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.

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.

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.

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.

Myco-Synthesized Selenium Nanoparticles as Wound Healing and Antibacterial Agent: An In Vitro and In Vivo Investigation.

Bacterial-associated wound infections are an obstacle for individuals and the medical industry. Developing versatile, antibiotic-free therapies helps heal wounds more quickly and efficiently. In the current study, fungal metabolites were employed as a reducing agent in fabricating selenium nanoparticles (SeNPs) for improved antibacterial and wound healing properties. Utilizing UV-visible spectroscopy, dynamic light scattering (DLS), zeta potential, X-ray diffraction (XRD), and electron microscopic examination, the properties of the synthesized nanoparticles were extensively evaluated. Myco-synthesized SeNPs demonstrated strong antibacterial activity against Staphylococcus aureus ATCC 6538 with a minimum inhibitory concentration of 0.3125 mg/mL, reducing cell number and shape distortion in scanning electron microscope (SEM) images. SeNPs' topical administration significantly reduced wound area and healing time, exhibiting the least bacterial load after six days compared to controls. After six and 11 days of treatment, SeNPs could decrease proinflammatory cytokines IL-6 and TNF-α production. The histopathological investigation showed a healed ulcer with moderate infiltration of inflammatory cells after exposing mice's skin to SeNPs for six and 11 days. The docking interaction indicated that SeNPs were highly efficient against the IL-6 and TNF-α binding receptors. These findings imply that myco-fabricated SeNPs might be used as topically applied antimicrobial agents for treating skin infections and wounds.

Cornu aspersum mucin attenuates indomethacins-induced gastric ulcers in mice via alleviating oxidative stress and inflammation.

In the past three decades, a significant progress has been made in the prevention and treatment of gastric ulcers. The incidence of the disease has decreased, but gastric ulcer is still a medical problem. Currently, the available drugs for gastric ulcer treatment have many side effects; therefore, searching for new and safe therapeutic agents is mandatory. The present study aims to investigate the gastroprotective potential of Cornu aspersum (C. aspersum) mucin against gastric ulcers, and the mechanisms related to oxidative stress and inflammation. C. aspersum mucin was collected from 50 snails. The characteristics of C. aspersum mucin (chemical and microbiological) were evaluated. Mice were pretreated with famotidine and C. aspersum mucin (7.5 and 15 ml/kg b.w.) for 5 days, and then gastric ulcers were induced by indomethacin. Macroscopic examination, biochemical estimations, and Quantitative real-time PCR were carried out. Also, histopathological and immunohistopathological examinations were evaluated. We found that the high dose of the mucin significantly decreased the gastric mucosal malondialdehyde (MDA) and nitric oxide (NO) contents as well as interleukin 1ß (IL-1ß) and nuclear factor kappa ß (NF-Ò¡B) expression, and inducible nitric oxide synthase (iNOS) immunostaining. It also increased the gastric mucosal GSH and catalase contents as well as hemoxygenase-1 (HO-1) and nuclear factor-erythroid 2-related factor 2 (Nrf2) expressions with regressions in gastric mucosal lesions. In conclusion, C. aspersum mucin could be a potential therapeutic candidate to protect against gastric ulceration.

Histopathological, Immunohistochemical, Biochemical, and In Silico Molecular Docking Study of Fungal-Mediated Selenium Oxide Nanoparticles on Biomphalaria alexandrina (Ehrenberg, 1831) Snails.

Daphnia magna and freshwater snails are used as delicate bioindicators of contaminated aquatic habitats. Due to their distinctive characteristics, selenium oxide nanoparticles (SeONPs) have received interest regarding their possible implications on aquatic environments. The current study attempted to investigate the probable mechanisms of fungal-mediated selenium nanoparticles' ecotoxicological effects on freshwater Biomphalaria alexandrina snails and Daphnia magna. SeONPs revealed a toxicological impact on D. magna, with a half-lethal concentration (LC50) of 1.62 mg/L after 24 h and 1.08 mg/L after 48 h. Survival, fecundity, and reproductive rate were decreased in B. alexandrina snails exposed to SeONPs. Furthermore, the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were markedly elevated, while albumin and total protein levels decreased. Histopathological damage in the hermaphrodite and digestive glands was detected by light, electron microscopy, and immunohistochemistry studies. The molecular docking study revealed interactions of selenium oxide with the ALT and AST. In conclusion, B. alexandrina snails and D. magna could be employed as bioindicators of selenium nanomaterial pollution in aquatic ecosystems. This study emphasizes the possible ecological effects of releasing SeONPs into aquatic habitats, which could serve as motivation for regulatory organizations to monitor and control the use and disposal of SeONPs in industry.

Elafibranor modulates ileal macrophage polarization to restore intestinal integrity in NASH: Potential crosstalk between ileal IL-10/STAT3 and hepatic TLR4/NF-κB axes.

Experimental and clinical evidence implicate disrupted gut barrier integrity in provoking innate immune responses, specifically macrophages, towards the progression of non-alcoholic steatohepatitis (NASH). Peroxisome proliferator-activated receptors (PPARs), a subset of the nuclear receptor superfamily, act to fine-tune several metabolic and inflammatory processes implicated in NASH. As such, the current study was carried out to decipher the potential role of dual PPAR α/δ activation using elafibranor (ELA) on ileal macrophage polarization (MP) and its likely impact on the liver in a NASH setting. To achieve this aim, an in vitro NASH model using fat-laden HepG2 cells was first used to validate the impact of ELA on hepatic fat accumulation. Afterwards, ELA was used in a combined model of dietary NASH and chronic colitis analogous to the clinical presentation of NASH parallel with intestinal barrier dysfunction. ELA mitigated fat accumulation in vitro as evidenced by Oil Red-O staining and curbed triglyceride levels. Additionally, ELA restored the expression of tight junctional proteins, claudin-1 and occludin, along with decreasing intestinal permeability and inflammation skewing ileal macrophages towards the M2 phenotype, as indicated by boosted arginase-1 (Arg1) and curtailed inducible nitric oxide synthase (iNOS) expression levels. These changes were aligned with a modulation in hepatic toll-like receptor-4 (TLR4)/nuclear factor kappa B (NF-κB) along with ileal interleukin-10 (IL-10)/signal transducer and activator of transcription-3 (STAT3) axes. Overall, the present findings suggest that the dual PPAR α/δ agonist, ELA, may drive MP in the ileum towards the M2 phenotype improving intestinal integrity towards alleviating NASH.

The antioxidant and anti-inflammatory effects of Eremina desertorum snail mucin on experimentally induced intestinal inflammation and testicular damage.

Eremina desertorum snail mucin antioxidant and anti-inflammatory effects were investigated against carbon tetrachloride (CCl4)-intestinal inflammation and testes damage. Male albino mice were intraperitoneally injected with 0.5 ml/kg b.wt of 40% CCl4, twice a week for 8 weeks. The treated groups were treated orally with mucin (after 8 weeks of CCl4 intoxication, twice a week for 4 weeks). CCl4 caused significant increases in C-reactive protein, lipid peroxidation, interleukin-2 levels and caspase-3, while decreasing the total proteins levels, activities of catalase, superoxide dismutase, and glutathione reductase contents, testosterone and 17ß estradiol levels compared with the control mice. The improvements of these parameters occurred after treatment with E. desertorum mucin, where all the biochemical measurements tended to restore to the normal values. Histopathologically, CCl4 caused ulceration in the columnar mucin secreting cells that lined the ileal mucosa, partial loss of goblet cells, abnormal villous/crypt ratio, and submucosal infiltrate of the inflammatory cells. Also, sections of testis showed alterations in the developmental spermatogenic arrangement of the same seminiferous tubules, with no spermatozoa in the center. Improvements in these architectures occurred after administration of mucin, where sections showed almost normal histological structure. In conclusion, E. desertorum mucin could be used as a supplementary material as it has antioxidant and anti-inflammatory effects; besides it has low cost.

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.

Vildagliptin alleviates liver fibrosis in NASH diabetic rats via modulation of insulin resistance, oxidative stress, and inflammatory cascades.

AIMS: This study investigates the therapeutic potential of Vilda in a NASH model with liver fibrosis and elucidates the underlying molecular mechanisms. MAIN METHODS: To induce NASH, male Sprague-Dawley rats were fed a high-fat diet for 24 weeks with a single dose of STZ (40 mg/kg, IP). Vilda was orally administered at two doses (10 and 20 mg/kg) for 20 weeks. KEY FINDINGS: The induction of NASH was validated by abnormalities in hepatotoxicity indices, lipid profile, oxidative stress markers, and pathologically by marked fat deposition in hepatic tissues together with severe inflammatory cell infiltration. Moreover, NASH-affected rats demonstrated reduced insulin sensitivity manifested as elevated fasting blood glucose levels and disrupted homeostasis model assessment for insulin resistance. Vilda, at both doses, effectively abrogated all these pathological features of NASH. Mechanistically, these hepatoprotective properties of Vilda can be attributed to its antioxidant effects, anti-inflammatory effects (by inhibiting the TNF-α, NF-κB, JNK, and JAK/STAT pathways), and insulin-sensitizing effect (by upregulating the IRS-1/PI3K/Akt pathway). Besides, Vilda successfully counteracted NASH-associated liver fibrosis by downregulating the TGF-ß1 pathway. SIGNIFICANCE: The hepatoprotective and antifibrotic effects of Vilda were mostly dose-dependent. Collectively, this study offered a promising therapeutic avenue for Vilda as a novel strategy for counteracting the pathological progression of NASH and associated liver fibrosis.

Obeticholic acid orchestrates the crosstalk between ileal autophagy and tight junctions in non-alcoholic steatohepatitis: Role of TLR4/TGF-ß1 axis.

An interplay exists between non-alcoholic steatohepatitis (NASH) and intestinal barrier dysfunction. A plethora of mechanisms are implicated in the regulation of intestinal integrity, among which is autophagy. Farnesoid X receptor (FXR) is a key metabolic regulator in the liver, however, its impact on ileal autophagy and barrier integrity in the context of NASH has not yet been unraveled. Accordingly, the present study aimed at investigating the impact of the FXR agonist, obeticholic acid (OCA), on modulating the aberrant ileal autophagy and barrier dysfunction in NASH, exploring the possible implication of the TLR4/TGF-ß1 axis. High-fat diet (HFD) and dextran sulfate sodium (DSS, MW ∼40 kDa) were used for 13 weeks to induce NASH with distorted intestinal integrity in Swiss albino male mice. Post-treatment with OCA (5 mg/kg/day; p.o; 4 weeks), histopathological evaluation revealed a restoration of normal hepatic and ileal architectures. OCA partially restored intestinal permeability, as evidenced by the FITC-dextran leakage assay, with no change in serum LPS or LBP levels. Meanwhile, ileal expression of the tight junctions; claudin-1, zonulin-1, and occludin, was upregulated. Hepatic and ileal TLR-4 and TGF-ß1 immunoreactivities were also decreased with no change observed in ileal phosphorylated Akt. In addition, ATG5 gene expression and LC3II/I protein ratio were upregulated in the ileum. Overall, the present study suggests a protective role of OCA on intestinal integrity in NASH, possibly through autophagy induction via interfering with the TLR4/TGF-ß1 pathway.

Immunotoxical, neurotoxical, histopathological and immunohistopathological alterations of Nerium oleander and Tecoma stans methanolic extract on Biomphalaria alexandrina snails.

Schistosomiasis is a severe illness that caused socioeconomic problems. The present study aimed to investigate the molluscicidal activities of the methanolic extract of Nerium oleander and Tecoma stans on B. alexandrina snails. The present results showed that N. oleander had the higher molluscicidal effect (LC50: 138.6 mg/l) than T. stans methanolic extract (LC50: 256.0 mg/l). These concentrations had no mortality effects on Daphnia magna during the first 12 h of the exposure, while, they had a cercaricidal activity. Exposure of B. alexandrina snails to the sub lethal concentrations (LC10 and LC25) of the methanolic extract of either N. oleander or T. stans caused a concentration- dependent significant decrease in their mean total number of hemocyte and hyalinocytes percent, while, both the round small and the granulocytes were increased than the control group. Exposure of B. alexandrina snails to LC25 of the methanolic extract of N. oleander or T. stans, caused morphological alterations in the hemocytes that were studied by both light and electron microscopy. The sub lethal concentration (LC25) significantly decreased the acetyl cholinesterase activities, acid and alkaline phosphatase levels and the protein content. Histopathological changes occurred in the digestive and the hermaphrodite glands of exposed B. alexandrina snails to LC25 of the methanolic extracts. These alterations were confirmed by Immunohistochemistry for PCNA and Cyclin D1 expressions. Conclusively, these plants could be used to decrease the spread of schistosomiasis as they are cheap and environmentally safe to replace the synthetic molluscicides for snail control.

Investigating the Impact of Optimized Trans-Cinnamic Acid-Loaded PLGA Nanoparticles on Epithelial to Mesenchymal Transition in Breast Cancer.

PURPOSE: To design and optimize trans-cinnamic acid-loaded PLGA nanoparticles (CIN-PLGA-NPs) and assess its inhibitory effect on epithelial-mesenchymal transition (EMT) in triple-negative breast cancer. METHODS: The quality by design approach was used to correlate the formulation parameters (PLGA amount and Poloxamer188 concentration) and critical quality attributes (entrapment efficiency percent, particle size and zeta potential). Design of CIN-PLGA-NPs formulations was done based on central composite response surface design and formulated by nanoprecipitation method. In addition, the optimized CIN-PLGA-NPs formulation was further evaluated for morphology using transmission electron microscopy and in vitro dissolution test. The cytotoxicity of CIN-PLGA-NPs optimized formula in comparison to the free trans-cinnamic acid (CIN-Free) was investigated in vitro using MDA-MB-231, triple-negative breast cancer cells, followed by scratch wound assay for evaluating the impact on the migratory potential of MDA-MB-231 cells. In vivo antitumor activity was evaluated using Ehrlich ascites carcinoma solid tumor animal model where tumor volumes were measured at different time points and necrotic/apoptotic indices were estimated in tumor sections. EMT markers, E- and N-cadherin, were assessed in solid tumors as well. RESULTS: The optimized formulation showed entrapment efficiency of 76.98%, particle size of 186.3 nm with a smooth spherical surface and zeta potential of -28.47 mV indicating its stability. Furthermore, CIN-PLGA-NPs optimized formula released 60.8±1.89% of the total CIN-Free within 24 hours compared to 29±1.25% of the raw CIN-Free indicating improved dissolution rate. The optimized formula showed superior cytotoxicity on MDA-MB-231 cells compared to its free counterpart as well as increased wound closure percentage along with reduced tumor size in mice and increased necrotic and apoptotic indices. Tumor levels of E-cadherin and N-cadherin were indicative of EMT inhibition. CONCLUSION: Our findings proved the capability of PLGA nanoparticles in loading trans-cinnamic acid in addition to enhancing its antitumor efficacy in triple-negative breast cancer possibly via inhibiting EMT.

Histopathological evaluation of insulin-DMSO formula designed for direct nose-to-brain delivery.

The combination of insulin and DMSO is a patented (Publication No US8987199B2), noninvasive, pharmaceutically strategized preparation for direct nose-to-brain delivery (DN2BD) suggested for the treatment of Alzheimer's disease (AD). Although its main ingredients have been individually researched, no histopathological investigations have been conducted to address this combination effect on the CNS and nasal tissues in animals. The present work was, therefore, designed to investigate the potential histopathological changes induced by this new pharmaceutical combination using a newly developed refractory staining method. The findings presented herein showed no signs of treatment-related lesions or behavioral changes in Sprague Dawley rats following a three-month successive treatment with two strengths of the formula.

Activation of FXR modulates SOCS3/Jak2/STAT3 signaling axis in a NASH-dependent hepatocellular carcinoma animal model.

Despite the recent substantial progress in the treatment of hepatocellular carcinoma (HCC) from viral etiology, non-alcoholic steatohepatitis (NASH) is on a trajectory to become the fastest growing indication for HCC-related liver transplantation. The Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily with multifaceted roles in several metabolic disorders, particularly NASH. Its role as a tumor suppressor was also highlighted. Herein, we investigated the effect of obeticholic acid (OCA), as an FXR agonist, on NASH-associated HCC (NASH-HCC) animal model induced by diethylnitrosamine and high fat choline-deficient diet, exploring the potential impact on the suppressor of cytokine signaling 3 (SOCS3)/Janus kinase 2 (Jak2)/signal transducer and activator of transcription 3 (STAT3) pathway. Results indicated that OCA treatment upregulated FXR and its key mediator, small heterodimer partner (SHP), with remarkable amelioration in the dysplastic foci observed in the NASH-HCC group. This was paralleled with noticeable downregulation of alpha fetoprotein along with reduction in interferon gamma and transforming growth factor beta-1 hepatic levels besides caspase-3 and p53 upregulation. Moreover, sirtuin-1 (SIRT-1), a key regulator of FXR that controls the regenerative response of the liver, was elevated following OCA treatment. Modulation in the SOCS3/Jak2/STAT3 signaling axis was also reported. In conclusion, OCA attenuated the development and progression of NASH-dependent HCC possibly by interfering with SOCS3/Jak2/STAT3 pathway suggesting the potential use of FXR activators in NASH-related disorders, even at later stages of the disease, to impede its progression to the more deteriorating condition of HCC.

Gut microbiota modulation as a promising therapy with metformin in rats with non-alcoholic steatohepatitis: Role of LPS/TLR4 and autophagy pathways.

Gut microbiota is a crucial factor in pathogenesis of non-alcoholic steatohepatitis (NASH). Therefore, targeting the gut-liver axis might be a novel therapeutic approach to treat NASH. This study aimed to investigate the therapeutic effects of a probiotic (Lactobacillus reuteri) and metronidazole (MTZ) (an antibiotic against Bacteroidetes) either alone or in combination with metformin (MTF) in experimentally-induced NASH. NASH was induced by feeding rats high fat diet (HFD) for 12 weeks. MTF (150 mg/kg/day) or L. reuteri (2x109 colony forming unit/day) were given orally for 8 weeks; meanwhile, MTZ (15 mg/kg/day, p.o.) was administered for 1 week. Treatment with L. reuteri and MTZ in combination with MTF showed additional benefit compared to MTF alone concerning lipid profile, liver function, oxidative stress, inflammatory and autophagic markers. Furthermore, combined regimen succeeded to modulate acetate: propionate: butyrate ratios as well as Firmicutes and Bacteroidetes fecal contents with improvement of insulin resistance (IR). Yet, the administration of MTF alone failed to normalize Bacteriodetes and acetate contents which could be the reason for its moderate effect. In conclusion, gut microbiota modulation may be an attractive therapeutic avenue against NASH. More attention should be paid to deciphering the crosstalk mechanisms linking gut microbiota to non-alcoholic fatty liver disease (NAFLD) to identify new therapeutic targets for this disease.

Crosstalk between aldehyde dehydrogenase-1 and chemoresistance in breast cancer: Insights into the role of vitamin D3.

AIMS: Aldehyde dehydrogenase-1 (ALDH-1) is considered a signature of breast cancer stem cells and is linked to poor outcomes in breast cancer patients. This study aimed at investigating the effect of vitamin D3 on enhancing the tumor responsiveness to different conventional chemotherapeutic agents, viz., cisplatin, methotrexate, and doxorubicin. MAIN METHODS: In vitro and in vivo experiments were performed using combinations of vitamin D3 and chemotherapeutic agents. Cell cycle analysis and apoptosis assays were performed. Moreover, ALDH-1 expression levels were estimated in cancer cell lines and solid tumors. For solid tumors, tumor volume and histopathological necrotic indices were estimated. Leukocyte presence was also evaluated in tumors using leukocyte common antigen (LCA). KEY FINDINGS: Results showed a synergistic interaction between vitamin D3 and each of the chemotherapeutic agents on breast cancer cell lines as well as cell cycle arrest at G2/M phase. A decrease in ALDH-1 levels was reported in both breast cancer cells and in tumor tissues. Reductions in tumor volume were also observed in the groups which received the combination therapy. An influence on necrosis rather than apoptosis was also reported, as evidenced by necrotic indices and Bcl-2 expression in tumor sections, respectively. Increased local leukocytes in tumors was also evident, as indicated by increased expression of leukocyte common antigen (LCA). SIGNIFICANCE: Overall, the present study shows that vitamin D3 has an impact on resistance to different chemotherapeutic agents which could be due to the inhibition of ALDH-1, suggesting its use as an adjuvant therapy in cancer patients receiving chemotherapy.

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.