19: Prognostic Factor Research.

BACKGROUND: The clinical profile and course of COVID-19 evolved perilously in a second wave, leading to the use of various treatment modalities that included homeopathy. This prognostic factor research (PFR) study aimed to identify clinically useful homeopathic medicines in this second wave. METHODS: This was a retrospective, multi-centred observational study performed from March 2021 to May 2021 on confirmed COVID-19 cases who were either in home isolation or at COVID Care Centres in Delhi, India. The data were collected from integrated COVID Care Centres where homeopathic medicines were prescribed along with conventional treatment. Only those cases that met a set of selection criteria were considered for analysis. The likelihood ratio (LR) was calculated for the frequently occurring symptoms of the prescribed medicines. An LR of 1.3 or greater was considered meaningful. RESULTS: Out of 769 confirmed COVID-19 cases reported, 514 cases were selected for analysis, including 467 in home isolation. The most common complaints were cough, fever, myalgia, sore throat, loss of taste and/or smell, and anxiety. Most cases improved and there was no adverse reaction. Certain new symptoms, e.g., headache, dryness of mouth and conjunctivitis, were also seen. Thirty-nine medicines were prescribed, the most frequent being Bryonia alba followed by Arsenicum album, Pulsatilla nigricans, Belladonna, Gelsemium sempervirens, Hepar sulphuris, Phosphorus, Rhus toxicodendron and Mercurius solubilis. By calculating LR, the prescribing indications of these nine medicines were ascertained. CONCLUSION: Add-on use of homeopathic medicines has shown encouraging results in the second wave of COVID-19 in integrated care facilities. Further COVID-related research is required to be undertaken on the most commonly prescribed medicines.

A holistic review on trend, occurrence, factors affecting pesticide concentration, and ecological risk assessment.

Demographic outbursts and increased food demands invoke excessive use of pesticides in the agricultural field for increasing productivity which leads to the relentless decline of riverine health and its tributaries. These tributaries are connected to a plethora of point and non-point sources that transport pollutants including pesticides into the Ganga river's mainstream. Simultaneous climate change and lack of rainfall significantly increase pesticide concentration in the soil and water matrix of the river basin. This paper is intended to review the paradigm shift of pesticide pollution in the last few decades in the river Ganga and its tributaries. Along with this, a comprehensive review suggests the ecological risk assessment method which facilitates policy development, sustainable riverine ecosystem management, and decision-making. Before 2011, the total mixture of Hexachlorocyclohexane was found at 0.004-0.026 ng/mL in Hooghly, but now, the concentration has increased up to 0.465-4.132 ng/mL. Aftermath of critical review, we observed maximum residual commodities and pesticide contamination reported in Uttar Pradesh > West Bengal > Bihar > Uttara Khand possibly because of agricultural load, increasing settlement, and incompetency of sewage treatment plant in the reclamation of pesticide contamination.

Click inspired novel pyrazole-triazole-persulfonimide & pyrazole-triazole-aryl derivatives; Design, synthesis, DPP-4 inhibitor with potential anti-diabetic agents.

This work presented the first report on designing, synthesizing of novel pyrazole-triazole-persulfonimide (7a-i) and pyrazole-triazole-aryl derivatives (8a-j) via click reaction using CuI catalyst and evaluated for their anti-diabetic activity and DPP-4 inhibitory effect. Click reactions went smoothly with CuI catalyst in the presence of tridentate chelating ligands and produced copper-free target pyrazole-triazole-persulfonimide analogues in excellent yield at RT. The designed compounds were docked against DPP-4 enzyme and showed excellent interaction with active amino acids residue. Further, all novel pyrazole-triazole-persulfonimide and pyrazole-triazole derivatives were subjected to enzyme-based in vitro DPP-4 inhibitory activity. Based on the SAR study DPP-4 inhibitory capacity compounds 7f (9.52 nM) and 8h (4.54 nM) possessed the significant inhibition of DPP-4. Finally compounds 7f and 8h were evaluated for their in vivo anti-diabetic activity using STZ induced diabetic mice model, and 8h showed a significant diabetic control effect compared to the sitagliptin drug. These studies demonstrated that the novel pyrazole-triazole-persulfonimide and pyrazole-triazole-aryl derivatives might be used as the leading compounds to develop novel DPP-4 inhibitors as potential anti-diabetic agents.

Generalizability of Homeopathic Prognostic Factor Research Outcome in COVID-19 Treatment: Comparison of Data.

BACKGROUND/OBJECTIVE: During the coronavirus disease 2019 (COVID-19) pandemic, several homeopathic prognostic factor research (PFR) projects have been undertaken. We found two projects with comparable outcomes to assess consistency and possible flaws. METHODS: Two comparisons were made. (1) Outcome of a PFR data collection from the Liga Medicorum Homoeopathica Internationalis (LMHI) by about 100 doctors with 541 cases was compared with a previous analysis of 161 cases in the same database. (2) The updated LMHI database was also compared with a data collection carried out in India by four doctors with a total of 1,445 cases. Differences that resulted in conflicting outcomes (indication in one, contraindication in the other) were examined for possible causes. RESULTS: There was only a single outcome in the updated LMHI database that conflicted with the previous dataset, and this could have been due to statistical variation. The Indian data contained many cases, from few doctors, while the LMHI database had few cases per doctor, but many doctors. The overlap between the projects (individual cases entered in both) was between zero and 22%. In 72 comparisons we found six (8.3%) conflicting outcomes. Possible causes were statistical error due to small numbers of cases and/or observers, confirmation bias, and keynote prescribing if this resulted in symptoms being inadequately checked. CONCLUSION: There was little conflict between the outcomes of the two versions of one project and between the two different PFR projects. Differences could mostly be explained by causes that can be managed. This consistency should primarily be interpreted as showing a strong overall consensus between homeopathic practitioners worldwide, but with variation of consensus between small groups of practitioners.

Impact of Bias in Data Collection of COVID-19 Cases.

BACKGROUND: Prognostic factor research (PFR), prevalence of symptoms and likelihood ratio (LR) play an important role in identifying prescribing indications of useful homeopathic remedies. It involves meticulous unbiased collection and analysis of data collected during clinical practice. This paper is an attempt to identify causes of bias and suggests ways to mitigate them for improving the accuracy in prescribing for better clinical outcomes and execution of randomized controlled studies. METHODS: A prospective, open label, observational study was performed from April 2020 to December 2020 at two COVID Health Centers. A custom-made Excel spreadsheet containing 71 fields covering a spectrum of COVID-19 symptoms was shared with doctors for regular reporting. Cases suitable for PFR were selected. LR was calculated for commonly occurring symptoms. Outlier values with LR ≥5 were identified and variance of LRs was calculated. RESULTS: Out of 1,889 treated cases of confirmed COVID-19, 1,445 cases were selected for pre-specified reasons. Nine medicines, Arsenicum album, Bryonia alba, Gelsemium sempervirens, Pulsatilla nigricans, Hepar sulphuricus, Magnesia muriaticum, Phosphorus, Nux vomica and Belladonna, were most frequently prescribed. Outlier values and large variance for Hepar sulphuricus and Magnesia muriaticum were noticed as indication of bias. Confirmation bias leading to lowering of symptom threshold, keynote prescribing, and deficiency in checking of all symptoms in each case were identified as the most important sources of bias. CONCLUSION: Careful identification of biases and remedial steps such as training of doctors, regular monitoring of data, checking of all pre-defined symptoms, and multicenter data collection are important steps to mitigate biases.

PVDF Nanofiber Sensor for Vibration Measurement in a String.

Flexible, self-powered and miniaturized sensors are extensively used in the areas of sports, soft robotics, health care and communication devices. Measurement of vibration is important for determining the mechanical properties of a structure, specifically the string tension in strings. In this work, a flexible, lightweight and self-powered sensor is developed and attached to a string to measure vibrations characteristics in strings. Electrospun poly(vinylidene) fluoride (PVDF) nanofibers are deposited on a flexible liquid crystal polymer (LCP) substrate for the development of the sensor. The electrospinning process is optimized for different needle sizes (0.34-0.84 mm) and flow rates (0.6-3 mL/h). The characterization of the sensor is done in a cantilever configuration and the test results indicate the sensor's capability to measure the frequency and strain in the required range. The comparison of the results from the developed PVDF sensor and a commercial Laser Displacement Sensor (LDS) showed good resemblance (±0.2%) and a linear voltage profile (0.2 mV/µÎµ). The sensor, upon attachment to a racket string, is able to measure single impacts and sinusoidal vibrations. The repeatability of the results on the measurement of vibrations produced by an impact hammer and a mini shaker demonstrate an exciting new application for piezoelectric sensors.

Changes in vasotocin levels in relation to ovarian development in the catfish Heteropneustes fossilis exposed to altered photoperiod and temperature.

Photoperiod and temperature are the major proximate factors that activate the brain-pituitary-gonadal-endocrine axis stimulating gonadal recrudescence. Vasotocin (VT), the basic nonapeptide hormone, is secreted by the nucleus preopticus in the hypothalamus and released from the pituitary into circulation as a neurohormone for physiological actions. Additionally, VT is secreted de novo in the ovary of the catfish and has been implicated in ovarian functions. In the present study, we evaluated the changes in VT secretion during altered photoperiod and temperature exposure. The ovarian changes were monitored over gonadosomatic index (GSI) and plasma steroid hormone levels. Exposure of the catfish to long photoperiod (LP, 16L:08D) daily, alone or in combination with high temperature (HT, 28 ± 2 °C), for 14 or 28 days resulted in a decrease in brain-pituitary VT level with a concomitant increase in plasma and ovarian VT levels. The changes were greater in the LP + HT group on day 28. Concurrently, the treatments stimulated the GSI and plasma estradiol-17ß (E2), testosterone (T) and progesterone (P4) levels with higher more responses in the LP + HT group. Exposure of the catfish to short photoperiod (SP, 08L:16D) daily or total darkness (TD, 24L:00D) daily, with or without changing the ambient temperature, for 14 or 28 days produced a depressing effect on VT, GSI and steroid hormone levels, the range of the response varied with the temperature. The brain VT level was low except in the TD + NT group. Plasma and ovarian VT levels decreased more in the SP and TD groups under ambient temperature than in the groups at the raised temperature. The GSI and plasma steroid hormones (E2, T and P4) responded in a similar manner. Plasma cortisol level registered a significant increase in all the groups compared to the initial control groups, and the increase was significantly higher on day 28. The simultaneous activation of VT secretion and ovarian recrudescence by photoperiod and temperature suggests the peptide's involvement in the hormonal control of gametogenesis.

Effect of micro-fractures on gas flow behavior in coal for enhanced coal bed methane recovery and CO2 storage.

This study investigates the impact of micro-fractures on gas flow behavior in coal formations, specifically within the context of CO2-based Enhanced Coal Bed Methane Recovery (ECBMR). Employing comparative analysis, various gas flow models, including Unipore Diffusion Model (UDM), Bidispersed Diffusion Model (BDM), Fractal Fractional Diffusion Model (FFDM), Time-Dependent Diffusivity Model (TDDM), Anomalous Sub-Diffusion Model (ASM), and Free Gas Density Gradient Model (FGDGM), are evaluated for their efficacy in capturing the complexities. The study aims to provide insights into the accuracy and applicability of these models, considering the heterogeneity of coal seams and the influence of micro-fractures on gas flow dynamics. The major findings include the categorization of different gas flow models based on their applicability to CO2-based ECBMR. For instance, the study suggests utilizing BDM and FFDM models while considering the heterogeneity of coal seams. Similarly using the TDDM model for time dynamics of ECBMR will give higher accuracy. The article contributes to a deeper understanding of gas migration processes in coal, particularly in the context of ECBMR, with implications for optimizing recovery strategies and addressing challenges associated with micro-fracture-induced variations in gas flow behavior.

Polystyrene microplastics induced disturbances in neuronal arborization and dendritic spine density in mice prefrontal cortex.

An increasing use of plastics in daily life leads to the accumulation of microplastics (MPs) in the environment, posing a serious threat to the ecosystem, including humans. It has been reported that MPs cause neurotoxicity, but the deleterious effect of polystyrene (PS) MPs on neuronal cytoarchitectural morphology in the prefrontal cortex (PFC) region of mice brain remains to be established. In the present study, Swiss albino male mice were orally exposed to 0.1, 1, and 10 ppm PS-MPs for 28 days. After exposure, we found a significant accumulation of PS-MPs with a decreased number of Nissl bodies in the PFC region of the entire treated group compared to the control. Morphometric analysis in the PFC neurons using Golgi-Cox staining accompanied by Sholl analysis showed a significant reduction in basal dendritic length, dendritic intersections, nodes, and number of intersections at seventh branch order in PFC neurons of 1 ppm treated PS-MPs. In neurons of 0.1 ppm treated mice, we found only decrease in the number of intersections at the seventh branch order. While 10 ppm treated neurons decreased in basal dendritic length, dendritic intersections, followed by the number of intersections at the third and seventh branch order were observed. As well, spine density on the apical secondary branches along with mRNA level of BDNF was significantly reduced in all the PS-MPs treated PFC neurons, mainly at 1 ppm versus control. These results suggest that PS-MPs exposure affects overall basal neuronal arborization, with the highest levels at 1 and 10 ppm, followed by 0.1 ppm treated neurons, which may be related to the down-regulation of BDNF expression in PFC.

Exploring the Intersection of Geophysics and Diagnostic Imaging in the Health Sciences.

To develop diagnostic imaging approaches, this paper emphasizes the transformational potential of merging geophysics with health sciences. Diagnostic imaging technology improvements have transformed the health sciences by enabling earlier and more precise disease identification, individualized therapy, and improved patient care. This review article examines the connection between geophysics and diagnostic imaging in the field of health sciences. Geophysics, which is typically used to explore Earth's subsurface, has provided new uses of its methodology in the medical field, providing innovative solutions to pressing medical problems. The article examines the different geophysical techniques like electrical imaging, seismic imaging, and geophysics and their corresponding imaging techniques used in health sciences like tomography, magnetic resonance imaging, ultrasound imaging, etc. The examination includes the description, similarities, differences, and challenges associated with these techniques and how modified geophysical techniques can be used in imaging methods in health sciences. Examining the progression of each method from geophysics to medical imaging and its contributions to illness diagnosis, treatment planning, and monitoring are highlighted. Also, the utilization of geophysical data analysis techniques like signal processing and inversion techniques in image processing in health sciences has been briefly explained, along with different mathematical and computational tools in geophysics and how they can be implemented for image processing in health sciences. The key findings include the development of machine learning and artificial intelligence in geophysics-driven medical imaging, demonstrating the revolutionary effects of data-driven methods on precision, speed, and predictive modeling.

Differential and reproductive stage-dependent regulation of vasotocin secretion by catecholamines in the catfish Heteropneustes fossilis.

Vasotocin (VT) is the basic nonapeptide hormone secreted by the neurohypophysis of non-mammalian vertebrates and is involved in the regulation of osmoregulation, metabolism, cardiovascular function, reproduction and behaviour. Among the reproductive function, VT is specifically implicated in final oocyte maturation, ovulation, oviposition/parturition in teleosts, amphibians, reptiles, and birds. The central catecholaminergic system is involved in the regulation of pituitary hormone secretion including gonadotropin, and mediates also changes in environmental photoperiod and temperature. The close apposition of the VT and catecholaminergic systems in the preoptic area of the hypothalamus signifies a strong possibility of their functional interaction. The aim of the present study was to investigate the effects of exogenously administered catecholamines on VT secretion in two different reproductive phases of female catfish Heteropneustes fossilis. For this, the catecholamine precursor L-dihydroxyphenylalanine (L-DOPA) and catecholamines (dopamine-DA, norepinephrine-NE, and epinephrine-E) were intraperitoneally injected in normal catfish and/or along with α-methylparatyrosine (α-MPT, a tyrosine hydroxylase inhibitor). Brain and plasma VT levels were measured by specific ELISA, 24h post injection. Both L-DOPA and DA inhibited brain and plasma VT levels in a concentration-dependent manner in preparatory and prespawning phases. In contrast, NE elicited dose-dependent effects: the lowest dose (0.5 ng/g body mass, BM) was ineffective, the median dose (1 ng/g BM) stimulated, and the high doses (10 and 100 ng/g BM) inhibited VT levels. E stimulated VT levels dose-dependently. A single injection of α-MPT (250 µg/g BM) strongly inhibited VT when given alone and enhanced the inhibitory effects of L-DOPA and DA in the combination groups. The α-MPT inhibition of VT was significantly reduced by the injection of NE (5 ng/g BM) and was restored or elevated by E. When the adrenergic neurotransmitters were given together with α-MPT, the inhibitory effect of the latter was abolished and VT levels were significantly elevated. Thus, the present data indicate that the physiological changes in VT is differentially regulated by the catecholamines (DA inhibits and NE/E stimulates VT).

Bottlenecks and reflections from turnkey installation of MRI in a tertiary care Greenfield project: a case study.

BACKGROUND: Turnkey projects are often pegged to be the solution for coordination issues and are common in procurement and installation of high-end expensive equipment. Considering the scale, cost and complexity of high-end diagnostic services like MRI, challenges during installation and commissioning have been commonly seen ever since the early days. The current case study elaborates on the lessons learnt from on-ground issues pertaining to delays in MRI installation in a Greenfield project. METHODS: Root cause analysis with Ishikawa chart was done. RESULTS: On detailed root cause analysis of the 5 broad issues, 20 causes for project delay were identified. These fall into three broad themes that can potentially affect performance of leadership. CONCLUSION: There are three key lessons/takeaways from the current case study. First, establishing proactive feedback loops and communication between all stakeholders. Second, the leadership should have strong control on events and milestones of the project by leveraging project management techniques and technologies. Third, unity of command and unity of direction are of paramount importance to steer the project out of doldrums. These lessons can be useful for healthcare leaders in effective project management.

Polystyrene microplastics modulated bdnf expression triggering neurotoxicity via apoptotic pathway in zebrafish embryos.

A ubiquitous presence of microplastics and nanoplastics created a new toxicological research area arising concept of "plastic rivers". But, the precise molecular mechanisms by which its exposure affects developmental neurotoxicity are poorly understood. Hence, in the present investigation, healthy zebrafish embryos were exposed to different concentrations of 500 nm polystyrene microplastics (0.1 ppm, 1 ppm and 10 ppm) to assess the neurotoxicity and the underlying biomolecular mechanism. On the last day of exposure, behaviour, accumulation, embryotoxicity, acridine orange staining, antioxidant enzyme assay, acetylcholinesterase assay, nitric oxide (NO) estimation, along with neurotransmitter (serotonin, dopamine) quantification and gene expression using qRT-PCR (bdnf, p53, bcl-2, caspase-3, caspase-9) were performed. As a result, we found that zebrafish embryos ingest and bioaccumulate microplastic without causing any morphological changes and lethality. The survival and hatching rates of the embryos were also unaffected but the swimming behaviour patterns were found to be altered. Further, acridine orange staining exhibited more apoptosis in treated groups with increased p53, caspase-3, caspase-9 and decreased bcl-2 gene expression. Moreover, polystyrene microplastics exposure resulted in reduced acetylcholinesterase activity leading to elevated NO concentration along with altered serotonin and dopamine levels and subsequently leading to down-regulated bdnf gene expression and modulated downstream apoptotic signalling, confirming the neurotoxicity potential of microplastics causing neuronal dysfunction. This study also compared the binding affinities between styrene and human proteins (Bdnf, p53 and Bcl-2) using bioinformatics methods, and docking results showed negative binding energy resulting in high binding affinities of Bcl-2 then p53 and Bdnf with styrene.

Role of ancillary ligands in selectivity towards acceptorless dehydrogenation versus dehydrogenative coupling of alcohols and amines catalyzed by cationic ruthenium(II)-CNC pincer complexes.

An unexpected reversal in catalytic activity for acceptorless dehydrogenative coupling compared to acceptorless alcohol dehydrogenation has been observed using a series of cationic Ru(II)-CNC pincer complexes with different ancillary ligands. In continuation of our study of cationic Ru(II)-CNC pincer complexes 1a-6a, new complexes with bulky N-wingtips [Ru(CNCiPr)(CO)(PPh3)Br]PF6 (1b), [Ru(CNCCy)(CO)(PPh3)Cl]PF6 (1c), [Ru(CNCCy)(CO)(PPh3)H]PF6 (2c), [Ru(CNCiPr)(PPh3)2Cl]PF6 (3b), [Ru(CNCCy)(PPh3)2Cl]PF6 (3c), [Ru(CNCiPr)(PPh3)2H]PF6 (4b), [Ru(CNCCy)(PPh3)2H]PF6 (4c), [Ru(CNCiPr)(DMSO)2Cl]PF6 (6b), and [Ru(CNCCy)(DMSO)2Cl]PF6 (6c) [CNCR = 2,6-bis(1-alkylimidazol-2-ylidene)-pyridine] have been synthesized and the catalytic activities of the new complexes have been compared with their N-methyl analogues for transfer hydrogenation of cyclohexanone and acceptorless dehydrogenation of benzyl alcohol. Furthermore, all complexes have been utilized as catalysts in the dehydrogenative coupling reaction of benzyl alcohol with amines. While the catalytic activities of the new complexes for transfer hydrogenation and acceptorless alcohol dehydrogenation were found to be in line with the previously observed trend based on the ancillary ligands (CO > COD > DMSO > PPh3), for the acceptorless dehydrogenative coupling reaction, complexes containing PPh3 and DMSO ligands performed better compared to complexes containing CO and COD ligands. Based on NMR and mass investigation of catalytic reactions, a plausible mechanism has been suggested to explain the difference in catalytic activity and its reversal during the dehydrogenative coupling reaction. Furthermore, the substrate scope for the dehydrogenative coupling reaction of benzyl alcohol with a wide range of amines has been explored, including synthesizing some pharmaceutically important imines. All new complexes have been characterized by various spectroscopic techniques, and the structures of 4b and 6b have been confirmed by the single-crystal X-ray diffraction technique.

PFOS-induced dyslipidemia and impaired cholinergic neurotransmission in developing zebrafish: Insight into its mechanisms.

Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant that has been widely detected in the environment and is known to accumulate in organisms, including humans. The study investigated dose-dependent mortality, hatching rates, malformations, lipid accumulation, lipid metabolism alterations, and impacts on cholinergic neurotransmission. Increasing PFOS concentration led to higher mortality, hindered hatching, and caused concentration-dependent malformations, indicating severe abnormalities in developing zebrafish. The results also demonstrated that PFOS exposure led to a significant increase in total lipids, triglycerides, total cholesterol, and LDL in a concentration-dependent manner, while HDL cholesterol levels were significantly decreased. Additionally, PFOS exposure led to a significant decrease in glucose levels. The study identified TGs, TCHO, and glucose as the most sensitive biomarkers in assessing lipid metabolism alterations. The study also revealed altered expression of genes involved in lipid metabolism, including upregulation of fasn, acaca, and hmgcr and downregulation of ldlr, pparα, and abca1, as well as decreased lipoprotein lipase (LPL) and increased fatty acid synthase (FAS) activity,suggesting an impact on fatty acid synthesis, cholesterol uptake, and lipid transport. Additionally, PFOS exposure led to impaired cholinergic neurotransmission, evidenced by a concentration-dependent inhibition of acetylcholinesterase activity, altered gene expressions related to neural development and function, and reduced Na+/K+-ATPase activity. STRING network analysis highlighted two distinct gene clusters related to lipid metabolism and cholinergic neurotransmission, with potential interactions through the pparα-creb1 pathway. Overall, this study provide important insights into the potential health risks associated with PFOS exposure, including dyslipidemia, cardiovascular disease, impaired glucose metabolism, and neurotoxicity. Further research is needed to fully elucidate the underlying mechanisms and potential long-term effects of PFOS exposure.

Base-free synthesis of benchtop stable Ru(III)-NHC complexes from RuCl3·3H2O and their use as precursors for Ru(II)-NHC complexes.

A series of Ru(III)-NHC complexes, identified as [RuIII(PyNHCR)(Cl)3(H2O)] (1a-c), have been prepared, starting from RuCl3·3H2O following a base-free route. The Lewis acidic Ru(III) centre operates via a halide-assisted, electrophilic C-H activation for carbene generation. The best results were obtained with azolium salts having the I- anion, while ligand precursors with Cl-, BF4-, and PF6- gave no complex formation and those with Br- gave a product with mixed halides. The structurally simple, air and moisture-stable complexes represent rare examples of paramagnetic Ru(III)-NHC complexes. Furthermore, these benchtop stable Ru(III)-NHC complexes were shown to be excellent metal precursors for the synthesis of new [RuII(PyNHCR)(Cl)2(PPh3)2] (2a-c) and [RuII(PyNHCR)(CNCMe)I]PF6 (3a-c) complexes. All the complexes have been characterised using spectroscopic methods, and the structures of 1a, 1b, 2c, and 3a have been determined using the single-crystal X-ray diffraction technique. This work allows easy access to new Ru-NHC complexes for the study of new properties and novel applications.

Polystyrene microplastics disrupt female reproductive health and fertility via sirt1 modulation in zebrafish (Danio rerio).

Microplastics (MPs) pollution poses an emerging threat to aquatic biota, which could hinder their physiological processes. Recently various evidence has demonstrated the toxic impacts of MPs on cellular and organismal levels, but still, the underlying molecular mechanism behind their toxicity remains ambiguous. The hypothalamic-pituitary-gonadal (HPG) axis regulates the synthesis and release of sex steroid hormones, and SIRT1 plays a vital role in this process. The current study aimed to elucidate the harmful effects of MPs on female reproduction via SIRT1 modulation. Healthy female zebrafish were exposed to different concentrations (50 and 500 µg/L) of polystyrene microplastics (PS-MPs). The results revealed a significant change in the gonadosomatic index (GSI) after exposure to PS-MPs. In addition, the decreased fecundity rate displayed an evident dosage effect, indicating that exposure to PS-MPs causes deleterious effects on fertilization. Furthermore, significantly enhanced levels of reactive oxygen species (ROS) and apoptotic signals through the TUNEL assay were evaluated in different treated groups. Moreover, morphological alterations in the gonads of zebrafish exposed to MPs were also observed through H&E staining. The subsequent change in plasma steroid hormone levels (E2/T ratio) showed an imbalance in hormonal homeostasis. Meanwhile, to follow PS-MPs' effects on the HPG axis via SIRT1 modulation and gene expression related to steroidogenesis, SIRT1/p53 pathway was evaluated through qPCR. The altered transcription levels of genes indicated the plausible interference of PS-MPs on the HPG axis function. Our in-silico molecular docking study proves that PS-MPs efficiently bind and inhibit endocrine receptors and SIRT1. Thus, these findings add to our understanding of the probable molecular mechanisms of reproductive impairment caused by PS-MPs in zebrafish.

Unraveling the mechanisms of perfluorooctanesulfonic acid-induced dopaminergic neurotoxicity and microglial activation in developing zebrafish.

Perfluorooctanesulfonic acid (PFOS) is a prevalent, persistent organic pollutant in environmental matrices, yet its precise mechanism of neurotoxicity remains unclear. This study investigated the developmental and neurobehavioral effects of PFOS exposure (0, 100, 500, and 1000 µg/L) on zebrafish. The findings indicated that PFOS exposure caused various developmental abnormalities, including increased mortality, delayed hatching, shortened body length, bent spine, and edema in the pericardial and yolk sac regions. Subsequently, larvae exhibited a significant decrease in spontaneous movement frequency, altered touch-evoked response, and locomotor behavior. In fact, aberrant cellular responses in the brain and cardiac regions were observed. Microglial activation is a critical component of the inflammatory immune responses related to neurotoxicity. Likewise, our findings indicated that PFOS-induced microglial activation might be responsible for neuronal inflammation and apoptosis. Furthermore, AChE activity and dopamine content at the neurotransmitter level were also disrupted after PFOS exposure. The gene expression of dopamine signaling pathways and neuroinflammation were also altered. Collectively, our findings highlight that PFOS exposure can induce dopaminergic neurotoxicity and neuroinflammation through microglial activation, thus ultimately affecting behavior. Taken together, this study will provide mechanistic effects underlying the pathophysiology of neurological disorders.