Molecular docking, characterization, ADME/toxicity prediction, and anti-ulcer activity of new quercetin derivatives on indomethacin-induced gastric ulcer in mice.

Gastric ulcer (GU) is a serious upper gastrointestinal tract disorder that affects people worldwide. The drugs now available for GU treatment have a high rate of relapses and drug interactions, as well as mild to severe side effects. As a result, new natural therapeutic medications for treating GU with fewer negative side effects are desperately needed. Because of quercetin's (QCT) diverse pharmacological effects and unique structural features, we decided to semi-synthesize new QCT derivatives and test them for antiulcer activity. Docking assays were performed on the synthesized compounds to determine their affinity for TLR-4/MD-2, MyD88/TIR, and NF-κB domains, an important inflammatory pathway involved in GU development and progression. Mice were given oral famotidine (40 mg/kg/day), QCT, QCT pentamethyl (QPM), or QCT pentaacetyl (QPA) (50 mg/kg/day) for 5 days before GU induction by a single intraperitoneal injection of indomethacin (INDO; 18 mg/kg). QPM and QPA have a stronger binding affinity for TLR-4/MD-2, MyD88/TIR and NF-κB domains than QCT. In comparison, they demonstrated the greatest reduction in ulcer score and index, gastric MDA and nitric oxide (NO) contents, MyD88 and NF-κB expressions, and gastric TLR-4 immunostaining. They also enhanced the levels of GSH, CAT, COX-1, and COX-2 in the gastric mucosa, as well as HO-1 and Nrf2 expression, with histological regression in gastric mucosal lesions, with QPA-treated mice demonstrating the best GU healing. QPA is safe against all of the target organs and adverse pathways studied, with good ADME properties. However, further in vitro experiments are necessary to demonstrate the inhibitory effects of QPM and QPA on the protein targets of interest. In addition, preclinical research on its bioavailability and safety is essential before clinical management can be undertaken. Overall, the new QPA derivative could one day serve as the basis for a new class of potential antiulcer drugs.

The role of vitamin D3 in modulating the interplay between NLRP3 inflammasome and autophagy in NASH.

Damage-associated molecular patterns released upon hepatocyte injury ensuing non-alcoholic steatohepatitis (NASH) can stimulate innate immunity by activating NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, thereby triggering pro-inflammatory cascades in the liver. Aberrant NLRP3 activation allied to compromised autophagic clearance of its components contributes to the progression of multiple inflammatory diseases. Such intricate interplay, however, was not fully deciphered in NASH. Prior studies have illuminated the ability of vitamin D3 to temper inflammasome activation in several contexts, prompting us to probe the impact of vitamin D3, particularly its active form, calcitriol (CAL), on NLRP3 overactivation in a high-fat diet (HFD)-based NASH model and its potential dependence on autophagy. Hydroxychloroquine (HCQ), an autophagy inhibitor, was co-administered with CAL to examine the likely modulation of the NLRP3/autophagy crosstalk. Our results showed that treatment with CAL countervailed the histopathological derangement reported in the livers of HFD-fed mice that paralleled a restoration of vitamin D receptor gene expression and reduction in sterol regulatory element binding protein 1c levels. Moreover, p62 was curtailed with CAL treatment indicating autophagy induction. CAL also prompted a reduction in NLRP3, caspase-1, gasdermin D, and IL-18 protein levels along with the apoptosis-associated speck-like protein (ASC) gene expression. Treatment with CAL also reduced IL-1ß and caspase-3 immunoreactivities compared to control. Intriguingly, CAL modulatory effects on inflammasome activation were curbed in the group that received HCQ, suggesting a potential autophagy dependency. Accordingly, the current study suggests that CAL was capable of ameliorating NASH via inhibiting NLRP3 inflammasome activation in an autophagy-dependent manner.

A multimodality therapeutic application on Toxoplasma gondii encephalitis utilizing Spiramycin and 'de novo' Ferula asafetida in immunodeficient mice.

This study investigated a 'de Novo' medicinal herb, Ferula asafetida (FA), against toxoplasma encephalitis either alone or combined with spiramycin (SP). Female Swiss-Webster mice (n = 72) were divided into three batches. Batch-I received no DMS to serve as an immunocompetent control, batch-II was immune-suppressed with the DMS (0.25 mg/g/day) for 14 days pre-infection, whilst batch-III was immune-suppressed with the DMS on the same day of infection. All experimental mice were inoculated with Toxoplasma gondii ME49 cysts (n = 75). Each batch was split into four subgroups: Mono-SP, mono-FA, combined drug (SP + FA), or neither. Therapies were administered on day zero of infection in batches (I and II) and 35 days post-infection in batch (III). Treatments lasted for 14 days, and mice were sacrificed 60 days post-infection. Histopathological changes, cysts load, and CD4 and CD8 T-cells were counted in brain tissues. The cyst-load count in mice receiving SP + FA was significantly (p < .0001) the least compared to the mono treatments in all protocols. Interestingly, the combined therapy demolished the T-cell subsets to zero in immunocompetent and immunocompromised infected mice. In conclusion, F. asafetida might be a powerfully natural, safe vehicle of SP in the digestive system and/or across the brain-blood barrier to control toxoplasmosis even through immunodeficient conditions.

Natural inhibitors for acetylcholinesterase and autophagy modulators as effective antagonists for tau and ß-amyloid in Alzheimer's rat model.

Background: Phytochemicals have amazing biological effects in relation to age-related illnesses and are increasingly being studied in clinical trials. The goal of this study was to examine the effectiveness of the aqueous extracts of Rosmarinus officinalis L. (Rosemary) and Crocus sativus L. (Saffron) and their combinations as tau and ß-amyloid antagonists in an Alzheimer's rat model. Methods: AlCl3 and D-galactose (150 & 300 mg/kg) were used to create the Alzheimer's neuroinflammation rat model. The animals were subsequently given the two extracts and their combinations (500 mg/kg) along 15 days. The cognitive impairment, oxidative stress, tau & amyloid neuroproteins, acetylcholine, acetylcholinesterase neurotransmitters, proinflammatory cytokines, LC3 as an autophagy marker, computational analysis, and morphological alterations were all assessed. Results: When compared to the conventional donepezil and normal groups, the treated groups showed a significant improvement in all calculated parameters. The cortex and hippocampus have a better morphological appearance. In silico analysis found that these extracts may have an affinity for and impede the activity of some proteins thought to be essential regulators of disease progression. Conclusion: Rosemary and Saffron extracts by the power of their constituents were able to alleviate the neurotoxicity of AlCl3 & D-galactose and regulate the natural autophagy process.

Toxicological, hepato-renal, endocrine disruption, oxidative stress and immunohistopathological responses of chitosan capped gold nanocomposite on Biomphalaria alexandrina snails.

The present investigation aimed to synthesize chitosan­gold nanocomposites (Ch-AuNPs) with gamma radiation, then to evaluate its toxic effect on the freshwater snails Biomphalaia alexandrina. Results showed that Ch-AuNPs is spherical shaped with average size 12 nm. It had a toxic effect against B. alexandrina snails with LC50 20.43 mg/l. Exposure of B. alexandrina snails to LC10 7.51 or LC25 13.63 mg/l of Ch-AuNPs, reduced the survival, reproductive and fecundity rates; total protein and albumin; both testosterone (T) and 17ß Estradiol (E) levels; SOD and CAT activities of exposed snails while increased the activities of transaminases (AST & ALT), uric acid, creatinine, TAC and MDA levels compared to the control group. Results were supported by histopathological and immunohistopathological alterations of the digestive and hermaphrodite glands. In conclusion B. alexandrina could be used as a model to screen the negative impact of nanomaterials. Also, Ch-AuNPs could be used as a molluscicidal agent.

Itraconazole, a cytochrome P450 inhibitor, enhanced the efficacy of praziquantel against Schistosoma mansoni infection and alleviated liver injury in mice.

Treatment of schistosomiasis is heavily reliant on the single antischistosomal drug praziquantel (PZQ). The use of synergistic drug-drug interactions is one possible solution, which could be used to mitigate PZQ's poor and variable bioavailability. Itraconazole (ITZ), a triazole antifungal agent, is a potent CYP3A inhibitor that can cause significant drug-drug interactions when used with CYP3A substrates. This study investigates the effect of ITZ as adjuvant therapy with PZQ on worm load, egg deposition and maturation, and the consequent histopathology and biochemical abnormalities in the liver during the immature and mature stages of Schistosoma mansoni (S. mansoni) infection. S. mansoni-infected mice were divided into five groups of eight-ten mice each: (I) infected untreated, (II) infected and treated with PZQ 3 weeks PI, (III) infected and treated with both ITZ and PZQ 3 weeks PI, (IV) infected and treated with PZQ 7 weeks PI, and (V) infected and treated with both ITZ and PZQ 7 weeks PI. All mice were killed by rapid decapitation 9 weeks PI. Data revealed that ITZ in combination with PZQ at both immature and mature stages improved the parasitological criteria of cure, and greatly reduced inflammation, granuloma and fibrotic tissue formation, and apoptosis versus PZQ alone. Furthermore, it showed the greatest impact on improving liver injury and oxidative stress markers. Notably, the effect was considerably stronger at the mature stage of S. mansoni infection. These findings support the notion that ITZ increased PZQ's antischistosomal activity by inhibiting CYP450 expression, potentially reducing PZQ metabolism and increasing systemic exposure.

Interleukin-4 Signaling Plays a Major Role in Urogenital Schistosomiasis-Associated Bladder Pathogenesis.

Interleukin-4 (IL-4) is crucial in many helminth infections, but its role in urogenital schistosomiasis, infection with Schistosoma haematobium worms, remains poorly understood due to a historical lack of animal models. The bladder pathology of urogenital schistosomiasis is caused by immune responses to eggs deposited in the bladder wall. A range of pathology occurs, including urothelial hyperplasia and cancer, but associated mechanisms and links to IL-4 are largely unknown. We modeled urogenital schistosomiasis by injecting the bladder walls of IL-4 receptor-alpha knockout (Il4ra-/- ) and wild-type mice with S. haematobium eggs. Readouts included bladder histology and ex vivo assessments of urothelial proliferation, cell cycle, and ploidy status. We also quantified the effects of exogenous IL-4 on urothelial cell proliferation in vitro, including cell cycle status and phosphorylation patterns of major downstream regulators in the IL-4 signaling pathway. There was a significant decrease in the intensity of granulomatous responses to bladder-wall-injected S. haematobium eggs in Il4ra-/- versus wild-type mice. S. haematobium egg injection triggered significant urothelial proliferation, including evidence of urothelial hyper-diploidy and cell cycle skewing in wild-type but not Il4ra-/- mice. Urothelial exposure to IL-4 in vitro led to cell cycle polarization and increased phosphorylation of AKT. Our results show that IL-4 signaling is required for key pathogenic features of urogenital schistosomiasis and that particular aspects of this signaling pathway may exert these effects directly on the urothelium. These findings point to potential mechanisms by which urogenital schistosomiasis promotes bladder carcinogenesis.

The phosphodiesterase-4 inhibitor roflumilast impacts Schistosoma mansoni ovipositing in vitro but displays only modest antischistosomal activity in vivo.

Praziquantel (PZQ) is the sole drug used to treat schistosomiasis, and the probability of developing resistance is growing the longer it is relied upon, justifying the search for alternatives. Phosphodiesterases (PDEs), particularly the PDE4 family, have attracted considerable attention as drug targets, including in Schistosoma mansoni, and especially SmPDE4A. This study investigates the potential antischistosomal activity of human PDE4 and potent SmPDE4A inhibitor roflumilast, either alone or combined with PZQ. In vitro, roflumilast resulted in a significant, concentration-dependent reduction in egg production but not of worm viability. In vitro exposure to roflumilast in combination with a low concentration of PZQ was less effective than PZQ alone, pointing to antagonism. S. mansoni-infected mice treated with roflumilast showed significant reductions in worm burden (27%) as well as hepatic and intestinal egg burdens (~28%) two weeks post treatment. Scanning EM of worms isolated from roflumilast-treated and untreated mice did not reveal noticeable changes to their tegument. S. mansoni-infected mice treated with a fixed dosage of roflumilast and a variable dosage of PZQ resulted in a higher reduction in worm burden, reduced hepatic egg counts, absence of immature eggs and a marked increase in dead eggs, compared to PZQ alone. However, the combination resulted in increased animal mortality, probably attributable to pharmacodynamic interactions between the two drugs. Although this study marks the first report of in vivo antischistosomal potential by a PDE inhibitor, an important proof of concept, we conclude that the antischistosomal effects of roflumilast are insufficient to warrant further development.

Dose-response relationship in Schistosoma mansoni juvenile and adult stages following limonin treatment in experimentally infected mice.

Preventive chemotherapy with praziquantel is the mainstay of schistosomiasis control. However, drug resistance is an imminent threat, particularly with large-scale administration of praziquantel, in addition to much less efficacy against young schistosomes. Several biological activities of limonin have been explored such as insecticidal, insect antifeedant, and growth-regulating activity on insects as well as antimalarial, antiviral, anticancer, cholesterol-lowering, and antioxidant activities. This study investigates limonin as an alternative antischistosomal compound using two novel, single, oral dose regimens. In the current work, the therapeutic efficacy of different limonin dosing protocols was evaluated in experimentally infected mice harboring Schistosoma mansoni (Egyptian strain) juvenile or adult stages. Oral administration of limonin in a single dose of 50 or 100 mg/kg on day 21 post-infection (p.i.) resulted in a significant worm burden reduction of 70.0 and 83.33 %, respectively. The same dose given on day 56 p.i. reduced total worm burdens by 41.09 and 60.27 %, respectively. In addition, significant reductions of 34.90 and 47.16 % in the hepatic and 46.67 and 56.1 % in the intestinal tissue egg loads, respectively, associated with significant alterations in the oogram pattern with elevated dead egg levels. Limonin produced ameliorations of hepatic pathology with reduction in dimensions and number of granulomas. Limonin also produced a variety of tegumental alterations in treated worms including tubercular disruption, edema, blebbing, and ulcerations. Results obtained by this work elucidated promising limonin bioactivity against S. mansoni juvenile and adult stages and provided a basis for subsequent experimental and clinical trials.

Metabolic profile and hepatoprotective activity of the anthocyanin-rich extract of Hibiscus sabdariffa calyces.

CONTEXT: Hibiscus sabdariffa L. (Malvaceae) is a common traditional tea that has many biological activities. OBJECTIVES: To evaluate the hepatoprotective effect and study the metabolic profile of the anthocyanin-rich extract of H. sabdariffa calyces (HSARE). MATERIALS AND METHODS: The hepatoprotective activity of HSARE was assessed (100 mg/kg/d for 4 weeks) by examining the hepatic, inflammatory, oxidative stress markers and performing a histopathological examination in rats with thioacetamide (TAA)-induced hepatotoxicity. HSARE was analyzed using ultra-performance liquid chromatography-quadrupole-time-of-flight-photodiode array-mass spectrometry (UPLC-qTOF-PDA-MS). RESULTS: The UPLC-qTOF-PDA-MS analysis of HSARE enabled the identification of 25 compounds represented by delphinidin and its derivatives, cyanidin, kaempferol, quercetin, myricetin aglycones and glycosides, together with hibiscus lactone, hibiscus acid and caffeoylquinic acids. Compared to the TAA-intoxicated group, HSARE significantly reduced the serum levels of alanine aminotransferase, aspartate aminotransferase and hepatic malondialdehyde by 37.96, 42.74 and 45.31%, respectively. It also decreased hepatic inflammatory markers, including tumour necrosis factor alpha, interleukin-6 and interferon gamma (INF-γ), by 85.39, 14.96 and 70.87%, respectively. Moreover, it decreased the immunopositivity of nuclear factor kappa-B and CYP2E1 in liver tissue, with an increase in the effector apoptotic marker (caspase-3 positive cells), restoration of the altered hepatic architecture and increases in the activities of superoxide dismutase (SOD) and glutathione by 150.08 and 89.23%, respectively. DISCUSSION AND CONCLUSION: HSARE revealed pronounced antioxidant and anti-inflammatory potential where SOD and INF-γ were significantly improved. HSARE possesses the added value of being more water-soluble and of natural origin with fewer side effects expected compared to silymarin.

Schistosoma haematobium egg-induced bladder urothelial abnormalities dependent on p53 are modulated by host sex.

INTRODUCTION AND OBJECTIVE: The bladder urothelium changes dramatically during Schistosoma haematobium infection (urogenital schistosomiasis). These alterations include hyperplasia, ulceration, dysplasia, squamous metaplasia and frank carcinogenesis. Defining the pathways underpinning these urothelial responses will contribute to a deeper understanding of how S. haematobium egg expulsion, hematuria, and bladder cancer develop in humans. The tumor suppressor gene p53 is of particular interest, given its role in many cancers, including bladder cancer generally and schistosomal bladder cancer specifically. METHODS: Transgenic mice featuring tamoxifen-inducible Cre recombinase activity in cells expressing the urothelial-specific gene uroplakin-3a (Upk3a-GCE mice) were crossed with either TdTomato-floxed-EGFP reporter or p53-floxed mice. Mice were administered tamoxifen or vehicle control to induce excision of floxed genes. TdTomato-EGFP reporter mice were sacrificed and their bladders harvested, sectioned, and imaged by fluorescence microscopy. p53-floxed mice underwent bladder wall injection with S. haematobium eggs or vehicle controls. Three months later, mice were sacrificed and their bladders subjected to histological analysis (H&E staining). RESULTS: We first confirmed the phenotypic fidelity of Upk3a-GCE mice by crossing them with TdTomato-floxed-EGFP reporter mice and administering tamoxifen to their progeny. As expected, these progeny switched from TdTomato to EGFP expression in their bladder urothelium. Having confirmed the phenotype of Upk3a-GCE mice, we next crossed them to p53-floxed mice. The resulting progeny were given tamoxifen or vehicle control to render them urothelial p53-haploinsufficient or -intact, respectively. Then, we injected S. haematobium eggs or control vehicle into the bladder walls of these mice. Male p53-intact, egg-injected mice exhibited similar histological changes as their p53-haploinsufficient counterparts, including urothelial hyperplasia and ulceration. In contrast, female p53-intact, egg-injected mice featured no urothelial ulceration, whereas their p53-haploinsufficient counterparts often had significant ulceration. CONCLUSIONS: Urothelial p53 signaling indeed seems to affect urothelial homeostasis during S. haematobium infection, albeit in a sex-specific manner. Ongoing work seeks to determine whether p53 mediates associated alterations in urothelial cell cycle status and frank carcinogenesis in the setting of urogenital schistosomiasis.

Ameliorative effect of bone marrow-derived stem cells on injured liver of mice infected with Schistosoma mansoni.

The technique of stem cells or hepatocytes transplantation has recently improved in order to bridge the time before whole-organ liver transplantation. In the present study, unfractionated bone marrow stem cells (BMSCs) were harvested from the tibial and femoral marrow compartments of male mice, which were cultured in Dulbecco's modified Eagle's medium (DMEM) with and without hepatocyte growth factor (HGF), and then transplanted into Schistosoma mansoni-infected female mice on their 8th week post-infection. Mice were sacrificed monthly until the third month of bone marrow transplantation, serum was collected, and albumin concentration, ALT, AST, and alkaline phosphatase (ALP) activities were assayed. On the other hand, immunohistopathological and immunohistochemical changes of granuloma size and number, collagen content, and cells expressing OV-6 were detected for identification of liver fibrosis. BMSCs were shown to differentiate into hepatocyte-like cells. Serum ALT, AST, and ALP were markedly reduced in the group of mice treated with BMSCs than in the untreated control group. Also, granuloma showed a marked decrease in size and number as compared to the BMSCs untreated group. Collagen content showed marked decrease after the third month of treatment with BMSCs. On the other hand, the expression of OV-6 increased detecting the presence of newly formed hepatocytes after BMSCs treatment. BMSCs with or without HGF infusion significantly enhanced hepatic regeneration in S. mansoni-induced fibrotic liver model and have pathologic and immunohistopathologic therapeutic effects. Also, this new therapeutic trend could generate new hepatocytes to improve the overall liver functions.

Hepatoprotective and antioxidant activity of Melaleuca styphelioides on carbon tetrachloride-induced hepatotoxicity in mice.

CONTEXT: Liver disease is a serious problem. Polyphenolic compounds have marked antioxidant effect and can prevent the liver damage caused by free radicals. In vitro studies have revealed the strong antioxidant activity of an ellagitannin-rich plant, namely, Melaleuca styphelioides Sm. (Myrtaceae). OBJECTIVE: In view of the limited therapeutic options available for the treatment of liver diseases, the hepatoprotective potential of the methanol extract of M. styphelioides leaves (MSE) was investigated against CCl4-induced liver injury in mice. MATERIALS AND METHODS: MSE was administered (500 and 1000 mg/kg/d p.o.) along with CCl4 for 6 weeks. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were determined in the serum. Glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione transferase (GST), and malondialdehyde (MDA) were estimated in the liver homogenate. The bioactive components of MSE were identified by NMR, UV and HRESI-MS/MS data. RESULTS: MSE treatment (500 and 1000 mg/kg/d) markedly inhibited the CCl4-induced increase in the levels of AST (31 and 38%), ALT (29 and 32%), ALP (13 and 19%), and MDA (22 and 37%) at the tested doses, respectively. MSE treatment markedly increased the levels of GSH (29 and 57%) and antioxidant enzymes compared with the CCl4-treated group. MSE was more effective than silymarin in restoring the liver architecture and reducing the fatty changes, central vein congestion, Kupffer cell hyperplasia, inflammatory infiltration, and necrosis induced by CCl4. The LD50 of MSE was more than 5000 mg/kg. CONCLUSION: MSE confers potent antioxidant and hepatoprotective effects against CCl4-induced toxicity.

Mitigation of intrahepatic cholestasis induced by 17α-ethinylestradiol via nanoformulation of Silybum marianum L.

BACKGROUND: Cholestasis is an important predisposing factor for hepatocyte damage, liver fibrosis, primary biliary cirrhosis, and even liver failure. Silybum marianum L. (SM) plant is used in teas or eaten in some countries due to its antioxidant and hepatoprotective properties. Because of its low and poor oral bioavailability, so we improve the therapeutic activity of Silybum marianum L. extract (SM) by studying the potential effects of nanoformulation of Silybum marianium L. extract (nano-SM) on 17α-ethinylestradiol (EE)-induced intrahepatic cholestasis. METHODS: Thirty female Sprague-Dawley rats were divided into 5 groups (6 rats/group). Group I: Rats were received the treatment vehicle and served as normal group. Group II:Rats were injected daily with EE (10 mg/kg) for five successive days. Group III-V: Rats were injected daily with EE (10 mg/kg) and treated with either Ursodeoxycholic acid (UDCA) (40 mg/kg), SM (100 mg/kg) and nano-SM (100 mg/kg) orally once/day throughout the trialfor five successive days, respectively. RESULTS: Nano-SM greatly dampened the increase in serum levels of total and direct bilirubin, alanine aminotransaminase, aspartate aminotransaminase, and alkaline phosphatase caused by EE. Furthermore, nano-SM increased the hepatic contents of reduced glutathione (GSH) and catalase (CAT) and also upregulated the relative hepatic gene expressions of Rho-kinase (ROCK-1), myosin light chain kinase (MLCK), and myosin phosphatase target subunit (MYPT1) compared to the EE-induced group. Administration of nano-SM reduced hepatic lipid peroxidation and downregulated the relative hepatic expressions of the nuclear factor-kappa B (NF-Ò¡B) and interleukin-1ß (IL-1ß). In addition, nano-SM improved the histopathological changes induced by EE. CONCLUSION: Nano-SM possessed a superior effect over SM, which can be considered an effective protective modality against EE-induced cholestatic liver injury through its antioxidant, anti-inflammatory activities, and enhancing bile acid (BA) efflux.

Impact of Schistosoma sp., Infection on Biological, Feeding, Physiological, Histological, and Genotoxicological Aspects of Biomphalaria alexandrina and Bulinus truncatus Snails.

BACKGROUND: Trematode infections of the genus Schistosoma can induce physiological and behavioral changes in intermediate snail hosts. This is because the parasite consumes essential resources necessary for the host's survival, prompting hosts to adapt their behavior to maintain some level of fitness before parasite-induced mortality occurs. METHODS: In this study, the reproductive and biochemical parameters of Biomphalaria alexandrina and Bulinus truncatus were examined during the cercareal shedding stage of infection with Schistosoma mansoni and Schistosoma haematobium, respectively, compared with controls. RESULTS: The study revealed an infection rate of 34.7% for S. mansoni and 30.4% for S. haematobium. In B. alexandrina infected with S. mansoni, a survival rate of 65.2% was recorded, along with a mean prepatent period of 30.3 ± 1.41 days, a mean shedding duration of 14.2 ± 0.16 days, and a mean lifespan of 44.1 ± 0.24 days. Meanwhile, in B. truncatus infected with S. haematobium, a survival rate of 56.4% was observed, with a mean prepatent period of 44.3 ± 1.41 days, a mean shedding duration of 22.6 ± 2.7 days, and a mean lifespan of 66.9 ± 1.6 days. Feeding increased in both infected species of snails, while the net reproductive rate (Ro) of the infected snails decreased. Total antioxidant (TAO) and lipid peroxidation activity increased in the two infected snail species during shedding, while Glutathione-S-transferase levels decreased. Lipid peroxidase activity and nitrogen oxide levels significantly decreased in infected B. alexandrina and increased in infected Bulinus. Steroid hormone levels were elevated in infected Biomphalaria, whereas they were reduced in infected Bulinus. Comet assay parameters showed an increase in the two infected genera after infection compared to control snails, indicating genotoxic damage and histopathological damage was observed. CONCLUSIONS: These findings demonstrate that infection with larva species diverse biochemical, hormonal, genotoxic, and histopathological changes in the tissues responsible for fecundity and reproduction in B. alexandrina and B. truncates comparing with controls.

Novel pyridine bearing pentose moiety-based anticancer agents: design, synthesis, radioiodination and bioassessments.

Pyridine compounds are one of the most important heterocyclic derivatives showing wide ranges in biological and pharmacological activities. Green chemistry eliminates or reduces the generation of hazardous compounds. It prevents pollution at a molecular level. The microwave technique used in heterocyclic compound synthesis is also an important branch of green chemistry techniques. In this study, we report designing and synthesizing a new pyridine-bearing pentose moiety via a one-pot multicomponent reaction using D-glucose and also investigate its behavior and reactivity toward some simple and heterocyclic amino derivatives. The chemical structures of the synthesized compounds were characterized and tested for their cytotoxic activities. Some of the test compounds exhibited slight to high cytotoxic activities against Caco2 (colon cancer) cells, HepG2 (hepatocellular carcinoma) cells and MCF-7 (human breast cancer) cells by MTT assay. The results showed clearly that compound 4 and compound 8 displayed strongest to moderate cytotoxic activity against the HepG2, Caco2 and MCF-7 respectively and compound 1 showed good activity against MCF-7 in comparison to the standard anticancer drug doxorubicin. These data were by cytopathological examination. An in-vivo radioactive tracing study of compound 4 proved its targeting ability to sarcoma cells in a tumor-bearing mice model. Our findings suggest that the synthesized compounds may be promising candidates as novel anticancer agents.

Diosmin alleviates ulcerative colitis in mice by increasing Akkermansia muciniphila abundance, improving intestinal barrier function, and modulating the NF-κB and Nrf2 pathways.

Ulcerative colitis is a common type of inflammatory bowel disease that affects millions of individuals around the world. Traditional UC treatment has focused on suppressing immune responses rather than treating the underlying causes of UC, which include oxidative stress, inflammation, and microbiota dysbiosis. Diosmin (DIO), a naturally occurring flavonoid, possesses antioxidant and anti-inflammatory properties. This study aimed to assess the efficacy of DIO in treating dextran-sulfate sodium (DSS)-induced colitis, and to investigate some of its underlying mechanisms, with an emphasis on Akkermansia muciniphila abundance, inflammatory markers, and intestinal barrier function. C57BL/6 mice were given 4% (w/v) DSS to induce colitis. DSS-induced mice were administered DIO (100 and 200 mg/kg) or sulfasalazine orally for 7 days. Every day, the disease activity index (DAI) was determined by recording body weight, diarrhea, and bloody stool. Changes in fecal A. muciniphila abundance, colonic MUC1 and MUC2 expression, as well as oxidative stress and inflammatory markers were all assessed. Histopathological changes, colonic PIK3PR3 and ZO-1 levels, and immunohistochemical examinations of occludin and claudin-1, were investigated. DIO administration resulted in a dose-dependent decrease in DAI, as well as increase in A. muciniphila abundance and MUC2 expression while decreasing MUC1 expression. DIO also dramatically reduced colonic oxidative stress and inflammation by regulating the NF-κB and Nrf2 cascades, restored intestinal barrier integrity by inhibiting PIK3R3 and inducing ZO-1, and improved occludin/claudin-1 gene expression and immunostaining. This study provides the first evidence that DIO preserves intestinal barrier integrity and increases A. muciniphila abundance in DSS-induced colitis. However, more research is required to explore the impact of DIO on the overall composition and diversity of the gut microbiota. Likewise, it will be important to fully understand the molecular mechanisms by which A. muciniphila maintains intestinal barrier function and its potential use as an adjuvant in the treatment of UC.

The Molluscicidal Activity of Green Synthesized Copper Oxide-Based Annona squamosa Seed Extract Nanoparticles on the Feeding Behavior, Biochemical, Molecular, and Immunohistochemical Alterations of Biomphalaria alexandrina Snails.

Because of their low ecological impact, plant molluscicides have garnered much attention. The work aimed to find out if Annona squamosa (AS) seed extract has a molluscicidal impact on Biomphalaria alexandrina snails and enhances this extract by adding CuO nanoparticles (NPs). Using a scanning electron microscope (SEM), transmission electron microscope (TEM), and PANalytical X'Pert PRO X-ray diffractometer (XRD), the presence of the green A. squamosa-based CuO NPs (AS-CuO NPs) was confirmed. After 24 h of exposure, the half-lethal concentration (LC50) of AS-CuO NPs was more toxic to mature B. alexandrina than the aqueous extract of AS seeds (LC50: 119.25 mg/L vs. 169.03 mg/L). The results show that snails exposed to sublethal doses of AS-CuO NPs at LC10 or LC25 (95.4 or 106.7 mg/L, respectively) had much higher glucose levels and alkaline phosphatase activity than those not exposed. Nevertheless, there was no discernible change in the protein content in general or glycogen phosphorylase production. Histological and immunohistochemical analysis showed that snails exposed to A. squamosa-derived CuO NPs LC10 had shrinking digestive tubules and degeneration as well as vacuolation of many digestive, secretory, ova, and sperm cells, with PCNA expressing positively in the hermaphrodite gland and digestive tubule cells. The toxic profile of green CuO NPs produced by A. squamosa may damage the biological activity of B. alexandrina snails; thus, this compound could be used as a molluscicidal base. Furthermore, B. alexandrina proved to be a useful biomarker of nanomaterial contamination.

Harnessing adrenergic blockade in stress-promoted TNBC in vitro and solid tumor in vivo: disrupting HIF-1α and GSK-3ß/ß-catenin driven resistance to doxorubicin.

Sympathetic activation triggered by chronic stress afflicting cancer survivors is an emerging modulator of tumorigenesis. Adrenergic blockade was previously associated with improving response to doxorubicin (DOX) in triple-negative breast cancer (TNBC), yet the precise underlying mechanisms remain obscure. The resilience of cancer stem cells (CSCs) during chemotherapy fosters resistance and relapse. Hypoxia-inducible factor-1α (HIF-1α) and ß-catenin are intertwined transcriptional factors that enrich CSCs and evidence suggests that their expression could be modulated by systemic adrenergic signals. Herein, we aimed to explore the impact of adrenoreceptor blockade using carvedilol (CAR) on DOX and its potential to modulate CSCs overcoming chemoresistance. To achieve this aim, in vitro studies were conducted using adrenaline-preincubated MDA-MB-231 cells and in vivo studies using a chronic restraint stress-promoted solid tumor mouse model. Results revealed that adrenaline increased TNBC proliferation and induced a phenotypic switch reminiscent of CSCs, as evidenced by enhanced mammosphere formation. These results paralleled an increase in aldehyde dehydrogenase-1 (ALDH-1) and Nanog expression levels as well as HIF-1α and ß-catenin upsurge. In vivo, larger tumor volumes were observed in mice under chronic stress compared to their unstressed counterparts. Adrenergic blockade using CAR, however, enhanced the impact DOX had on halting TNBC cell proliferation and tumor growth via enhanced apoptosis. CAR also curbed HIF-1α and ß-catenin tumor levels subsequently suppressing ALDH-1 and SOX2. Our study unveils a central role for HIF-1α linking stress-induced sympathetic activation fueling CSC enrichment via the ß-catenin pathway. It also highlights novel insights into CAR's capacity in reversing DOX chemoresistance in TNBC.

Effect of ketoconazole, a cytochrome P450 inhibitor, on the efficacy of quinine and halofantrine against Schistosoma mansoni in mice.

The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. The antimalarials quinine (QN) and halofantrine (HF) possess moderate antischistosomal properties. The major metabolic pathway of QN and HF is through cytochrome P450 (CYP) 3A4. Accordingly, this study investigates the effects of CYP3A4 inhibitor, ketoconazole (KTZ), on the antischistosomal potential of these quinolines against Schistosoma mansoni infection by evaluating parasitological, histopathological, and biochemical parameters. Mice were classified into 7 groups: uninfected untreated (I), infected untreated (II), infected treated orally with PZQ (1,000 mg/kg) (III), QN (400 mg/kg) (IV), KTZ (10 mg/kg)+QN as group IV (V), HF (400 mg/kg) (VI), and KTZ (as group V)+HF (as group VI) (VII). KTZ plus QN or HF produced more inhibition (P<0.05) in hepatic CYP450 (85.7% and 83.8%) and CYT b5 (75.5% and 73.5%) activities, respectively, than in groups treated with QN or HF alone. This was accompanied with more reduction in female (89.0% and 79.3%), total worms (81.4% and 70.3%), and eggs burden (hepatic; 83.8%, 66.0% and intestinal; 68%, 64.5%), respectively, and encountering the granulomatous reaction to parasite eggs trapped in the liver. QN and HF significantly (P<0.05) elevated malondialdehyde levels when used alone or with KTZ. Meanwhile, KTZ plus QN or HF restored serum levels of ALT, albumin, and reduced hepatic glutathione (KTZ+HF) to their control values. KTZ enhanced the therapeutic antischistosomal potential of QN and HF over each drug alone. Moreover, the effect of KTZ+QN was more evident than KTZ+HF.