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Breast cancer progression is strongly influenced by estrogen receptor-α (ERα), a ligand-activated transcription factor that regulates hormone binding, DNA interaction, and transcriptional activation. ERα plays a key role in promoting cell proliferation in breast tissue, and its overexpression is associated with the advancement of breast cancer through estrogen-mediated signaling pathways. Targeting ERα is, therefore, a promising therapeutic strategy for breast cancer. However, there are currently no phytochemical-based drug candidates approved for effectively inhibiting breast cancer progression driven by elevated ERα expression. This study aims to identify phytochemical inhibitors from Croton bonplandianum against ERα using pharmacoinformatics approaches. Eighty-three bioactive compounds from C. bonplandianum were retrieved from the IMPPAT (Indian Medicinal Plants, Phytochemistry, and Therapeutics) database and screened through molecular docking for their binding affinity to ERα. The top candidates were further evaluated through molecular dynamics simulations, ADME analysis, toxicity assessment, and quantum mechanics-based DFT calculations. The thermodynamic properties and HOMO-LUMO energy gap values indicated that the selected compounds were both stable and active. Among them, 2,3-oxidosqualene (CID-5366020) and 5,8,11-eicosatriynoic acid, trimethylsilyl ester (CID-91696396) demonstrated the most potent inhibitory activity against ERα. These findings suggest that these compounds have significant potential as therapeutic agents for breast cancer treatment by targeting ERα. [ABSTRACT FROM AUTHOR]

Apigenin is an organic flavonoid abundant in some plants such as parsley, chamomile, or celery. Recently, it has been investigated for several of its pharmacological characteristics, such as its ability to act as an antioxidant, reduce inflammation, and inhibit the growth of cancer cells. The purpose of this review is to provide a summary of the existing knowledge regarding the effects of apigenin on female reproductive systems and its dysfunctions. Apigenin can influence reproductive processes by regulating multiple biological events, including oxidative processes, cell proliferation, apoptosis, cell renewal and viability, ovarian blood supply, and the release of reproductive hormones. It could stimulate ovarian folliculogenesis, as well as ovarian and embryonal cell proliferation and viability, which can lead to an increase in fertility and influence the release of reproductive hormones, which may exert its effects on female reproductive health. Furthermore, apigenin could inhibit the activities of ovarian cancer cells and alleviate the pathological changes in the female reproductive system caused by environmental pollutants, harmful medications, cancer, polycystic ovarian syndrome, ischemia, as well as endometriosis. Therefore, apigenin may have potential as a biostimulator for female reproductive processes and as a therapeutic agent for certain reproductive diseases. [ABSTRACT FROM AUTHOR]

Autophagy, an evolutionarily conserved cellular mechanism essential for maintaining internal stability, plays a crucial function in female reproductive ability. In this review, we discuss the complex interplay between autophagy and several facets of female reproductive health, encompassing pregnancy, ovarian functions, gynecologic malignancies, endometriosis, and infertility. Existing research emphasizes the crucial significance of autophagy in embryo implantation, specifically in the endometrium, highlighting its necessity in ensuring proper fetal development. Although some knowledge has been gained, there is still a lack of research on the specific molecular impacts of autophagy on the quality of oocytes, the growth of follicles, and general reproductive health. Autophagy plays a role in the maturation, quality, and development of oocytes. It is also involved in reproductive aging, contributing to reductions in reproductive function that occur with age. This review explores the physiological functions of autophagy in the female reproductive system, its participation in reproductive toxicity, and its important connections with the endometrium and embryo. In addition, this study investigates the possibility of emerging treatment approaches that aim to modify autophagy, using both natural substances and synthetic molecules, to improve female fertility and reproductive outcomes. Additionally, this review intends to inspire future exploration into the intricate role of autophagy in female reproductive health by reviewing recent studies and pinpointing areas where current knowledge is lacking. Subsequent investigations should prioritize the conversion of these discoveries into practical uses in the medical field, which could potentially result in groundbreaking therapies for infertility and other difficulties related to reproduction. Therefore, gaining a comprehensive understanding of the many effects of autophagy on female fertility would not only further the field of reproductive biology but also open new possibilities for diagnostic and treatment methods. [ABSTRACT FROM AUTHOR]

Autophagy, an intrinsic catabolic mechanism that eliminates misfolded proteins, dysfunctional organelles, and lipid droplets, plays a vital function in energy balance and cytoplasmic quality control, in addition to maintaining cellular homeostasis. Liver cancer such as hepatocellular carcinoma (HCC) is one of the most common causes of cancer deaths globally and shows resistance to several anticancer drugs. Despite the rising incidence and poor prognosis of malignant HCC, the underlying molecular mechanisms driving this aggressive cancer remain unclear. Several natural compounds, such as phytochemicals of dietary and non-dietary origin, affect hepatocarcinogenesis signaling pathways in vitro and in vivo, which may help prevent and treat HCC cells. Current HCC cells treatments include chemotherapy, radiation, and surgery. However, these standard therapies have substantial side effects, and combination therapy enhances side effects for an acceptable therapeutic benefit. Therefore, there is a need to develop treatment strategies for HCC cells that are more efficacious and have fewer adverse effects. Multiple genetic and epigenetic factors are responsible for the HCC cells to become resistant to standard treatment. Autophagy contributes to maintain cellular homeostasis, which activates autophagy for biosynthesis and mitochondrial regulation and recycling. Therefore, modifying autophagic signaling would present a promising opportunity to identify novel therapies to treat HCC cells resistant to current standard treatments. This comprehensive review illustrates how natural compounds demonstrate their anti-hepatocellular carcinoma function through autophagy. [ABSTRACT FROM AUTHOR]

Autophagy is a globally conserved cellular activity that plays a critical role in maintaining cellular homeostasis through the breakdown and recycling of cellular constituents. In recent years, there has been much emphasis given to its complex role in cancer stem cells (CSCs) and stem cell treatment. This study examines the molecular processes that support autophagy and how it is regulated in the context of CSCs and stem cell treatment. Although autophagy plays a dual role in the management of CSCs, affecting their removal as well as their maintenance, the intricate interaction between the several signaling channels that control cellular survival and death as part of the molecular mechanism of autophagy has not been well elucidated. Given that CSCs have a role in the development, progression, and resistance to treatment of tumors, it is imperative to comprehend their biological activities. CSCs are important for cancer biology because they also show a tissue regeneration model that helps with organoid regeneration. In other words, the manipulation of autophagy is a viable therapeutic approach in the treatment of cancer and stem cell therapy. Both synthetic and natural substances that target autophagy pathways have demonstrated promise in improving stem cell-based therapies and eliminating CSCs. Nevertheless, there are difficulties associated with the limitations of autophagy in CSC regulation, including resistance mechanisms and off-target effects. Thus, the regulation of autophagy offers a versatile strategy for focusing on CSCs and enhancing the results of stem cell therapy. Therefore, understanding the complex interactions between autophagy and CSC biology would be essential for creating therapeutic treatments that work in both regenerative medicine and cancer treatment. [ABSTRACT FROM AUTHOR]

Mycotoxins are produced by more than one hundred fungi and produce secondary metabolites that contaminate various agricultural commodities, especially rice and corn. Their presence in the food chain is considered a serious problem worldwide. In recent years, a link between exposure to mycotoxins and impaired fertility has been suggested. Consequently, it has become vital to investigate the interactive effects of these mycotoxins on ovarian function. In this study, we investigated the intergenerational effects of the mycotoxin fumonisin B1 (FB1) on ovarian structure and function. Virgin Wistar albino female rats were separated into control and FB1 treatment groups and examined from day 6 of pregnancy until delivery (20 and 50 mg/kg b.w./day). The obtained female rats of the first (F1) and second generations (F2) were euthanized at 4 weeks of age, and ovary samples were collected. We found that the ovary weight index increased with the high dose of the treatment (50 mg/kg b.w./day) among both F1 and F2, in a manner similar to that observed in polycystic ovary syndrome. As expected, FB1 at a high dose (50 mg/kg b.w.) reduced the number of primordial follicles in F1 and F2, leading to an accelerated age-related decline in reproductive capacity. Moreover, it reduced the fertility rate among the F1 female rats by affecting follicle growth and development, as the number of secondary and tertiary follicles decreased. Histopathological changes were evidenced by the altered structures of most of the growing follicle oocytes, as revealed by a thinning irregular zona pellucida and pyknosis in granulosa cells. These findings are concomitant with steroidogenesis- and folliculogenesis-related gene expression, as evidenced by the decrease in CYP19 activity and estrogen receptor beta (ESR2) gene expression. Additionally, GDF-9 mRNA levels were significantly decreased, and IGF-1 mRNA levels were significantly increased. However, the results from the ovaries of the F2 treatment groups were different and unexpected. While there was no significant variation in CYP19 activity compared to the control, the ESR2 significantly increased, leading to stereological and histopathological changes similar to those of the control, except for some altered follicles. The hallmark histological feature was the appearance of vacuolar structures within the oocyte and between granulosa cell layers. Interestingly, the autophagic marker LC3 was significantly increased in the F2 offspring, whereas this protein was significantly decreased in the F1 offspring. Therefore, we suggest that the promotion of autophagy in the ovaries of the F2 offspring may be considered a recovery mechanism from the effect of prenatal FB1 exposure. Thus, autophagy corrected the effect of FB1 during the early life of the F1 female rats, leading to F2 offspring with ovarian structure and function similar to those of the control. However, the offspring, treated female rats may experience early ovarian aging because their ovarian pool was affected. [ABSTRACT FROM AUTHOR]

A grapevine shoot extract (GSE) was obtained using ultrasound-assisted extraction and characterized. The main phenolic constituents were identified as stilbenoids. Among them, trans-resveratrol and trans-ε-viniferin stood out. The GSE was administered to an isoproterenol-induced myocardial injury animal model. The extract alleviated the associated symptoms of the administration of the drug, i.e., the plasma lipid profile was improved, while the disturbed plasma ion concentration, the cardiac dysfunction markers, the DNA laddering, and the necrosis of myocardial tissue were diminished. This effect could be related to the anti-oxidative potential of GSE associated with its antioxidant properties, the increased levels of endogenous antioxidants (glutathione and enzymatic antioxidants), and the diminished lipid peroxidative markers in the heart. The results also revealed angiotensin-converting enzyme (ACE)-inhibitory activity, which indicated the potential of GSE to deal with cardiovascular disease events. This work suggests that not only trans-resveratrol has a protective role in heart function but also GSE containing this biomolecule and derivatives. Therefore, GSE has the potential to be utilized in the creation of innovative functional ingredients. [ABSTRACT FROM AUTHOR]

The aim of the current work was to examine for the first time the nephropreventive capacity of Ephedra alata seed extract (E) against maternal exposure to acephate in rat offspring. The in vivo results revealed that E. alata supplementation for 28 days (40 mg/kg b.w.) significantly attenuated the nephrotoxicity in adult offspring induced by acephate. In fact, it decreased the levels of creatinine and uric acid and increased the albumin content compared to the intoxicated group. The in utero studies showed that E. alata inhibited the renal oxidative stress generated by acephate exposure by reducing lipid peroxidation and enhancing antioxidant biomarker activities (GSH, CAT, and SOD). The inhibition of DNA fragmentation and the improvement of the ultrastructural changes highlighted the prophylactic effect of E. alata in renal tissue. Additionally, the immunofluorescence study showed the upregulation of LC3 gene expression, suggesting the capacity of E. alata extract to stimulate autophagic processes as a protective mechanism. Molecular docking analysis indicated that hexadecasphinganine, the major compound in E. alata, has a higher affinity toward the Na+/K+-ATPase, epithelial sodium channel (ENaC), and sodium hydrogen exchanger 3 (NHE3) genes than acephate. Hexadecasphinganine could be considered a potential inhibitor of the activity of these genes and therefore exerted its preventive capacity. The obtained findings confirmed that E. alata seed extract exerted nephropreventive capacities, which could be related to its bioactive compounds, which possess antioxidant activities. [ABSTRACT FROM AUTHOR]

Fumonisin B1 (FB1), a mycotoxin produced by Fusarium verticillioides, is one of the most common pollutants in natural foods and agricultural crops. It can cause chronic and severe health issues in humans and animals. The aim of this study was to evaluate the transgenerational effects of FB1 exposure on the structure and function of the kidneys in offspring. Virgin female Wistar rats were randomly divided into three groups: group one (control) received sterile water, and groups two and three were intragastrically administered low (20 mg/kg) and high (50 mg/kg) doses of FB1, respectively, from day 6 of pregnancy until delivery. Our results showed that exposure to either dose of FB1 caused histopathological changes, such as atrophy, hypercellularity, hemorrhage, calcification, and a decrease in the glomerular diameter, in both the first and second generations. The levels of the antioxidant markers glutathione, glutathione S-transferase, and catalase significantly decreased, while malondialdehyde levels increased. Moreover, autophagy was induced, as immunofluorescence analysis revealed that LC-3 protein expression was significantly increased in both generations after exposure to either dose of FB1. However, a significant decrease in methyltransferase (DNMT3) protein expression was observed in the first generation in both treatment groups (20 mg/kg and 50 mg/kg), indicating a decrease in DNA methylation as a result of early-life exposure to FB1. Interestingly, global hypomethylation was also observed in the second generation in both treatment groups despite the fact that the mothers of these rats were not exposed to FB1. Thus, early-life exposure to FB1 induced nephrotoxicity in offspring of the first and second generations. The mechanisms of action underlying this transgenerational effect may include oxidative stress, autophagy, and DNA hypomethylation. [ABSTRACT FROM AUTHOR]

As part of the valorization of agricultural waste into bioactive compounds, a series of structurally novel oleanolic acid ((3β-hydroxyolean-12-en-28-oic acid, OA-1)-phtalimidines (isoindolinones) conjugates 18a–u bearing 1,2,3-triazole moieties were designed and synthesized by treating an azide 4 previously prepared from OA-1 isolated from olive pomace (Olea europaea L.) with a wide range of propargylated phtalimidines using the Cu(I)-catalyzed click chemistry approach. OA-1 and its newly prepared analogues, 18a–u, were screened in vitro for their antibacterial activity against two Gram-positive bacteria, Staphylococcus aureus and Listeria monocytogenes, and two Gram-negative bacteria, Salmonella thyphimurium and Pseudomonas aeruginosa. Attractive results were obtained, notably against L. monocytogenes. Compounds 18d, 18g, and 18h exhibited the highest antibacterial activity when compared with OA-1 and other compounds in the series against tested pathogenic bacterial strains. A molecular docking study was performed to explore the binding mode of the most active derivatives into the active site of the ABC substrate-binding protein Lmo0181 from L. monocytogenes. Results showed the importance of both hydrogen bonding and hydrophobic interactions with the target protein and are in favor of the experimental data. [ABSTRACT FROM AUTHOR]

This work investigated the protective effects of microalga Halamphora sp. extract (HExt), a nutraceutical and pharmacological natural product, on human lead-intoxicated liver and kidney cells in vitro and in vivo in Wistar rats. The human hepatocellular carcinoma cell line HepG2 and the human embryonic kidney cell line HEK293 were used for the in vitro study. The analysis of the fatty acid methyl esters in the extract was performed via GC/MS. The cells were pretreated with HExt at 100 µg mL−1, followed by treatment with different concentrations of lead acetate, ranging from 25 to 200 µM for 24 h. The cultures were incubated (5% CO, 37 °C) for 24 h. Four groups, each containing six rats, were used for the in vivo experiment. The rats were exposed to subchronic treatment with a low dose of lead acetate (5 mg kg−1 b.w. per day). Pretreating HepG2 and HEK293 cells with the extract (100 µg mL−1) significantly (p < 0.05) protected against the cytotoxicity induced by lead exposure. For the in vivo experiment, the biochemical parameters in serum—namely, the level of malondialdehyde (MDA), and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)—were measured in the organ homogenate supernatants. HExt was found to be rich in fatty acids, mainly palmitic and palmitoleic acids (29.464% and 42.066%, respectively). In both the in vitro and in vivo experiments, cotreatment with HExt protected the liver and kidney cell structures and significantly preserved the normal antioxidant and biochemical parameters in rats. This study discovered the possible protective effect of HExt, which could be beneficial for Pb-intoxicated cells. [ABSTRACT FROM AUTHOR]

Background: The annual prevalence of gestational diabetes mellitus—characterized by an increase in blood glucose in pregnant women—has been increasing worldwide. The goal of this study was to evaluate the expression of glucose transporter 1 (GLUT1) and glucose transporter 3 (GLUT3) in the placenta of women with gestational diabetes mellitus. Methods: Sixty-five placentas from women admitted to the King Saud University Medical City, Riyadh, Saudi Arabia, were analyzed; 34 and 31 placentas were from healthy pregnant women and women with gestational diabetes, respectively. The expressions of GLUT1 and GLUT3 were assessed using RT-PCR, Western blotting, and immunohistochemical methods. The degree of apoptosis in the placental villi was estimated via a TUNEL assay. Results: The results of the protein expression assays and immunohistochemical staining showed that the levels of GLUT1 and GLUT3 were significantly higher in the placentas of pregnant women with gestational diabetes than those in the placentas of healthy pregnant women. In addition, the findings showed an increase in apoptosis in the placenta of pregnant women with gestational diabetes compared to that in the placenta of healthy pregnant women. However, the results of gene expression assays showed no significant difference between the two groups. Conclusions: Based on these results, we conclude that gestational diabetes mellitus leads to an increased incidence of apoptosis in the placental villi and alters the level of GLUT1 and GLUT3 protein expressions in the placenta of women with gestational diabetes. Understanding the conditions in which the fetus develops in the womb of a pregnant woman with gestational diabetes may help researchers understand the underlying causes of the development of chronic diseases later in life. [ABSTRACT FROM AUTHOR]

Simple Summary: Although continuous exposure to conventional pesticides has been linked to tissue dysfunction among humans and animals, there is little information regarding the environmental disturbances and their harmful effects on fetuses. In the present study, we investigated the anomalies caused by oral acephate exposure on the kidney function in rat offspring in utero. Moreover, this harmful organic pollutant has been reported to promote the development of various cell injuries and tissue functional disorders, such as reproductive toxicity and diabetes. In addition, we found that exposure to acephate during pregnancy can alter renal integrity and induce nephrotoxicity in rat offspring. Furthermore, acephate exposure aggravated kidney injury by enhancing oxidative stress, autophagy, apoptosis, and histopathological alterations. As humans experience increased exposure to agrochemicals worldwide, the obtained data will advance the knowledge of how an unfavorable fetal environment can affect the offspring's health during adulthood. This study examined how maternal exposure to acephate—an organophosphate-based insecticide—affected the renal development in rat offspring during adulthood. Virgin female Wistar rats were randomly allocated to three groups: group 1 (control) received sterile water; groups 2 and 3 were intragastrically exposed to low (14 mg/kg) and high (28 mg/kg) doses of acephate from day 6 of pregnancy until delivery, respectively. Further, the offspring of the adult female rats were euthanized in postnatal week 8. Compared with the controls, the adult rat offspring with exposure to low and high doses of acephate exhibited elevated plasma creatinine and blood urea nitrogen levels. Additionally, immunofluorescence analysis revealed the upregulation of autophagic marker genes (Beclin-1 and LC-3) in the acephate-treated rat offspring, thereby suggesting the induction of an autophagic mechanism. Notably, the increased malondialdehyde level, decreased glutathione level, and decreased superoxide dismutase and catalase activities confirmed the ability of acephate to induce oxidative stress and apoptosis in the kidneys of the rat offspring. This may explain the renal histopathological injury detected using hematoxylin and eosin staining. Furthermore, a reverse transcription polymerase chain reaction revealed that the mRNA expression levels of the Na+/K+-ATPase and the epithelial sodium channel (ENaC) genes were significantly higher in the kidney of female offspring than that of controls owing to acephate toxicity. However, there was no significant effect of acephate on the expression of NHE3 in the treatment group compared with the control group. Overall, the present findings suggest that oxidative stress caused by prenatal exposure to acephate causes nephrotoxicity and histopathological alterations in adult rat offspring, likely by actions on renal ENaC and Na+/K+-ATPase genes as well as the autophagic markers Beclin-1 and LC-3. [ABSTRACT FROM AUTHOR]

The aim of the present study was to examine, for the first time, the phytochemical content of Ephedra alata pulp extract (EAP) and explore its antioxidant and anti-inflammatory capacities. High-performance liquid chromatography-electrospray ionization-quadrupole-time-of-flight mass spectrometry (HPLC–ESI–QTOF/MS) was used for phytochemical analysis and three in vitro antioxidant assays together with three in vitro anti-inflammatory tests were used for the assessment of biological activity. The HPLC–ESI–QTOF/MS analysis revealed the presence of 42 metabolites, including flavonoids, sphingolipides, fatty acids, ephedrine derivatives, and amino acid derivatives. In vitro findings revealed that EAP has interesting 2,2-diphenyl-1-picrylhydrazyl (DPPH), superoxide, and ferrous ion chelating capacities (IC50 values were 0.57 mg/mL, 0.55 mg/mL, and 0.51 mg/mL for DPPH, superoxide radical, and ferrous ion, respectively). Furthermore, EAP showed a noticeable anti-inflammatory ability by inhibiting the two cyclooxygenase isoforms, COX-1 and COX-2 (IC50 of 59.1 and 58.8 µg/mL for COX-1 and COX-2, respectively), preventing protein denaturation (IC50 = 0.51 mg/mL), and protecting membrane stabilization (IC50 = 0.53 mg/mL). The results highlighted the use of Ephedra alata pulp as a potential source of natural compounds with therapeutic effects for the management of inflammatory disorders. [ABSTRACT FROM AUTHOR]

Simple Summary: The multiple effects of endocrine disruptors on aquatic invertebrates have rarely been assessed based on integrative approaches, despite the clear advantage of exploring histology in association with traditional acute toxicology tools. Applying such approaches is critical in significantly reducing health risks for human populations that regularly consume seafood such as bivalves. The data presented here support the use of the European clam Ruditapes decussatus as a biological indicator of the presence of triclosan in seawater, and demonstrate the usefulness of biomarker assessment and histological features in determining environmental thresholds and government guidelines. The aim of this work was to study the ecotoxicological effects of an endocrine disruptor triclosan on the clam Ruditapes decussatus. The bivalves were exposed to three concentrations of this biocide (C1 = 100 ng/L, C2 = 200 ng/L and C3 = 500 ng/L) for three and seven days. The impact was assessed at the gills and digestive glands, through activities of an antioxidant defense biomarker (Gluthatione S-Transferase, GST), a damage biomarker (Malondialdehyde, MDA), and a neurotoxicity biomarker (Acetylcholinesterase, AChE). Furthermore, histological traits were approached in different organs to evaluate any possible alteration induced by triclosan. It appears from this study that both gills and digestive glands responded discernibly to triclosan and effects were concentration-dependent. The stressed clams showed a significant increase in their GST and MDA activities in gills and digestive glands compared to controls for both time slots considered. In turn, the AChE activity was clearly inhibited in both organs in a time dependent way. The histological study made it possible to observe several structural pathologies caused by triclosan in the gills and the digestive gland. These alterations consisted mainly of inflammatory reactions, malformations of the lamellae and fusion of the gill filaments, degeneration of the connective tissue, and the erosion of the gill cilia with the appearance of certain severe alterations (cell necrosis and apoptosis), which can thus cause a malfunction of the gills and eventually lead to a reduction in oxygen consumption and a disruption of the osmoregulation for bivalves. Alterations in the digestive gland have also been detected, mainly by epithelial alterations, thinning of the tubules, and alteration of the basal cell membrane which can impair the ability of clams to absorb food. At germinal cells, several damages were observed in the oocytes which probably disturbed the reproductive function and the fertility of the clams. The damages observed in female gonads were caused by the cytolysis of a large number of oocytes through autophagy and necrosis at 200 ng triclosan/L. Moreover, at 500 ng triclosan/L, hemocytic infiltration was observed in acini and apoptotic bodies reflected in the fragmentation of more than 90% of oocytes. [ABSTRACT FROM AUTHOR]

In recent decades, the use of herbs and plants has been of great interest, as they have been the sources of natural products, commonly named as bioactive compounds. In specific, the natural compounds from the Capparaceae family which has been proved to have antioxidant, anti-inflammatory, antimicrobial and anti-carcinogenic activities, by several studies. Cleome arabica L. (CA) specie is the most used medicinal plants in Tunisia and elsewhere in North African countries for treatment of various diseases including diabetes, rheumatism, inflammation, cancer, and digestive disorders. The current work was undertaken to estimate the total phenolic, flavonoid and condensed tannin contents, to identify and quantify the polyphenolic compounds, and to evaluate the antioxidant and the anti-inflammatory proprieties of CA fruits extract against formalin induced chronic inflammation in Female Wistar rats. In fact, the antioxidant activity was tested by Diphenyl-1-Picrylhydrazyl free radical scavenging (DPPH), Ferric reducing antioxidant power (FRAP) and Nitric Oxide radical (NO·). Anti-inflammatory effect of fruits extract was examined using formalin (2%) induced paw edema in rats. Molecular docking tools were used to investigate the interaction of some compounds from CA fruits extract with the cyclooxygenase-2 (COX-2) target protein. Our results showed that, the total phenolic, flavonoid and tannins contents, which were assessed by the Folin-Ciocalteu, Quercetin, and Catechin methods, respectively, were 230.22 mg gallic acid equivalent/g dry weight (mg GAE/g DW), 55.08 mg quercetin equivalent/g dry weight (QE/g DW) and 15.17 mg catechin equivalents/g dry weight (CatE/g DW), respectively. HPLC analysis revealed the presence of five polyphenolic compounds whose catechin was found to be the most abundant compounds. The antioxidant activity of extract was quantified by DPPH, FRAP and NO· tests and IC50 reached the values of 3.346 mg/mL, 2.306 and 0.023 mg/mL, respectively. Cleome fruits ameliorated the histological integrity of the skin and alleviated the disruptions in hematological parameters (WBC, LYM, RBC, and HGB), inflammatory cytokines (IL-1β, IL-6, TNF-α), C-reactive protein, and some oxidative stress markers (TBARS (−49%) and AOPP (−42%) levels, SOD (+33%) and GPx (+75%) activities, and GSH (+49%) content) induced by formalin injection. Moreover, the in-silico investigation had shown that CA fruits extract compounds have a stronger interaction with COX-2 active site, more than the reference drug "indomethacin" (two H-bonds). Our research gives pharmacological backing to the healthcare utilization of Cleome plant in the treatment of inflammatory diseases and oxidative harm. [ABSTRACT FROM AUTHOR]

Simple Summary: The multiple impacts of polycylic aromatic hydrocarbon on the aquatic invertebrates were rarely assessed in a chronic way and multiple-species experiments, despite the clear advantage of better mimicking natural conditions compared to traditional acute and single-species-focused toxicological experiments. The application of such an approach is essential to lower the health risks for populations that regularly consume seafood. The data presented herein supported the use of Mytilus galloprovincyalis and Ruditapes decussatus as bioindicators of phenanthrene in water and/or sediment and proved the efficacy of the biomarkers' assessment and molecular modelling in determining environmental thresholds and policies for governments. The aim of the current study was to assess the multifaceted effects of the polycylic aromatic hydrocarbon phenanthrene, mainly used in the colouring, explosive, and pharmaceutical industries, on the physiology of two bivalve species with economic value as seafood, namely, the Mediterranean mussel Mytilus galloprovincyalis and the European clam Ruditapes decussatus. The current study assessed how the phenanthrene affected several biomarkers and biometric endpoints in both bivalves, based on an in vivo experiment in silico approach. The bivalves were exposed during four time slots (i.e., 7, 15, 21, and 28 days) to two concentrations of phenanthrene in water (50 µg/L and 100 µg/L). For the clam R. decussatus, an additional contamination of sediment was applied due their typical benthic lifestyle (50 µg/kg and 100 µg/kg). The phenanthrene significantly reduced the ability of bivalves to tolerate desiccation and their Median Lethal Time, and also inhibited the activity of the enzyme acetylcholinesterase in a time-dependent manner. The activity of catalase indicated that bivalves also experienced oxidative stress during the first 21 days of the experiment. The significant decline in catalase activity observed during the last week of the experiment for the mussel M. galloprovincyalis supported a depletion of enzymes caused by the phenanthrene. The phenanthrene has also toxicokinetic and toxicodynamic properties, as assessed by the in silico approach. Overall, the results obtained suggest that the bivalves Ruditapes decussatus and M. galloprovincyalis can be used as a sentinel species in monitoring studies to assess the environmental impact of phenanthene in marine ecosystems. The significance of our findings is based on the fact that in ecotoxicology, little is known about the chronic effects, the simultaneous use of multiple species as bioindicators, and the interactions molecular modelling. [ABSTRACT FROM AUTHOR]

In addition to vaccines, antiviral drugs are essential in order to suppress COVID-19. Although some inhibitor candidates have been determined to target the SARS-CoV-2 protein, there is still an urgent need to continue researching novel inhibitors of the SARS-CoV-2 main protease 'Omicron P132H', a protein that has recently been discovered. In the present study, in the search for therapeutic alternatives to treat COVID-19 and its recent variants, we conducted a structure-based virtual screening using docking studies for a new series of pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives 5–13, which were synthesized from the condensation reaction of pyrazolopyrimidinone-hydrazide (4) with a series of electrophiles. Some significant ADMET predictions–in addition to the docking results–were obtained based on the types of interactions formed and the binding energy values were compared to the reference anti- SARS-CoV-2 redocked drug nirmatrelvir. [ABSTRACT FROM AUTHOR]

The increased concern regarding the reduction in female fertility and the impressive numbers of women undergoing fertility treatment support the existence of environmental factors beyond inappropriate programming of developing ovaries. Among these factors are pyrethroids, which are currently some of the most commonly used pesticides worldwide. The present study was performed to investigate the developmental effects of the pyrethroid-based insecticide allethrin on ovarian function in rat offspring in adulthood. We mainly focused on the roles of oxidative stress, apoptosis, autophagy and the related pathways in ovarian injury. Thirty-day-old Wistar albino female rats were intragastrically administered 0 (control), 34.2 or 68.5 mg/kg body weight allethrin after breeding from Day 6 of pregnancy until delivery. We found that allethrin-induced ovarian histopathological damage was accompanied by elevations in oxidative stress and apoptosis. Interestingly, the number of autophagosomes in allethrin-treated ovaries was higher, and this increase was correlated with the upregulated expression of genes and proteins related to the autophagic marker LC-3. Furthermore, allethrin downregulated the expression of PI3K, AKT and mTOR in allethrin-treated ovaries compared with control ovaries. Taken together, the findings of this study suggest that exposure to the pyrethroid-based insecticide allethrin adversely affects both the follicle structure and function in rat offspring during adulthood. Specifically, allethrin can induce excessive oxidative stress and defective autophagy-related apoptosis, probably through inactivation of the PI3K/AKT/mTOR signaling pathway, and these effects may contribute to ovarian dysfunction and impaired fertility in female offspring. [ABSTRACT FROM AUTHOR]

Increasing concentrations of the antidepressants amitriptyline and paroxetine were determined recently in marine habitats. However, their impact on marine biota is understudied, despite multiple undesirable effects they have on the environment. An important behavioral aspect that is increasingly measured following exposure to contaminants is the migration of fauna from contaminated areas. Hence, our aim was to better understand the migration pattern of marine meiobenthic fauna, but with a main focus on nematodes, following the exposure to both antidepressants, alone or in mixture. The experiment was carried out in microcosms, which comprised an uncontaminated upper and a lower contaminated compartment, where amitriptyline was added, alone or mixed with paroxetine, at concentrations of 0.4 and 40 µg L−1. The overall abundance of meiobenthic groups decreased significantly following exposure to amitriptyline in both compartments, a pattern augmented by the mixture with paroxetine. The migration of nematodes towards the upper compartments of microcosms was triggered by the level of contamination with antidepressants. As such, the species Terschellingia longicaudata showed no significant change in abundance, suggesting tolerance to both antidepressants. On the other hand, the abundances of nematode taxa Cyatholaimus prinzi, Calomicrolaimus sp., Calomicrolaimus honestus, Neochromadora sp., Chromadorina sp. and Chromadorina minor decreased significantly following the exposure to both antidepressants, even at low concentrations. At the end of the experiment, the dominant migratory nematodes belonged to deposit-feeders and omnivores-carnivores trophic guilds, with tail shapes of e/f types and body-sizes longer than 2 mm. Such functional traits increase their mobility in sediments and the chance to move away from contaminated habitats. Moreover, the sex ratio was imbalanced in the favor of males in contaminated lower compartments with mixtures of the lowest and highest concentrations of amitriptyline and paroxetine, suggesting that these drugs also affect the hormone system. In conclusion, the exposure to the antidepressants amitriptyline and paroxetine triggered important changes within nematode communities, as changes in taxonomic composition were a result of migration and survival of tolerant taxa, but equally acting on the hormone system and leading to unbalanced sex-ratio among the residents. [ABSTRACT FROM AUTHOR]

The toxic effects of two commonly used glucocorticoids, the dexamethasone and prednisolone, on meiobenthic nematodes were assessed in a laboratory experiment for 30 days. Nine treatments were employed, comprised of two single and mixed concentrations of dexamethasone and prednisolone (i.e., 0.14 and 1.4 µg·L−1). The exposure to both glucocorticoids showed significant effects on the abundance and taxonomic diversity of nematodes. Such changes were mainly induced by the decrease in the abundance of the species Microlaimus honestus, considered to be sensitive to prednisolone and by the increase in Enoplolaimus longicaudatus abundance, which can be considered tolerant. The exposure to these glucocorticoids also led to a decrease in 2A feeding groups, 2–4 mm body-size interval, and c-p3 life history type in most treatments, with type of life history and shape of amphids as the most relevant functional traits impacted by these two glucocorticoids. The results could also be explained by the potential antagonism between these two pharmaceuticals. [ABSTRACT FROM AUTHOR]

Superparamagnetic Fe3O4 nanoparticles on hydroxyapatite nanorod based nanostructures (Fe3O4/HAp) were synthesized using hydrothermal techniques at 180 °C for 12 h and were used as drug delivery nanocarriers for cancer cell therapeutic applications. The synthesized Fe3O4/HAp nanocomposites were characterized by X-ray diffraction analysis (XRD), Field emission scanning electron microscopy (FESEM), Fourier transform infrared spectroscopy (FTIR), Brunauer-Emmett-Teller (BET)-analysis, and vibrating sample magnetometry (VSM). The morphologies of the Fe3O4/HAp nanocomposites show 15 nm Fe3O4 nanoparticles dispersed in the form of rods. The BET result shows that the synthesized samples have a high specific surface area of 80 m² g-1 with mesoporous structures. Magnetic measurements revealed that the sample has high saturation magnetization of 18 emu/g with low coercivity. The Fe3O4/HAp nanocomposites had a large specific surface area (SSA), high mesoporous volume, and good magnetic property, which made it a suitable nanocarrier for targeted drug delivery systems. The chemotherapeutic agent, andrographolide, was used to investigate the drug delivery behavior of the Fe3O4/HAp nanocomposites. The human epidermoid skin cancer cells (A431) were used as the model targeting cell lines by treating with andrographolide loaded Fe3O4/HAp nanosystems and were further evaluated for their antiproliferative activities and the induction of apoptosis. Also, the present nanocomposite shows better biocompatibility, therefore it can be used as suitable drug vehicle for cancer therapy applications. [ABSTRACT FROM AUTHOR]

Microgravity impairs tissue organization and critical pathways involved in the cell–microenvironment interplay, where fibroblasts have a critical role. We exposed dermal fibroblasts to simulated microgravity by means of a Random Positioning Machine (RPM), a device that reproduces conditions of weightlessness. Molecular and structural changes were analyzed and compared to control samples growing in a normal gravity field. Simulated microgravity impairs fibroblast conversion into myofibroblast and inhibits their migratory properties. Consequently, the normal interplay between fibroblasts and keratinocytes were remarkably altered in 3D co-culture experiments, giving rise to several ultra-structural abnormalities. Such phenotypic changes are associated with down-regulation of α-SMA that translocate in the nucleoplasm, altogether with the concomitant modification of the actin-vinculin apparatus. Noticeably, the stress associated with weightlessness induced oxidative damage, which seemed to concur with such modifications. These findings disclose new opportunities to establish antioxidant strategies that counteract the microgravity-induced disruptive effects on fibroblasts and tissue organization. [ABSTRACT FROM AUTHOR]

Simple Summary: Toluene, as one of the volatile organic solvents, has important industrial applications and can be used in a wide range of consumer and commercial products. It can be inhaled and absorbed easily by the human body and can therefore affect the individual's health through damaging different body tissues, including the ovary. This organic solvent has been one of the most well-studied neurotoxins in recent decades. Studies reporting its effects on ovarian function are still limited. To advance our knowledge on the effect of toluene on female reproduction, an in vivo study using female Wistar rats was investigated. We found that toluene exposure affected ovarian structure and hormone balance by increasing progesterone and testosterone levels. In addition, it has disrupted most of the ovarian markers involved in granulosa cell proliferation and differentiation. Interestingly, Toluene exposure induced both apoptosis and autophagy, confirming the crosstalk between both mechanisms. The promising results of this study may contribute to the prevention of reproductive problems in society by raising the awareness about the use of this hydrocarbon. Toluene has been shown to be highly toxic to humans and animals and can cause damage to various tissues. However, studies reporting its effects on ovarian function are still limited. In this study, we investigated the in vivo effect of toluene using female Wistar rats. We found that toluene exposure decreased ovarian weight and affected ovarian structure by increasing the number of abnormally growing follicles. Moreover, it significantly increased progesterone and testosterone levels. We also showed that toluene exposure decreased GDF-9 protein and its encoding gene. In addition, it inhibited the expression of most of the genes involved in granulosa cell proliferation and differentiation, such as Insl3, ccnd2 and actb. The TUNEL assay showed that apoptosis occurred at the middle and high doses only (4000 and 8000 ppm, respectively), whereas no effect was observed at the low dose (2000 ppm). Interestingly, we showed that toluene exposure induced autophagy as LC3 protein and its encoding gene significantly increased for all doses of treatment. These results may suggest that the activation of autophagy at a low dose of exposure was to protect ovarian cells against death by inhibiting apoptosis, whereas its activation at high doses of exposure triggered apoptosis leading to cell death. [ABSTRACT FROM AUTHOR]

To explore a new set of anticancer agents, a novel series of pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine derivativeshave been designed and synthesized viacyclocondensation reactions of pyrazolo-enaminone with a series of arylidenemalononitriles; compound 5 was obtained from 5-amino-4-cyanopyrazole. The structures of the target compounds were investigated by spectral techniques and elemental analysis (IR, UV–Vis, 1H NMR, 13C NMR and ESI-MS). All compounds were evaluated for their in vitro cytotoxicity employing a panel of different human tumor cell lines, A375, HT29, MCF7, A2780, FaDu as well as non-malignant NIH 3T3 and HEK293 cells. It has been found that the pyrazolo-pyrido-pyrimidine analog bearing a 4-Br-phenyl moiety was the most active toward many cell lines with EC50 values ranging between 9.1 and 13.5 µM. Moreover, in silico docking studies of the latter with six anticancer drug targets, i.e., DHFR, VEGFR2, HER-2/neu, hCA-IX, CDK6 and LOX5, were also performed, in order to gain some insights into their putative mode of binding interaction and to estimate the free binding energy of this bioactive molecule. [ABSTRACT FROM AUTHOR]

Background. Health and social management of the SARS-CoV-2 epidemic, responsible for the COVID-19 disease, requires both screening tools and diagnostic procedures. Reliable screening tests aim at identifying (truely) infectious individuals that can spread the viral infection and therefore are essential for tracing and harnessing the epidemic diffusion. Instead, diagnostic tests should supplement clinical and radiological findings, thus helping in establishing the diagnosis. Several analytical assays, mostly using RT-PCR-based technologies, have become commercially available for healthcare workers and clinical laboratories. However, such tests showed some critical limitations, given that a relevant number of both false-positive and false-negative cases have been so far reported. Moreover, those analytical techniques demonstrated to be significantly influenced by pre-analytical biases, while the sensitivity showed a dramatic time dependency. Aim. Herein, we critically investigate limits and perspectives of currently available RT-PCR techniques, especially when referring to the required performances in providing reliable epidemiological and clinical information. Key Concepts. Current data cast doubt on the use of RT-PCR swabs as a screening procedure for tracing the evolution of the current SARS-COV-2 pandemic. Indeed, the huge number of both false-positive and false-negative results deprives the trustworthiness of decision making based on those data. Therefore, we should refine current available analytical tests to quickly identify individuals able to really transmit the virus, with the aim to control and prevent large outbreaks. [ABSTRACT FROM AUTHOR]

In this review, we explore the current literature on the influence of the plant isoflavone daidzein and its metabolite equol on animal and human physiological processes, with an emphasis on female reproduction including ovarian functions (the ovarian cycle; follicullo- and oogenesis), fundamental ovarian-cell functions (viability, proliferation, and apoptosis), the pituitary and ovarian endocrine regulators of these functions, and the possible intracellular mechanisms of daidzein action. Furthermore, we discuss the applicability of daidzein for the control of animal and human female reproductive processes, and how to make this application more efficient. The existing literature demonstrates the influence of daidzein and its metabolite equol on various nonreproductive and reproductive processes and their disorders. Daidzein and equol can both up- and downregulate the ovarian reception of gonadotropins, healthy and cancerous ovarian-cell proliferation, apoptosis, viability, ovarian growth, follicullo- and oogenesis, and follicular atresia. These effects could be mediated by daidzein and equol on hormone production and reception, reactive oxygen species, and intracellular regulators of proliferation and apoptosis. Both the stimulatory and the inhibitory effects of daidzein and equol could be useful for reproductive stimulation, the prevention and mitigation of cancer development, and the adverse effects of environmental stressors in reproductive biology and medicine. [ABSTRACT FROM AUTHOR]

The present study examined the effects of maternal Ramadan-type fasting during selected days in the first, second, or third trimester, or during the entire pregnancy, on the kidney structure of male rat offspring. Pregnant rats were provided with food ad libitum during pregnancy (control group, C), or they were exposed to 16 h of fasting/day for three consecutive days in the middle of the first (FT1), second (FT2), or third trimester (FT3), or during whole pregnancy (FWP). Our results showed that dams in the FWP group demonstrated lower food intake and body weight during gestation. Litter size was unaltered by fasting in all groups; however, litter weight was significantly reduced only in the FWP group. Nephron number was decreased in the FWP group, but it remained unchanged in the other fasting groups. The ultrastructure of the glomerular filtration barrier indicated that the kidneys of offspring of the FWP group demonstrated wider diameters of fenestrations and filtration slits and smaller diameters of basement membranes. This was reflected by a significant increase in proteinuria in FWP only. These results suggest that, unlike with short-term fasting, which seems to be safe, maternal long-term fasting induces structural changes that were non-reversible, and that may contribute to impaired renal function, leading to chronic diseases in later life. [ABSTRACT FROM AUTHOR]

The aim of the present research was to determine the chemical composition and the cytotoxic effects of Tetraclinis articulata trunk bark essential oil (HEE) obtained by steam distillation and five fractions obtained by normal phase silica chromatographic separation. Chemical analysis allowed the identification of 54 known compounds. Relatively high amounts of oxygenated sesquiterpenes (44.4–70.2%) were detected, mainly consisting of caryophyllene oxide (13.1–26.6%), carotol (9.2–21.2%),14-hydroxy-9-epi-(E)-caryophyllene (3.2–15.5%) and humulene epoxide II (2.6–7.2%). The cytotoxic activity against human mammary carcinoma cell lines (MDA-MB-231) and colorectal carcinoma cell lines (SW620) of the essential oil and its fractions were assessed. All the samples displayed moderate to weak activity compared to 5-fluorouracil. The colorectal carcinoma cell line was relatively more sensitive to the essential oil and its fractions compared to the breast cancer cell line, showing IC50 values from 25.7 to 96.5 μg/mL. In addition, the essential oil and its fraction E.2 revealed a cytotoxic activity against colorectal carcinoma cell line, with IC50 values lower than 30 μg/mL. This is the first report on the chemical composition and cytotoxic activity of the trunk bark essential oil of T. articulata. [ABSTRACT FROM AUTHOR]

Metazoan living cells exposed to microgravity undergo dramatic changes in morphological and biological properties, which ultimately lead to apoptosis and phenotype reprogramming. However, apoptosis can occur at very different rates depending on the experimental model, and in some cases, cells seem to be paradoxically protected from programmed cell death during weightlessness. These controversial results can be explained by considering the notion that the behavior of adherent cells dramatically diverges in respect to that of detached cells, organized into organoids-like, floating structures. We investigated both normal (MCF10A) and cancerous (MCF-7) breast cells and found that appreciable apoptosis occurs only after 72 h in MCF-7 cells growing in organoid-like structures, in which major modifications of cytoskeleton components were observed. Indeed, preserving cell attachment to the substrate allows cells to upregulate distinct Akt- and ERK-dependent pathways in MCF-7 and MCF-10A cells, respectively. These findings show that survival strategies may differ between cell types but cannot provide sufficient protection against weightlessness-induced apoptosis alone if adhesion to the substrate is perturbed. [ABSTRACT FROM AUTHOR]

Some yet unidentified factors released by both oocyte and embryonic microenvironments demonstrated to be non-permissive for tumor development and display the remarkable ability to foster cell/tissue reprogramming, thus ultimately reversing the malignant phenotype. In the present study we observed how molecular factors extracted from Zebrafish embryos during specific developmental phases (20 somites) significantly antagonize proliferation of breast cancer cells, while reversing a number of prominent aspects of malignancy. Embryo extracts reduce cell proliferation, enhance apoptosis, and dramatically inhibit both invasiveness and migrating capabilities of cancer cells. Counteracting the invasive phenotype is a relevant issue in controlling tumor spreading and metastasis. Moreover, such effect is not limited to cancerous cells as embryo extracts were also effective in inhibiting migration and invasiveness displayed by normal breast cells undergoing epithelial–mesenchymal transition upon TGF-β1 stimulation. The reversion program involves the modulation of E-cadherin/β-catenin pathway, cytoskeleton remodeling with dramatic reduction in vinculin, as well as downregulation of TCTP and the concomitant increase in p53 levels. Our findings highlight that—contrary to the prevailing current "dogma", which posits that neoplastic cells are irreversibly "committed"—the malignant phenotype can ultimately be "reversed", at least partially, in response to environmental morphogenetic influences. [ABSTRACT FROM AUTHOR]

In recent decades, the use of herbs and plants has been of great interest, as they have been the sources of natural products, commonly named as bioactive compounds. In specific, the natural compounds from the Capparaceae family which has been proved to have antioxidant, anti-inflammatory, antimicrobial and anti-carcinogenic activities, by several studies. Cleome arabica L. (CA) specie is the most used medicinal plants in Tunisia and elsewhere in North African countries for treatment of various diseases including diabetes, rheumatism, inflammation, cancer, and digestive disorders. The current work was undertaken to estimate the total phenolic, flavonoid and condensed tannin contents, to identify and quantify the polyphenolic compounds, and to evaluate the antioxidant and the anti-inflammatory proprieties of CA fruits extract against formalin induced chronic inflammation in Female Wistar rats. In fact, the antioxidant activity was tested by Diphenyl-1-Picrylhydrazyl free radical scavenging (DPPH), Ferric reducing antioxidant power (FRAP) and Nitric Oxide radical (NO·). Anti-inflammatory effect of fruits extract was examined using formalin (2%) induced paw edema in rats. Molecular docking tools were used to investigate the interaction of some compounds from CA fruits extract with the cyclooxygenase-2 (COX-2) target protein. Our results showed that, the total phenolic, flavonoid and tannins contents, which were assessed by the Folin-Ciocalteu, Quercetin, and Catechin methods, respectively, were 230.22 mg gallic acid equivalent/g dry weight (mg GAE/g DW), 55.08 mg quercetin equivalent/g dry weight (QE/g DW) and 15.17 mg catechin equivalents/g dry weight (CatE/g DW), respectively. HPLC analysis revealed the presence of five polyphenolic compounds whose catechin was found to be the most abundant compounds. The antioxidant activity of extract was quantified by DPPH, FRAP and NO· tests and IC 50 reached the values of 3.346 mg/mL, 2.306 and 0.023 mg/mL, respectively. Cleome fruits ameliorated the histological integrity of the skin and alleviated the disruptions in hematological parameters (WBC, LYM, RBC, and HGB), inflammatory cytokines (IL-1β, IL-6, TNF-α), C-reactive protein, and some oxidative stress markers (TBARS (-49%) and AOPP (-42%) levels, SOD (+33%) and GPx (+75%) activities, and GSH (+49%) content) induced by formalin injection. Moreover, the in-silico investigation had shown that CA fruits extract compounds have a stronger interaction with COX-2 active site, more than the reference drug "indomethacin" (two H-bonds). Our research gives pharmacological backing to the healthcare utilization of Cleome plant in the treatment of inflammatory diseases and oxidative harm.