Mitigation of Cisplatin-Induced Hepatotoxicity by Salvia officinalis: Attenuation of Oxidative Damage and Inflammation in Rats.

Salvia officinalis L., commonly known as sage and belonging to the Lamiaceae family, is a medicinal herb indigenous to the Mediterranean region. It is celebrated for its diverse pharmacological properties and traditional uses in folk medicine, particularly in addressing hepatotoxicity. Cisplatin (Cis), a potent chemotherapeutic agent widely employed in cancer treatment, is recognized for its efficacy but often accompanied by adverse effects, including hepatotoxicity. The aim of this study was to assess whether an ethanolic S. officinalis extract (ESOE) could provide protection against Cis-induced hepatotoxicity in an experimental rat model. The ESOE was prepared using standard extraction techniques, and its chemical constituents were elucidated through UPLC-ESI-MS/MS analysis, revealing the presence of bioactive compounds such as alkaloids, phenolic compounds, and flavonoids, which are associated with various therapeutic effects, including hepatoprotection. Adult male albino rats were allocated into four groups: control, ESOE (250 mg/kg), Cis (7.5 mg/kg), and ESOE (250 mg/kg) + Cis (7.5 mg/kg). The treatment duration lasted 21 days, with Cis administration on the 22nd day. Twenty-four hours post-Cis administration, blood and liver samples were collected for analysis. Cis-induced hepatotoxicity was evidenced by alterations in hematological parameters, including erythrocyte, thrombocyte, leukocyte, and lymphocyte counts, alongside elevated serum levels of liver enzymes (ALT, LDH, AST, ALP, and GGT), indicative of liver damage. Furthermore, Cis exposure resulted in increased hepatic malondialdehyde (MDA) and Nitric oxide (NO) levels, oxidative stress markers, coupled with decreased levels of reduced glutathione (GSH), a non-enzymatic antioxidant, and histopathological changes in liver tissue, characterized by necrosis and inflammation. Additionally, Cis treatment led to elevated levels of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), TNF-α, and IL-6, indicating oxidative stress and inflammation. Remarkably, pretreatment with ESOE ameliorated these Cis-induced hepatotoxic effects, as evidenced by improved hematological parameters, reduced liver enzyme activities, alleviated oxidative stress, and ameliorated histopathological alterations. The observed hepatoprotective effects of ESOE against Cis-induced liver injury may be attributed to its antioxidant and anti-inflammatory properties, highlighting its potential as a natural therapeutic agent in mitigating chemotherapy-associated hepatotoxicity.

Analyzing the impact of pesticides on the indus river: contamination levels in water, sediment, fish, and associated human health risks.

Pesticides are frequently used to protect crop yields and manage malaria vectors; however, their inadvertent transport into aquatic habitats poses a significant concern. Various anthropogenic activities influence the Indus River in Pakistan. This study aimed to assess the presence of eight pesticide residues at three different sites (Kalabagh, Kundian, and Chashma) in water, sediment, and the fish species (Labeo rohita) during both dry and wet seasons to measure the intensity of this pressure. Pesticide analysis was carried out using gas chromatography equipped with an electron capture detector. The results revealed the highest concentrations of pesticides during both dry and wet seasons at all sites, measuring 0.83 and 0.62 µg/l (water), 12.37 and 9.20 µg/g/dw (sediment), and 14.27 and 11.29 µg/g/ww (L. rohita), respectively. Overall, pesticide concentrations were higher in the dry season than in the wet season across all study sites. Based on detection frequency and concentration in both seasons at all sites, dominant pesticides included cypermethrin and carbofuran (in water), as well as endosulfan and cypermethrin (in sediment and fish tissue). Levels of endosulfan and cypermethrin exceeded standard limits. Moreover, principal component analysis (PCA) indicated no correlation among pesticides in fish tissue, sediment, and water. However, pesticides exhibited different behavior in different seasons. Furthermore, endosulfan and triazophos impose great human health risk, as indicated by the THQ value (> 1). The overall HI value was greater for site 1 in the dry season (8.378). The study concluded that the presence of agricultural pesticides in the Indus River poses a risk to aquatic life and has the potential to disrupt the entire food chain. This highlights the importance of sustainable practices for the study area and Pakistan overall agricultural and environmental sustainability. It is further recommended to strengthen regulations for reduced pesticide use and promote eco-friendly pest management.

The effect mechanism of ergosterol from the nutritional mushroom Leucocalocybe mongolica in breast cancer cells: Protein expression modulation and metabolomic profiling using UHPLC-ESI-Q.

The ergosterol from mushrooms has gained significant ethnopharmacological importance in various cultures, including China, Japan, and Europe. This compound has been found to possess immune-boosting and anti-inflammatory properties, making it useful in the treatment of immune disorders. In this study, we focused on investigating the potential anticancer properties of ergosterol isolated from the edible mushroom Leucocalocybe mongolica in breast cancer cell lines. The ergosterol was purified and identified using advanced analytical techniques such as ESI-MS and NMR. We conducted cell proliferation assays on 4 T1 breast cancer cells to assess the cytotoxic effects of ergosterol. Furthermore, we analyzed the transcription levels of BAX, caspase-7, BCL-2, STAT-3, and PARP proteins using real-time PCR and Western blot analysis. Additionally, we employed non-targeted ultra-high-performance liquid chromatography and high-resolution mass spectrometry (UPLC-MS/MS) to study the potential mechanisms underlying the anticancer effects of ergosterol at the metabolomics level. The results demonstrated a significant reduction in cell viability and the induction of apoptosis upon treatment with ergosterol, especially at higher concentrations (P < 0.05). Moreover, ergosterol affected the expression of cancer-related genes, upregulating pro-apoptotic proteins such as BAX, caspase-7, and PARP, while downregulating the anti-apoptotic proteins BCL-2 and STAT-3 (P < 0.05). Western blot analysis confirmed these findings and provided further evidence of ergosterol's role in inducing apoptosis. Metabolomics analysis revealed substantial changes in pathways related to amino acid, antioxidant, and carbohydrate metabolism. In conclusion, our study demonstrates that ergosterol exhibits anticancer effects by inducing apoptosis and modulating metabolic pathways in breast cancer cells.

Nickel oxide nanoparticles: A new generation nanoparticles to combat bacteria Xanthomonas oryzae pv. oryzae and enhance rice plant growth.

Recently, nanotechnology is among the most promising technologies used in all areas of research. The production of metal nanoparticles using plant parts has received significant attention for its environmental friendliness and effectiveness. Therefore, we investigated the possible applications of biological synthesized nickel oxide nanoparticles (NiONPs). In this study, NiONPs were synthesized through biological method using an aqueous extract of saffron stigmas (Crocus sativus L). The structure, morphology, purity, and physicochemical properties of the obtained NPs were confirmed through Scanning/Transmission Electron Microscopy attached with Energy Dispersive Spectrum, X-ray Diffraction, and Fourier transform infrared. The spherically shaped NiONPs were found by Debye Scherer's formula to have a mean dimension of 41.19 nm. The application of NiONPs in vitro at 50, 100, and 200 µg/mL, respectively, produced a clear region of 2.0, 2.2, and 2.5 cm. Treatment of Xoo cell with NiONPs reduced the growth and biofilm formation, respectively, by 88.68% and 83.69% at 200 µg/mL. Adding 200 µg/mL NiONPs into Xoo cells produced a significant amount of ROS in comparison with the control. Bacterial apoptosis increased dramatically from 1.05% (control) to 99.80% (200 µg/mL NiONPs). When compared to the control, rice plants treated with 200 µg/mL NiONPs significantly improved growth characteristics and biomass. Interestingly, the proportion of diseased leaf area in infected plants with Xoo treated with NiONPs reduced to 22% from 74% in diseased plants. Taken together, NiONPs demonstrates its effectiveness as a promising tool as a nano-bactericide in managing bacterial infection caused by Xoo.

Sublethal Concentrations of Cadmium and Lead: Effects on Hemato-Biochemical Parameters and Tissue Accumulation in Wallagu attu.

The exposure of fish to heavy metals can significantly impact physiological processes and potentially lead to adverse health effects. This study assesses the effects of exposure to Cd and Pb sublethal concentrations in water on Wallagu attu. A total of 48 fish with an average body weight of 145.5 ± 26 g were distributed among three groups (control, Cd-treated, and Pb-treated) within 60 L fiberglass tanks. They were exposed to 30% sublethal concentrations of Cd and Pb for durations of 1, 15, and 30 days. Following this exposure, an assessment was conducted on metal bioaccumulation and hemato-biochemical responses. Results revealed a significantly (P < 0.05) higher concentration of heavy metals in the fish tissues of metals exposed groups than in the control. The concentration of Cd and Pb increases in fish tissues (kidney > gills > intestine) with exposure time. In most cases, the Pb-exposed group exhibited significantly (P < 0.05) higher concentrations of Pb in different tissues than the Cd-treated group. With extended exposure time, the activities of CAT and SOD show a significant decrease in both Cd and Pb-treated groups. However, the reduction in activities was more pronounced in the Cd-exposed group. On 15 and 30 days, the levels of red blood cells (RBC), hemoglobin (HB), hematocrit (HCT), and total protein (TP) decrease in groups exposed to Cd and Pb. The cortisol and glucose levels exhibit a more noticeable (P < 0.05) increase with prolonged exposure to Cd and Pb than the control group. On day 30, the survival rate decreased more in the Pb-exposed group. The findings of this study indicate that exposure to sublethal doses of Cd and Pb induces stress in Wallagu attu, resulting in rapid changes in specific hemato-biochemical parameters.

Phytosynthesized Iron Oxide Nanoparticles Using Aqueous Extract of Saccharum arundinaceum (Hardy Sugar Cane), Their Characterizations, Antiglycation, and Cytotoxic Activities.

The goal of the current study is to achieve plant-mediated synthesis of iron oxide nanoparticles (Fe2O3 NPs). The plant extract of Saccharum arundinaceum was used as a reducing and stabilizing agent for the synthesis of Fe2O3 NPs. Different techniques such as energy-dispersive X-ray analysis (EDX), X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR), and UV-visible spectroscopy (UV-vis) were used to characterize the synthesis of Fe2O3 NPs. UV-visible spectroscopy verified the synthesis of Fe2O3 NPs using a surface plasmon resonance peak at a wavelength of 370 nm. SEM analysis specifies the spherical morphology of the synthesized nanoparticles with a size range between 30 and 70 nm. The reducing and capping materials of Fe2O3 NPs were revealed by FT-IR analysis based on functional group identification. The plant extract contained essential functional groups, such as C-H, C-O, N-H, -CH2, and -OH, that facilitate the green synthesis of Fe2O3 NPs. The EDX analysis detected the atomic percentage with the elemental composition of Fe2O3 NPs, while the XRD pattern demonstrated the crystallinity of Fe2O3 NPs. Furthermore, the synthesized Fe2O3 NPs showed potential antiglycation activity under in vitro conditions, which was confirmed by the efficient zone of inhibition on glycation of bovine serum albumin/glucose (BSA-glucose) in the order <100 < 500 < 1000 µg/mL, which revealed that Fe2O3 NPs showed significant antiglycation activity. Additionally, the cytotoxic activity against brain glioblastoma cells was assessed using the MTT assay, which exhibited diminished cytotoxic activity at concentrations lower than 300 µg/mL. Thus, we assumed that the resulting Fe2O3 NPs are a good option for use in drug delivery and cancer treatments.

Mechanistic inhibition of gastric cancer-associated bacteria Helicobacter pylori by selected phytocompounds: A new cutting-edge computational approach.

Background: Helicobacter pylori (H. pylori) is a persistent bacterial inhabitant in the stomachs of approximately half the global populace. This bacterium is directly linked to chronic gastritis, leading to a heightened risk of duodenal and gastric ulcer diseases, and is the predominant risk factor for gastric cancer - the second most common cause of cancer-related deaths globally. The increasing prevalence of antibiotic resistance necessitates the exploration of innovative treatment alternatives to mitigate the H. pylori menace. Methods: Initiating our study, we curated a list of thirty phytochemicals based on previous literature and subjected them to molecular docking studies. Subsequently, eight phytocompounds-Glabridin, Isoliquiritin, Sanguinarine, Liquiritin, Glycyrrhetic acid, Beta-carotin, Diosgenin, and Sarsasapogenin-were meticulously chosen based on superior binding scores. These were further subjected to an extensive computational analysis encompassing ADMET profiling, drug-likeness evaluation, principal component analysis (PCA), and molecular dynamic simulations (MDs) in comparison with the conventional drug, Mitomycin. Results: The natural compounds investigated demonstrated superior docking affinities to H. pylori targets compared to the standard Mitomycin. Notably, the phytocompounds Diosgenin and Sarsasapogenin stood out due to their exceptional binding affinities and pharmacokinetic properties, including favorable ADMET profiles. Conclusion: Our comprehensive and technologically-advanced approach showcases the potential of identified phytocompounds as pioneering therapeutic agents against H. pylori-induced gastric malignancies. In light of our promising in silico results, we recommend these natural compounds as potential candidates for advancing H. pylori-targeted drug development. Given their potential, we strongly advocate for subsequent in vitro and in vivo studies to validate their therapeutic efficacy against this formidable gastrointestinal bacterium.

Survivin-targeted nanomedicine for increased potency of abiraterone and enzalutamide against prostate cancer.

Prostate cancer is the leading and most aggressive cancer around the world, several therapeutic approaches have emerged but none have achieved the satisfactory result. However, these therapeutic approaches face many challenges related to their delivery to target cells, including their in vivo decay, the limited uptake by target cells, the requirements for nuclear penetration (in some cases), and the damage caused to healthy cells. These barriers can be avoided by effective, targeted, combinatorial approaches, with minimal side effects, which are being investigated for the treatment of cancer. Here, we developed a combinatorial nanomedicine comprising abiraterone and enzalutamide bioconjugated survivin-encapsulated gold nanoparticles (AbEzSvGNPs) for targeted therapy of prostate cancer. AbEzSvGNPs were characterized by different biophysical techniques such as UV visible spectroscopy, dynamic light scattering, zeta potential, transmission electron microscope, and Fourier transform infrared spectroscopy. Interestingly, the effect of abiraterone, enzalutamide and surviving encapsulated gold nanoparticles was found to be synergistic in nature in AbEzSvGNPs against DU 145 (IC50 = 4.21 µM) and PC-3 (IC50 = 5.58 µM) cells and their potential was observed to be greatly enhanced as compared with the combined effect of the drugs (abiraterone and enzalutamide) in their free form. Furthermore, AbEzSvGNPs were found to be highly safe and did not exhibit significant cytotoxicity against normal rat kidney cells. The observed effects of AbEzSvGNPs involved the modulation of different signaling pathways in prostate cancer cells. This delivery system employed non-androgen receptor-dependent delivery of abiraterone and enzalutamide. The anionic AbEzSvGNPs delivered abiraterone and enzalutamide unaltered into the nucleus through caveolae mediated internalization to act nonspecifically on DNA; internalization of the anionic nanoparticles into the cytoplasm was also observed via other routes. AbEzSvGNPs synthesized and evaluated in this study are promising candidates for prostate cancer therapy.

IgG antibodies mediated gold nanoparticles conjugated to methotrexate as targeted chemotherapy for lung cancer.

Vincamine, a natural chemical, was used as a reducing agent in the synthesis of IgG antibodies mediated biogenic gold nanoparticles (IgGAuNPs). Eventually, the synthesised IgGAuNPs were bioconjugated with the chemotherapeutic drug methotrexate (MTX-IgGAuNPs). The IgG isotype can target cancer cells through polymorphic Fc gamma receptors (FcγRs) and have therapeutic effects. They can restrict cell division by inhibiting different intracellular signal transduction pathways and activating NK cells and macrophages through antibody-dependent cellular cytotoxicity and macrophage-mediated antibody-dependent phagocytosis, respectively. Further, IgGAuNPs and MTX-IgGAuNPs were characterised by physical techniques. Moreover, 3D conformational changes in the structure of IgG were analysed by fluorescence spectroscopy during and after the synthesis of IgGAuNPs. Furthermore, the IgGAuNPs and MTX-IgGAuNPs were effective against lung cancer (A549 cells), while they were found to be non-toxic against normal cells (NRK cells). The effectiveness of IgGAuNPs and MTX-IgGAuNPs was examined by MTT cytotoxicity assay, DCFDA method for the production of ROS, and release of Cyt-c from the mitochondria for caspase-3-mediated apoptosis. Moreover, the confirmation of internalisation of particles into the nucleus was examined under the DAPI assay, and it was found that particles caused nuclear fragmentation, which was also an indication of apoptosis.

Protective role of Dodonaea viscosa extract against streptozotocin-induced hepatotoxicity and nephrotoxicity in rats.

Previous investigations have shown that D. viscosa herbal extract is often used to treat a variety of diseases. Therefore, the purpose of this study was to investigate any additional potential impacts on rat liver and kidney damage induced by diabetes. Streptozotocin (STZ) (60 mg/kg/day) was given as a single dosage to cause type 1 diabetes. After then, diabetic rats received oral doses of D. viscosa for four weeks at 150 and 300 mg/kg/day. Blood, liver, and kidney tissues were collected at the end of the treatment and examined. Analysis was made of the serum lipid profile, liver, and kidney functions, as well as blood biochemistry. Moreover, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1ß), prostaglandin E-2 (PGE-2), and nitric oxide (NO) were estimated in serum. In liver and kidney samples, thiobarbituric acid reactive substances (TBARs) and reduced glutathione (GSH), as well as the pro-inflammatory cytokines and enzymatic activities of glutathione peroxidase (GPx), glutathione reeducates (GR), glutathione-S-transferase (GST), catalase (CAT), and superoxide dismutase (SOD) were analyzed. Histological changes in liver and kidney cross-sections were also observed. Our findings demonstrated that D. viscosa dramatically decreased pro-inflammatory indicators in blood, kidney, and liver tissues as well as blood glucose, and restored insulin levels, and lipid profiles. Additionally, it significantly raises the antioxidant enzyme activity SOD, CAT, GPx, and GST, while significantly lowering TBARs levels. The above-mentioned biochemical changes that took place in tissues were further supported by histological alterations. These findings imply that D. viscosa protects against STZ-induced hyperglycemia, aberrant lipid synthesis, and oxidative stress and that these benefits may be mediated by interacting with various targets to increase the levels of antioxidant enzymes in the liver and kidneys. Its mode of action and safety for use as medicine against various metabolic problems caused by diabetes require more research.

Identification of novel candidate targets for suppressing ovarian cancer progression through IL-33/ST2 axis components using the system biology approach.

Background: Cancer-associated fibroblasts (CAFs) of ovarian cancer (OvC) are the most prevalent element of the tumor microenvironment (TM). By promoting angiogenesis, immunological suppression, and invasion, CAFs speed up the growth of tumors by changing the extracellular matrix's structure and composition and/or initiating the epithelial cells (EPT). IL-33/ST2 signaling has drawn a lot of attention since it acts as a pro-tumor alarmin and encourages spread by altering TM. Methods: Differentially expressed genes (DEGs) of the OvC tumor microenvironment were found in the GEO database, qRT-PCR, western blotting, and immunohistochemistry, and their presence and changes in healthy and tumor tissue content were examined. Primary cultures of healthy fibroblasts and CAFs obtained from healthy and tumor tissues retrieved from OvC samples were used for in vitro and in vivo investigations. Cultured primary human CAFs were utilized to investigate the regulation and the IL-33/ST2 axis role in the inflammation reactions. Results: Although ST2 and IL-33 expression was detected in both epithelial (EPT) and fibroblast cells of ovarian cancer, they are more abundant in CAFs. Lipopolysaccharides, serum amyloid A1, and IL-1ß, the inflammatory mediators, could all induce IL-33 expression through NF-κB activation in human CAFs. In turn, via the ST2 receptor, IL-33 affected the production of IL-6, IL-1ß, and PTGS2 in human CAFs via the MAPKs-NF-κB pathway. Conclusion: Our findings suggest that IL-33/ST2 is affected by the interaction of CAFs and epithelial cells inside the tumor microenvironment. Activation of this axis leads to increased expression of inflammatory factors in tumor CAFs and EPT cells. Therefore, targeting the IL-33/ST2 axis could have potential value in the prevention of OvC progression.

CABG Patients Develop Global DNA Hypermethylation, That Negatively Affect the Mitochondrial Function and Promote Post-Surgical Cognitive Decline: A Proof of Concept in Small Cohort.

Global DNA hypermethylation and mitochondrial dysfunction are reported to be associated with the development of mild cognitive decline (MCI). The present study aims to generate preliminary data that connect the above association with post-surgical coronary artery bypass grafting (CABG) cognitive decline in patients. Data were collected from 70 CABG patients and 25 age-matched controls. Cognitive function was assessed using the Montreal Cognitive Assessment (MOCA) test on day 1 (before surgery) and on the day of discharge. Similarly, blood was collected before and one day after the CABG procedure for mitochondrial functional analysis and expression of DNA methylation genes. Test analysis score suggested 31 (44%) patients had MCI before discharge. These patients showed a significant decrease in complex I activity and an increase in malondialdehyde levels (p < 0.001) from the control blood samples. Post-surgical samples showed a significant reduction in blood MT-ND1 mRNA expression from control and from pre-surgical samples (p < 0.005), along with elevated DNMT1 gene expression (p < 0.047), with an insignificant increase in TET1 and TET3 gene expression. Correlation analysis showed a significant positive relation between cognitive decline and elevated blood DNMT1 and declined blood complex I activity, signifying that cognitive decline experienced by post-surgical CABG patients is associated with increased DNMT1 expression and declined complex I activity. Based on the data, we conclude that both DNA hypermethylation and mitochondrial dysfunction are associated with post-CABG MCI, where the former is negatively correlated, and the latter is positively correlated with post-surgical MCI in CABG cases. Additionally, a multimarker approach that comprises MOCA, DNA methylation, DNMT, and NQR activities can be utilized to stratify the population that is sensitive to developing post-CABG MCI.

Antiplatelet, cytotoxic activities and characterization of green-synthesized zinc oxide nanoparticles using aqueous extract of Nephrolepis exaltata.

The goal of the current study was to synthesize zinc oxide nanoparticles (ZnO-NPs) using ZnCl2.2H2O salt precursor and an aqueous extract of Nephrolepis exaltata (N. exaltata), which act as a capping and reducing agent. N. exaltata plant extract-mediated ZnO-NPs were further characterized by various techniques, such as X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transforms infrared spectroscopy (FT-IR), UV-visible (UV-Vis), and energy-dispersive X-ray (EDX) analysis. The nanoscale crystalline phase of ZnO-NPs was analyzed by the XRD patterns. The FT-IR analysis revealed different functional groups of biomolecules involved in the reduction and stabilization of the ZnO-NPs. The light absorption and optical properties of ZnO-NPs were examined by UV-Vis spectroscopy at a wavelength of 380 nm. The spherical shape morphology of ZnO-NPs with mean particle size ranges between 60 and 80 nm was confirmed by SEM images. While the EDX analysis was used to identify the elemental composition of ZnO-NPs. Furthermore, the synthesized ZnO-NPs demonstrate potential antiplatelet activity by inhibiting the platelet aggregation induced by platelet activation factor (PAF) and arachidonic acid (AA). The results showed that synthesized ZnO-NPs were more effective in inhibiting platelet aggregation induced by AA with IC50 (56% and 10 µg/mL) and PAF (63% and 10 µg/mL), respectively. However, the biocompatibility of ZnO-NPs was assessed in human lung cancer cell line (A549) under in vitro conditions. The cytotoxicity of synthesized nanoparticles revealed that cell viability decreased and the IC50 was found to be 46.7% at a concentration of 75 µg/mL. The present work concluded the green synthesis of ZnO-NPs that was achieved by N. exaltata plant extract and showed good antiplatelet and cytotoxic activity, which demonstrates the lack of harmful effects making them more effective for use in pharmaceutical and medical fields to treat thrombotic disorders.

A Mendelian Randomization Analysis Investigates Causal Associations between Inflammatory Bowel Diseases and Variable Risk Factors.

The question of whether variable risk factors and various nutrients are causally related to inflammatory bowel diseases (IBDs) has remained unanswered so far. Thus, this study investigated whether genetically predicted risk factors and nutrients play a function in the occurrence of inflammatory bowel diseases, including ulcerative colitis (UC), non-infective colitis (NIC), and Crohn's disease (CD), using Mendelian randomization (MR) analysis. Utilizing the data of genome-wide association studies (GWASs) with 37 exposure factors, we ran Mendelian randomization analyses based on up to 458,109 participants. Univariable and multivariable MR analyses were conducted to determine causal risk factors for IBD diseases. Genetic predisposition to smoking and appendectomy as well as vegetable and fruit intake, breastfeeding, n-3 PUFAs, n-6 PUFAs, vitamin D, total cholesterol, whole-body fat mass, and physical activity were related to the risk of UC (p < 0.05). The effect of lifestyle behaviors on UC was attenuated after correcting for appendectomy. Genetically driven smoking, alcohol consumption, appendectomy, tonsillectomy, blood calcium, tea intake, autoimmune diseases, type 2 diabetes, cesarean delivery, vitamin D deficiency, and antibiotic exposure increased the risk of CD (p < 0.05), while vegetable and fruit intake, breastfeeding, physical activity, blood zinc, and n-3 PUFAs decreased the risk of CD (p < 0.05). Appendectomy, antibiotics, physical activity, blood zinc, n-3 PUFAs, and vegetable fruit intake remained significant predictors in multivariable MR (p < 0.05). Besides smoking, breastfeeding, alcoholic drinks, vegetable and fruit intake, vitamin D, appendectomy, and n-3 PUFAs were associated with NIC (p < 0.05). Smoking, alcoholic drinks, vegetable and fruit intake, vitamin D, appendectomy, and n-3 PUFAs remained significant predictors in multivariable MR (p < 0.05). Our results provide new and comprehensive evidence demonstrating that there are approving causal effects of various risk factors on IBDs. These findings also supply some suggestions for the treatment and prevention of these diseases.

Nicotine and cotinine quantification after a 4-week inhalation of electronic cigarette vapors in male and female mice using UPLC-MS/MS.

OBJECTIVES: To detect the cotinine and nicotine serum concentrations of female and male C57BL/6J mice after a 4-week exposure to electronic (e)-cigarette vapors using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). METHODS: This experimental study was carried out at an animal facility and laboratories, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, between January and August 2020. A 4-week exposure to e-cigarettes was carried out using male and female mice and serum samples were obtained for cotinine and nicotine quantification using UPLC-MS/MS. The chromatographic procedures involved the use of a BEH HSS T3 C18 column (100 mm x 2.1 mm, 1.7 µm) with acetonitrile as a mobile phase and 0.1% formic acid (2:98 v/v). RESULTS: The applied methodology has highly efficient properties of detection, estimation, and extraction, where the limit of quantification (LOQ) for nicotine was 0.57 ng/mL and limit of detection (LOD) for nicotine was 0.19 ng/mL, while the LOQ for cotinine was 1.11 ng/mL and LOD for cotinine was 0.38 ng/mL. The correlation coefficient was r2>0.99 for both compounds. The average recovery rate was 101.6±1.33 for nicotine and 100.4±0.54 for cotinine, while the precision and accuracy for cotinine and nicotine were less than 6.1. The serum cotinine level was higher in males (433.7±19.55) than females (362.3±16.27). CONCLUSION: This study showed that the gender factor might play a crucial role in nicotine metabolism.

Effects of Chronic Inhalation of Electronic Cigarette Vapor Containing Nicotine on Neurobehaviors and Pre/Postsynaptic Neuron Markers.

Nicotine-exposed animal models exhibit neurobehavioral changes linked to impaired synaptic plasticity. Previous studies highlighted alterations in neurotransmitter levels following nicotine exposure. Vesicular glutamate transporter (VGLUT1) and vesicular gamma-aminobutyric acid (GABA) transporter (VGAT) are essential for the transport and release of glutamate and GABA, respectively, from presynaptic neurons into synapses. In our work, an e-cigarette device was used to deliver vapor containing nicotine to C57BL/6J mice for four weeks. Novel object recognition, locomotion, and Y-maze tests were performed to investigate the behavioral parameters. Protein studies were conducted to study the hippocampal expression of VGLUT1, VGAT, and postsynaptic density protein 95 (PSD95) as well as brain cytokine markers. Long-term memory and locomotion tests revealed that e-cigarette aerosols containing nicotine modulated recognition memory and motor behaviors. We found that vapor exposure increased VGLUT1 expression and decreased VGAT expression in the hippocampus. No alterations were found in PSD95 expression. We observed that vapor-containing nicotine exposure altered certain brain cytokines such as IFNß-1 and MCP-5. Our work provides evidence of an association between neurobehavioral changes and altered hippocampal VGLUT1 and VGAT expression in mice exposed to e-cigarette vapors containing nicotine. Such exposure was also associated with altered neurobehaviors, which might affect neurodegenerative diseases.

Pharmacological Effects of Marine-Derived Enterococcus faecium EA9 against Acute Lung Injury and Inflammation in Cecal Ligated and Punctured Septic Rats.

Microorganisms obtained from the marine environment may represent a potential therapeutic value for multiple diseases. This study explored the possible protective role of marine-derived potential probiotic Enterococcus faecium EA9 (E. faecium) against pulmonary inflammation and oxidative stress using the cecal ligation and puncture (CLP) model of sepsis in Wistar rats. Animals were pretreated with E. faecium for 10 days before either sham or CLP surgeries. Animals were sacrificed 72 hours following the surgical intervention. The histological architecture of lung tissues was evaluated as indicated by the lung injury score. In addition, the extend of pulmonary edema was determined as wet/dry weight ratio. The inflammatory cytokines were estimated in lung tissues, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1ß) using the enzyme-linked-immunosorbent-assay (ELISA) technique. Moreover, markers for lipid peroxidation such as thiobarbituric acid reaction substances (TBARs), and endogenous antioxidants, including reduced glutathione (GSH) were determined in lung tissues. Finally, the enzymatic activities of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) were assayed in the lungs. Pretreatment with E. faecium markedly attenuated CLP-induced lung injury and pulmonary edema. Markers for inflammation, including TNF-α, IL-6, and IL-1ß were augmented in the lung tissues of CLP animals, while E. faecium ameliorated their augmented levels. E. faecium pretreatment also restored the elevated TBARS levels and the prohibited CAT, SOD, and GPx enzymatic activities in CLP animals. GSH levels were corrected by E. faecium in CLP animals. The inflammatory and lipid peroxidation mediators were positively correlated, while antioxidant enzymatic activities were negatively correlated with CLP-induced lung injury and pulmonary edema. Collectively, marine-derived Enterococcus faecium EA9 might be considered as a prospective therapeutic tool for the management of pulmonary dysfunction associated with sepsis.

Virtual Screening for Potential Phytobioactives as Therapeutic Leads to Inhibit NQO1 for Selective Anticancer Therapy.

NAD(P)H:quinone acceptor oxidoreductase-1 (NQO1) is a ubiquitous flavin adenine dinucleotide-dependent flavoprotein that promotes obligatory two-electron reductions of quinones, quinonimines, nitroaromatics, and azo dyes. NQO1 is a multifunctional antioxidant enzyme whose expression and deletion are linked to reduced and increased oxidative stress susceptibilities. NQO1 acts as both a tumor suppressor and tumor promoter; thus, the inhibition of NQO1 results in less tumor burden. In addition, the high expression of NQO1 is associated with a shorter survival time of cancer patients. Inhibiting NQO1 also enables certain anticancer agents to evade the detoxification process. In this study, a series of phytobioactives were screened based on their chemical classes such as coumarins, flavonoids, and triterpenoids for their action on NQO1. The in silico evaluations were conducted using PyRx virtual screening tools, where the flavone compound, Orientin showed a better binding affinity score of -8.18 when compared with standard inhibitor Dicumarol with favorable ADME properties. An MD simulation study found that the Orientin binding to NQO1 away from the substrate-binding site induces a potential conformational change in the substrate-binding site, thereby inhibiting substrate accessibility towards the FAD-binding domain. Furthermore, with this computational approach we are offering a scope for validation of the new therapeutic components for their in vitro and in vivo efficacy against NQO1.

Flavonoids from Marine-Derived Actinobacteria as Anticancer Drugs.

Flavonoids represent a large diverse group of natural products that are used as a traditional medicine against various infectious diseases. They possess many biological activities including antimicrobial, antioxidant, anti-inflammatory, anti-cancer and anti-diabetic activities. Commercially, flavonoids are mainly obtained from plants, however, several challenges are faced during their extraction. Microorganisms have been known as natural sources of a wide range of bioactive compounds including flavonoids. Actinobacteria are the most prolific group of microorganisms for the production of bioactive secondary metabolites, thus facilitating the production of flavonoids. The screening programs for bioactive compounds revealed the potential application of actinobacteria to produce flavonoids with interesting biological activities, especially anticancer activities. Since marine actinobacteria are recognized as a potential source of novel anticancer agents, they are highly expected to be potential producers of anticancer flavonoids with unusual structures and properties. In this review, we highlight the production of flavonoids by actinobacteria through classical fermentation, engineering of plant biosynthetic genes in a recombinant actinobacterium and the de novo biosynthesis approach. Through these approaches, we can control and improve the production of interesting flavonoids or their derivatives for the treatment of cancer.

Coadministration of Ketamine and Perampanel Improves Behavioral Function and Reduces Inflammation in Acute Traumatic Brain Injury Mouse Model.

Traumatic brain injury (TBI) is among the most debilitating neurological disorders with inadequate therapeutic options. It affects all age groups globally leading to post-TBI behavioral challenges and life-long disabilities requiring interventions for these health issues. In the current study, C57BL/6J mice were induced with TBI through the weight-drop method, and outcomes of acutely administered ketamine alone and in combination with perampanel were observed. The impact of test drugs was evaluated for post-TBI behavioral changes by employing the open field test (OFT), Y-maze test, and novel object recognition test (NOR). After that, isolated plasma and brain homogenates were analyzed for inflammatory modulators, i.e., NF-κB and iNOS, through ELISA. Moreover, metabolomic studies were carried out to further authenticate the TBI rescuing potential of drugs. The animals treated with ketamine-perampanel combination demonstrated improved exploratory behavior in OFT (P < 0.05), while ketamine alone as well as in combination yielded anxiolytic effect (P < 0.05-0.001) in posttraumatic mice. Similarly, the % spontaneous alternation and % discrimination index were increased after the administration of ketamine alone (P < 0.05) and ketamine-perampanel combination (P < 0.01-0.001) in the Y-maze test and NOR test, respectively. ELISA demonstrated the reduced central and peripheral expression of NF-κB (P < 0.05) and iNOS (P < 0.01-0.0001) after ketamine-perampanel polypharmacy. The TBI-imparted alteration in plasma metabolites was restored by drug combination as evidenced by metabolomic studies. The outcomes were fruitful with ketamine, but the combination therapy proved more significant in improving all studied parameters. The benefits of this new investigated polypharmacy might be due to their antiglutamatergic, antioxidant, and neuroprotective capacity.