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.

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.

The ponatinib/gossypol novel combination provides enhanced anticancer activity against murine solid Ehrlich carcinoma via triggering apoptosis and inhibiting proliferation/angiogenesis.

The search for new antitumor agents or combinations that are more effective and, hopefully, provide fewer health hazards is ongoing. Therefore, this study investigated the efficacy of a novel combination of ponatinib, a multi-targeted tyrosine kinase inhibitor, and the natural phytochemical gossypol against murine solid Ehrlich carcinoma. Six groups of ten mice each received vehicle (I), ponatinib in doses of 10 and 15 mg/kg (II, III) respectively, gossypol in a dose of 4 mg/kg (IV), and ponatinib (10 or 15 mg/kg) in combination with gossypol (4 mg/kg; V, VI). All treatments started on the 12th post-Ehrlich ascites carcinoma (EAC) implantation day and were administered intraperitoneally in daily doses for 3 weeks. Treatment of EAC-bearing mice with ponatinib/gossypol combination improved anticancer efficacy over either drug alone, as demonstrated by greater decreases in tumor weight and volume, and ponatinib (10 mg/kg)/gossypol combination was more efficient than ponatinib (15 mg/kg). Mechanistically, the ponatinib/gossypol combination significantly increased apoptotic markers p53, Bax, and caspase-9 while decreasing anti-apoptotic marker Bcl-2. Furthermore, it greatly decreased proliferative and angiogenic markers, FGFR4 and VEGF, respectively. Histopathology revealed a significant decline in neoplastic cells, the majority of which have necrotic changes and numerous apoptotic bodies, as well as a decrease in mitotic figures and tumor giant cells, indicating the capacity to suppress cancer proliferation/persistence. Overall, gossypol could be used as an adjuvant medication for ponatinib in cancer treatment, possibly leading to successful dose reductions and fewer side effects; however, further research is needed before a clinical application could be feasible.

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.

Deciphering the enzymatic target of a new family of antischistosomal agents bearing a quinazoline scaffold using complementary computational tools.

A previous phenotypic screening campaign led to the identification of a quinazoline derivative with promising in vitro activity against Schistosoma mansoni. Follow-up studies of the antischistosomal potential of this candidate are presented here. The in vivo studies in a S. mansoni mouse model show a significant reduction of total worms and a complete disappearance of immature eggs when administered concomitantly with praziquantel in comparison with the administration of praziquantel alone. This fact is of utmost importance because eggs are responsible for the pathology and transmission of the disease. Subsequently, the chemical optimisation of the structure in order to improve the metabolic stability of the parent compound was carried out leading to derivatives with improved drug-like properties. Additionally, the putative target of this new class of antischistosomal compounds was envisaged by using computational tools and the binding mode to the target enzyme, aldose reductase, was proposed.

Bioavailability of paracetamol with/without caffeine in Egyptian patients with hepatitis C virus.

PURPOSE: This study investigates the involvement of liver dysfunction in the modulation of paracetamol pharmacokinetic profile in genotype-4 HCV patients treated with either paracetamol alone (Para) or in combination with caffeine (Para-Caf). METHODS: Twenty healthy volunteers and 20 Child-Pugh B HCV patients, each divided into two equal subgroups, were examined, whose liver/kidney functions were correlated with their main clinical manifestation. After an overnight fasting, healthy and hepatic subjects received either a single dose of Para (1000 mg paracetamol) or Para-Caf (1000 mg paracetamol/130 mg caffeine). Two milliliters of saliva samples were collected prior to and at different time-intervals after drug administration and analyzed using HPLC. RESULTS: There was a noticeable increase in the mean concentration time profile of salivary paracetamol concentrations in hepatic patients, with concomitant decrease in paracetamol clearance (CLT), along with induction in the primary pharmacokinetic (PK) parameters, C max, AUC(0-8 h) and AUC(0-∞) (by about 95, 82, and 64 %, respectively, after treatment with Para, and 98, 96, and 101 %, respectively, after treatment with Para-Caf), when compared with the corresponding parameters in healthy subjects. Additionally, the healthy subjects treated with Para-Caf exhibited bioinequivalent increase in C max, K a, and t 1/2 with decrease in T max when compared with the healthy individuals treated with Para alone. A similar pattern was recorded in hepatic patients after addition of caffeine to paracetamol, with even augmented significant increase in K a and t 1/2 (by 100 and 32 %, respectively). CONCLUSIONS: Liver dysfunction modified the PK of paracetamol expressed as earlier effective paracetamol concentration, with obvious decrease in its clearance. Caffeine induced faster absorption (evidenced by shorter T max and higher K a) and prolonged t 1/2 of paracetamol, the effects that were more profound in hepatic patients. Further studies are needed to evaluate the influence of liver damage on paracetamol pharmacokinetics whenever repeated dosing is applied, to avoid possible drug accumulation.

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.

Praziquantel in a clay nanoformulation shows more bioavailability and higher efficacy against murine Schistosoma mansoni infection.

Consideration of existing compounds always simplifies and shortens the long and difficult process of discovering new drugs specifically for diseases of developing countries, an approach that may add to the significant potential cost savings. This study focused on improving the biological characteristics of the already-existing antischistosomal praziquantel (PZQ) by incorporating it into montmorillonite (MMT) clay as a delivery carrier to overcome its known bioavailability drawbacks. The oral bioavailability of a PZQ-MMT clay nanoformulation and its in vivo efficacy against Schistosoma mansoni were investigated. The PZQ-MMT clay nanoformulation provided a preparation with a controlled release rate, a decrease in crystallinity, and an appreciable reduction in particle size. Uninfected and infected mice treated with PZQ-MMT clay showed 3.61- and 1.96-fold and 2.16- and 1.94-fold increases, respectively, in area under the concentration-time curve from 0 to 8 h (AUC0-8) and maximum concentration of drug in serum (Cmax), with a decrease in elimination rate constant (kel) by 2.84- and 1.35-fold and increases in the absorption rate constant (ka) and half-life (t1/2e) by 2.11- and 1.51-fold and 2.86- and 1.34-fold, respectively, versus the corresponding conventional PZQ-treated groups. This improved bioavailability has been expressed in higher efficacy of the drug, where the dose necessary to kill 50% of the worms was reduced by >3-fold (PZQ 50% effective dose [ED50] was 20.25 mg/kg of body weight for PZQ-MMT clay compared to 74.07 mg/kg for conventional PZQ), with significant reduction in total tissue egg load and increase in total immature, mature, and dead eggs in most of the drug-treated groups. This formulation showed better bioavailability, enhanced antischistosomal efficacy, and a safer profile despite the longer period of residence in the systemic circulation. Although the conventional drug's toxicity was not examined, animal mortality rates were not different between groups receiving the test PZQ-clay nanoformulation and conventional PZQ.

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.

Potential effect of the medicinal plants Calotropis procera, Ficus elastica and Zingiber officinale against Schistosoma mansoni in mice.

CONTEXT: Calotropis procera (Ait.) R. Br. (Asclepiadaceae), Ficus elastica Roxb. (Moraceae) and Zingiber officinale Roscoe (Zingiberaceae) have been traditionally used to treat many diseases. OBJECTIVE: The antischistosomal activity of these plant extracts was evaluated against Schistosoma mansoni. MATERIALS AND METHODS: Male mice exposed to 80 ± 10 cercariae per mouse were divided into two batches. The first was divided into five groups: (I) infected untreated, while groups from (II-V) were treated orally (500 mg/kg for three consecutive days) by aqueous stem latex and flowers of C. procera, latex of F. elastica and ether extract of Z. officinale, respectively. The second batch was divided into four comparable groups (except Z. officinale-treated group) similarly treated as the first batch in addition to the antacid ranitidine (30 mg/kg) 1 h before extract administration. Safety, worm recovery, tissues egg load and oogram pattern were assessed. RESULTS: Calotropis procera latex and flower extracts are toxic (50-70% mortality) even in a small dose (250 mg/kg) before washing off their toxic rubber. Zingiber officinale extract insignificantly decrease (7.26%) S. mansoni worms. When toxic rubber was washed off and ranitidine was used, C. procera (stem latex and flowers) and F. elastica extracts revealed significant S. mansoni worm reductions by 45.31, 53.7 and 16.71%, respectively. Moreover, C. procera extracts produced significant reductions in tissue egg load (∼34-38.5%) and positively affected oogram pattern. CONCLUSION: The present study may be useful to supplement information with regard to C. procera and F. elastica antischistosomal activity and provide a basis for further experimental trials.

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.

Haemin enhances the in vivo efficacy of artemether against juvenile and adult Schistosoma mansoni in mice.

Among the potential alternatives to praziquantel, interestingly, the antimalarial artemether (Art) also exhibits antischistosomal properties. Previous in vitro studies suggested that Art interacts with haemin and together produce a lethal agent against schistosomes. This study investigates the in vivo effect of Art plus haemin on juvenile and adult Schistosoma mansoni worms and on their antioxidant enzymes. Infected mice were allocated into two batches each in four groups (I-IV): (I) untreated control; (II) injected with haemin (ip, 100 mg/kg/day) on days 26, 27, and 28 post-infection (PI) for juvenile stage and on days 47, 48, and 49 PI for adult stage; (III) treated with a single oral dose of Art (300 mg/kg) either after 28 or 49 days PI, respectively; and (IV) received both haemin, as group (II) and Art as group (III). Half of mice for each batch were killed 72 h; meanwhile, the remaining half was killed 3 weeks after Art administration. Parasitological criteria of cure and worms' antioxidant enzymes were assessed. Glutathione S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), and superoxide dismutase (SOD) activities were lower in juvenile worms than adult ones and in females than males. Haemin plus Art at the juvenile and adult stages produced significant inhibition in worms' GST, GPx, and SOD activities 72 h after Art treatment, compared with Art-treated group, with enhanced killing of females (96.98 and 91.47 % versus 87.04 and 72.97 %, respectively) and total worms (91 and 83.39 % versus 75 and 59.01 %, respectively) 3 weeks posttreatment. In conclusion, Art plus haemin has a higher harmful effect on juvenile and adult schistosomes and antioxidant capacity than Art alone. This gives new insights into the importance of haemin in the antischistosomal properties of artemether.

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.

Bioavailability and in vivo efficacy of a praziquantel-polyvinylpyrrolidone solid dispersion in Schistosoma mansoni-infected mice.

One of the problems of praziquantel (PZQ) is its very low aqueous solubility. Moreover, its dissolution rate is considered the limiting factor for its bioavailability. This work correlates the physical properties and the dissolution behavior of PZQ-polyvinylpyrrolidone (PVP) solid dispersion (SD) at the ratios of 1:1 and 3:7 with its oral bioavailability and its in vivo efficacy against Schistosoma mansoni (S. mansoni). The PZQ and PZQ-PVP SD were characterized by infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy (SEM) and solubility test. Results showed a decrease in crystallinity, possible interaction between PZQ and PVP, greater increase in dissolution rate and appreciable reduction in particle size. S. mansoni-infected mice treated orally with either pure PZQ or PZQ-PVP at a single dose of 500 mg/kg showed a higher increase in AUC((0-8h)), C (max), K(a) and t (1/2e) with a significant decrease in k (el) versus the corresponding uninfected mice. Moreover, uninfected and infected mice treated with PZQ-PVP SD showed 2.3-, 1.6- and 1.3-, 1.25-fold increase, respectively, in AUC((0-8h)) and C(max), with a decrease in k(el) and increase in t (1/2e) by twofold versus the corresponding pure PZQ-treated groups. Percentage worm reduction at all administered doses (62.5, 125, 250, 500 and 1,000 mg/kg) was significantly higher (1- to 1.5-fold) in mice treated with PZQ-PVP SD (ED50 = 40.92) versus those treated with pure PZQ (ED50 = 99.29). In addition, a significant reduction in total tissue egg load concomitant with a significant decrease in total immature and mature eggs and an increase in dead eggs in PZQ-PVP SD-treated groups versus their corresponding pure PZQ-treated groups was recorded. Solid dispersion of PZQ with PVP could lead to a further improvement in the effectiveness of PZQ therapy especially with the appearance of some PZQ-tolerant S. mansoni isolates.

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.

Potential antifibrotic effects of AT1 receptor antagonist, losartan, and/or praziquantel on acute and chronic experimental liver fibrosis induced by Schistosoma mansoni.

1. This study investigates the potential antifibrotic effect of losartan, AT-1 receptor antagonist, and/or praziquantel (PZQ) on acute and chronic hepatic fibrosis induced by Schistosoma mansoni (S. mansoni). 2. Schistosoma mansoni-infected mice were in two batches (I & II), each in four groups: (i) Infected untreated; (ii) treated with losartan, starting from the 4th or 12th weeks post-infection (PI); (iii) treated with PZQ in the 7th week PI; and (iv) treated with losartan, as group (ii) plus PZQ as group (iii). Comparable groups of uninfected mice were run in parallel with infected groups. Mice of batches I and II were killed 10 and 18 weeks PI, respectively. Hepatic content of hydroxyproline (HYP), serum levels and tissue expression of matrix metalloproteinase-2 (MMP-2), and transforming growth factor-ß1 (TGF-ß1) were determined. Parasitological, biochemical and histological parameters, which reflect disease severity and morbidity, were examined. 3. Losartan alone caused a considerable decrease in worm burden, hepatic tissue egg load with an increase in percentage of dead eggs, modulation of granuloma size and regression of inflammatory reactions, which was less obvious in the chronic stage. The best results were obtained when losartan was co-administered with PZQ, especially in the acute stage. This was revealed by a remarkable reduction in serum levels and tissue expression of MMP-2, TGF-ß1 and HYP content, accompanied by conservation of hepatic reduced glutathione (GSH) versus the PZQ-treated group. 4. In conclusion, losartan has a promising antifibrotic action and could be introduced as a therapeutic tool with PZQ especially in acute schistosomal hepatic fibrosis.

The use of pentoxifylline as adjuvant therapy with praziquantel downregulates profibrogenic cytokines, collagen deposition and oxidative stress in experimental schistosomiasis mansoni.

UNLABELLED: This study investigates the possible use of pentoxifylline (PTX), with antifibrotic and anti-inflammatory properties, as adjuvant in treatment of schistosomal liver fibrosis through determination of some profibrogenic cytokines, oxidative stress and collagen deposition. Animals were classified into seven groups: normal control (i), Schistosoma mansoni-infected untreated (ii), infected treated with praziquantel (PZQ) curative, 1000mg/kg (iii) or sub curative, 200mg/kg dose (iv), infected treated with PTX alone (10mg/kg/day; 5days/wk) for 8weeks starting from the 2nd to the 10th week post infection (v), or in addition to curative (vi) or sub curative dose of PZQ (vii). Serum transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor-α (TNF-α), matrix metalloproteinases-2 (MMP-2) and hepatic hydroxyproline (Hyp) content, glutathione related antioxidant enzymes and malondialdehyde (MDA) were determined. Results showed that S. mansoni infection produced remarkable elevations in the serum levels of TGF-ß1, TNF-α, MMP-2 and the hepatic contents of Hyp, glutathione reductase (GR), MDA with significant reduction in reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and superoxide dismutase (SOD) when compared with their corresponding normal controls. Treatment of infected mice with PTX in addition to PZQ curative rather than its sub curative dose produced the best results evidenced by complete normalization in the previously mentioned serum and hepatic parameters. CONCLUSION: PTX could attenuate liver fibrosis in early stages of S. mansoni infection through downregulation of profibrogenic cytokines, oxidative stress and collagen deposition.

Comparative efficacy and bioavailability of different praziquantel brands.

This study investigates the efficacy, bioavailability and drug metabolizing enzymes mainly involved in the metabolism of the commercial brands of praziquantel (PZQ) in Egypt in comparison with the original pure powder. Mice infected with PZQ-susceptible (CD) or PZQ-insusceptible (EE2) Schistosoma mansoni isolates were divided each into seven groups, six of them received PZQ brands (Distocide, Epiquantel, Biltricide, Bilharzid, Praziquantel, and pure PZQ), while the seventh one was left as infected untreated. Seven weeks post-infection, worms were quantified and hepatic CYP450 and CYT b5 were examined. For PZQ pharmacokinetics, groups of normal mice were given the different PZQ brands and divided into subgroups, killed at 2, 5, 15, 30, 60, 90, 120,150, 180, 240 and 360 min post-dosing. Physicochemical examination revealed better dissolution rates for Biltricide, Distocide and PZQ T3A rather than Epiquantel and Bilharzid. Significant decrease in worm burden was recorded in all groups of mice regardless of the brand of PZQ used, but with better results obtained with CD isolate rather than the EE2 isolate. Biltricide and Distocide showed higher C(max) and AUC(0-6h) in normal mice, in addition to higher worm reduction with least inhibition of CYP450 and CYT b5 in EE2-infected mice. PZQ T3A, Bilharzid and Epiquantel showed, in addition to lower efficacy, higher K(el), lower t(1/2e), C(max) and AUC(0-6h). The 32-46% reduction of their bioavailability reflected on their antischistosomal efficacy and recovery of drug metabolizing enzymes. Quality of generic PZQ should include, in addition to examining the physicochemical characteristics of the brands, biological testing including efficacy and bioavailability studies.

Pharmacodynamics of mefloquine and praziquantel combination therapy in mice harbouring juvenile and adult Schistosoma mansoni.

Praziquantel (PZQ) is currently the only drug widely used for the treatment of schistosomiasis, but the antimalarial drug mefloquine (Mef) possesses interesting antischistosomal properties. Combination therapy with these two drugs has been suggested as a strategy for transmission control, as PZQ is active against adult worms and Mef is active against schistosomula. To examine the efficacy of combination therapy, Schistosoma mansoni-reinfected mice were separated into seven groups: untreated (I), treated with PZQ in doses of 200 mg/kg (II) or 1,000 mg/kg (III), treated with Mef in doses of 200 mg/kg (IV) or 400 mg/kg (V); each dose was divided equally and given on two consecutive days. Group VI was treated with doses of PZQ + Mef as in groups II and IV, respectively, while group VII was treated with PZQ + Mef as in groups III and V, respectively. PZQ + Mef at the reduced doses of 200 mg/kg each enhanced the therapeutic efficacy over the reduced PZQ dose alone as shown by a very high reduction in the total numbers of mature worms (95% vs. 49%), immature worms (96% vs. 29%) and the complete eradication of immature females, mature females and immature eggs. The reduction in worm burden was associated with the healing of hepatic granulomatous lesions and the normalisation of all liver enzymes. Therefore, the use of Mef with PZQ is more effective than PZQ alone and should be considered for clinical trials in humans as a potential treatment regimen to prevent treatment failures in areas with high rates of schistosomiasis.

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.