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Haemaphysalis longicornis is a common Ixodida tick species found in temperate areas of Asian countries. An anti-tick assay was conducted on adult female H . longicornis ticks. Plant extract solutions were prepared at concentrations of 50, 25, and 10 mg/mL. Tick survival and mortality were assessed by counting the number of dead and live ticks at 24 h, 48 h, 72 h, and 96 h posttreatment. Out of 11 plant extracts screened, Artemisia judaica extract exhibited the highest potency with 100% mortality (5/5) at 48 h when applied at high and moderate concentrations (50 and 25 mg/mL). Similar results were observed at 96 h for the 10 mg/mL group compared to the untreated ticks. Cleome droserifolia extract demonstrated partial activity with 60% (3/5) and 20% (1/5) mortality at 96 h posttreatment at concentrations of 50 and 25 mg/mL, respectively. Forsskaolea tenacissima extract showed a weak effect with 100% tick mortality (5/5) only at the highest treatment concentration after 96 h. To confirm the activity of A . judaica , trial 2 was conducted. A . judaica demonstrated potency within 48 h in high dose and 72 h in moderate dose, with 100% mortality (15/15) at 96 h posttreatment compared to untreated ticks. The median lethal time 50 (LT 50 ) values were 30.37 h for the high and 55.08 h for the moderate doses. Liquid chromatography‒mass spectrometry was performed on the most potent candidate ( A . judaica ) to identify its phytochemical components. The results revealed the presence of 9 compounds identified through manual annotation and 74 compounds from the Global Natural Products Social library. These compounds included terpenoids, steroids, phenylpropanoids, flavonoid glycosides, flavonoids, and benzenoids. Camphor was identified as the major component via both approaches. These findings suggest the potential use of A . judaica extract in the future development of acaricidal therapeutics.

Rationale: Liver cirrhosis is known to affect drug pharmacokinetics, but the functional assessment of the underlying pathophysiological alterations in drug metabolism is difficult. Methods: Cirrhosis in mice was induced by repeated treatment with carbon tetrachloride for 12 months. A cocktail of six drugs was administered, and parent compounds as well as phase I and II metabolites were quantified in blood, bile, and urine in a time-dependent manner. Pharmacokinetics were modeled in relation to the altered expression of metabolizing enzymes. In discrepancy with computational predictions, a strong increase of glucuronides in blood was observed in cirrhotic mice compared to vehicle controls. Results: The deviation between experimental findings and computational simulations observed by analyzing different hypotheses could be explained by increased sinusoidal export and corresponded to increased expression of export carriers ( Abcc3 and Abcc4 ). Formation of phase I metabolites and clearance of the parent compounds were surprisingly robust in cirrhosis, although the phase I enzymes critical for the metabolism of the administered drugs in healthy mice, Cyp1a2 and Cyp2c29 , were downregulated in cirrhotic livers. RNA-sequencing revealed the upregulation of numerous other phase I metabolizing enzymes which may compensate for the lost CYP isoenzymes. Comparison of genome-wide data of cirrhotic mouse and human liver tissue revealed similar features of expression changes, including increased sinusoidal export and reduced uptake carriers. Conclusion: Liver cirrhosis leads to increased blood concentrations of glucuronides because of increased export from hepatocytes into the sinusoidal blood. Although individual metabolic pathways are massively altered in cirrhosis, the overall clearance of the parent compounds was relatively robust due to compensatory mechanisms.

Fluorophore-coupled bile acids (BA) represent an important tool for intravital analysis of BA flux in animal models of cholestatic diseases. However, addition of a fluorophore to a BA may alter transport properties. We developed and validated a 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole-coupled taurocholic acid (3β-NBD-TCA) as a probe for intravital analysis of BA homeostasis. We compared transport of 3β-NBD-TCA to [3H]-TCA in HEK293 cells stably expressing the mouse hepatic or renal BA carriers mNtcp or mAsbt, respectively. We also studied distribution kinetics intravitally in livers and kidneys of anesthetized wildtype and mOatp1a/1b cluster knockout mice (OatpKO) with and without administration of the Ntcp inhibitor Myrcludex B and the ASBT inhibitor AS0369. In vitro, 3β-NBD-TCA and [3H]-TCA showed comparable concentration- and time-dependent transport via mNtcp and mAsbt as well as similar inhibition kinetics for Myrcludex B and AS0369. Intravital analysis in the livers of wildtype and OatpKO mice revealed contribution of both mNtcp and mOatp1a/1b in the 3β-NBD-TCA uptake from the sinusoidal blood into hepatocytes. Combined deletion of mOatp1a/1b and inhibition of mNtcp by Myrcludex B blocked the uptake of 3β-NBD-TCA from sinusoidal blood into hepatocytes. This led to an increase of 3β-NBD-TCA signal in the systemic circulation including renal capillaries, followed by strong enrichment in a subpopulation of proximal renal tubular epithelial cells (TEC). The enrichment of 3β-NBD-TCA in TEC was strongly reduced by the systemic ASBT inhibitor AS0369. NBD-coupled TCA has similar transport kinetics as [3H]-TCA and can be used as a tool to study hepatorenal BA transport. See also the graphical abstract(Fig. 1).

Background Medicinal plants have been successfully used as an alternative source of drugs for the treatment of microbial diseases. Finding a novel treatment for malaria is still challenging, and various extracts from different wild desert plants have been reported to have multiple medicinal uses for human public health, this study evaluated the antimalarial efficacy of several Egyptian plant extracts. Methods We assessed the cytotoxic potential of 13 plant extracts and their abilities to inhibit the in vitro growth of Plasmodium falciparum (3D7), and to treat infection with non-lethal Plasmodium yoelii 17XNL in an in vivo malaria model in BALB/c mice. Results In vitro screening identified four promising candidates, Trichodesma africanum, Artemisia judaica, Cleome droserifolia , and Vachellia tortilis , with weak-to-moderate activity against P. falciparum erythrocytic blood stages with mean half-maximal inhibitory concentration 50 (IC 50 ) of 11.7 μg/ml, 20.0 μg/ml, 32.1 μg/ml, and 40.0 μg/ml, respectively. Their selectivity index values were 35.2, 15.8, 11.5, and 13.8, respectively. Among these four candidates, T. africanum crude extract exhibited the highest parasite suppression in a murine malaria model against P. yoelii . Conclusion Our study identified novel natural antimalarial agents of plant origin that have potential for development into therapeutics for treating malaria.

Purpose Acid ceramidase (AC) occupies an important place in the control of cancer cell proliferation. We tested the influence of AC inhibition on the effects of PSC 833, a P-glycoprotein antagonist with potent ceramide-generating capacity, to determine whether AC could be a therapeutic target in pancreatic cancer. Methods Ceramide metabolism was followed using 3 H-palmitate, and molecular species were determined by mass spectroscopy. Apoptosis was measured by DNA fragmentation, autophagy by acridine orange staining, and cell cycle was assessed by flow cytometry and RB phosphorylation. AC was measured in intact cells using fluorescent substrate. Results Exposure of human PANC-1 or MIA-PaCa-2 cells to PSC 833 promoted increases in de novo (dihydro)ceramides, (dihydro)glucosylceramides, and (dihydro)sphingomyelins, demarking ceramide generation and robust metabolism. Despite the multifold increases in (dihydro)ceramide levels, cells were refractory to PSC 833. However, PSC 833 produced a dose-dependent decrease in DNA synthesis and dose- and time-dependent decreases in RB phosphorylation, consistent with cell cycle arrest as demonstrated at G1. Cytostatic effects of PSC 833 were converted to cytotoxic end-point by acid ceramidase inhibition. Cytotoxicity was accompanied by formation of acridine orange-stained acidic vesicles and an increase in LC3 expression, indicative of autophagic response. Cell death was not reversed by preexposure to myriocin, which blocks PSC 833-induced ceramide generation. Conclusion Although the role of ceramide in end-point cytotoxicity is unclear, our results suggest that acid ceramidase is a viable target in pancreatic cancer. We propose that AC inhibition will be effective in concert with other anticancer therapies.

For thousands of years, Vachellia nilotica has been widely used as an herbal medicine to treat some diseases and symptoms, including respiratory, gastrointestinal and urogenital ailments. The present study was adapted to document and assemble existing information about V. nilotica and its evidence-based ethnopharmacological activities, with brief reviews on the description, geographical distribution, ecology, medical uses and phytochemistry. A literature review and information up to 2024 was performed in various scientific databases, including PubMed, Science Direct and Google Scholar. The keywords were “Acacia nilotica”, “Botany”, “ecology”, “Traditional uses”, “Phytochemistry”, “Polyphenols”, “Molecular docking”, “Ethnopharmacological activities” and “toxicity”, among others. V. nilotica has a wide range of uses, with low toxicity, reported in different countries. It can be infused into oils or tea or incorporated into paste, poultice and biscuits, used as an emollient, antidiarrheal, astringent and as an antidote for bite poisons. Glucose and lipid-lowering, anti-inflammatory, analgesic, antipyretic, antioxidant, antihypertensive, antibacterial, antifungal, antiviral and anthelmintic activities are the most prominent. Over 150 chemical components have been identified from V. nilotica that could be associated with its potential actions. Quercetin, rutin, kaempferol, naringenin, catechin, epicatechin, gallic acid, ellagic acid, lupeol and niloticane are its main active constituents. From the research data, and despite the fact that human clinical trials and detailed methodological studies are scarce, V. nilotica has shown wide-ranging activities, though the most robust evidence is related to the treatment of microbial infections, diarrhea, wound and ulcer healing and for topical application. More pharmacological and toxicological studies are required to further elucidate the mechanisms of action, potential side effects, and optimal dosages for these treatments. Additionally, more clinical trials are needed to validate these traditional uses in human populations and to ensure the safety and efficacy of V. nilotica for these applications. This article offers an overview of therapeutic applications by utilizing traditional uses and recent findings on phytochemical studies, and clinical and pharmacological research.

Acetaminophen (APAP) is known to cause a breach of the blood–bile barrier in mice that, via a mechanism called futile bile acid (BA) cycling, increases BA concentrations in hepatocytes above cytotoxic thresholds. Here, we compared this mechanism in mice and rats, because both species differ massively in their susceptibility to APAP and compared the results to available human data. Dose and time-dependent APAP experiments were performed in male C57BL6/N mice and Wistar rats. The time course of BA concentrations in liver tissue and in blood was analyzed by MALDI-MSI and LC–MS/MS. APAP and its derivatives were measured in the blood by LC–MS. APAP-induced liver damage was analyzed by histopathology, immunohistochemistry, and by clinical chemistry. In mice, a transient increase of BA in blood and in peri-central hepatocytes preceded hepatocyte death. The BA increase coincided with oxidative stress in liver tissue and a compromised morphology of bile canaliculi and immunohistochemically visualized tight junction proteins. Rats showed a reduced metabolic activation of APAP compared to mice. However, even at very high doses that caused cell death of hepatocytes, no increase of BA concentrations was observed neither in liver tissue nor in the blood. Correspondingly, no oxidative stress was detectable, and the morphology of bile canaliculi and tight junction proteins remained unaltered. In conclusion, different mechanisms cause cell death in rats and mice, whereby oxidative stress and a breach of the blood–bile barrier are seen only in mice. Since transient cholestasis also occurs in human patients with APAP overdose, mice are a clinically relevant species to study APAP hepatotoxicity but not rats.

For thousands of years, Vachellia nilotica has been widely used as an herbal medicine to treat some diseases and symptoms, including respiratory, gastrointestinal and urogenital ailments. The present study was adapted to document and assemble existing information about V. nilotica and its evidence-based ethnopharmacological activities, with brief reviews on the description, geographical distribution, ecology, medical uses and phytochemistry. A literature review and information up to 2024 was performed in various scientific databases, including PubMed, Science Direct and Google Scholar. The keywords were “Acacia nilotica”, “Botany”, “ecology”, “Traditional uses”, “Phytochemistry”, “Polyphenols”, “Molecular docking”, “Ethnopharmacological activities” and “toxicity”, among others. V. nilotica has a wide range of uses, with low toxicity, reported in different countries. It can be infused into oils or tea or incorporated into paste, poultice and biscuits, used as an emollient, antidiarrheal, astringent and as an antidote for bite poisons. Glucose and lipid-lowering, anti-inflammatory, analgesic, antipyretic, antioxidant, antihypertensive, antibacterial, antifungal, antiviral and anthelmintic activities are the most prominent. Over 150 chemical components have been identified from V. nilotica that could be associated with its potential actions. Quercetin, rutin, kaempferol, naringenin, catechin, epicatechin, gallic acid, ellagic acid, lupeol and niloticane are its main active constituents. From the research data, and despite the fact that human clinical trials and detailed methodological studies are scarce, V. nilotica has shown wide-ranging activities, though the most robust evidence is related to the treatment of microbial infections, diarrhea, wound and ulcer healing and for topical application. More pharmacological and toxicological studies are required to further elucidate the mechanisms of action, potential side effects, and optimal dosages for these treatments. Additionally, more clinical trials are needed to validate these traditional uses in human populations and to ensure the safety and efficacy of V. nilotica for these applications. This article offers an overview of therapeutic applications by utilizing traditional uses and recent findings on phytochemical studies, and clinical and pharmacological research.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are classical antimalarial drugs, and recently have been used for other applications including coronavirus disease 2019 (COVID-19). Although they are considered safe, cardiomyopathy may associate CQ and HCQ applications particularly at overdoses. The goal of the present study was to evaluate the potential protective effect of the nootropic agent vinpocetine against CQ and HCQ adverse effects with a specific focus on the heart. For this purpose, a mouse model of CQ (0.5 up to 2.5 g/kg)/HCQ (1 up to 2 g/kg) toxicity was used, and the effect of vinpocetine was evaluated by survival, biochemical, as well as histopathological analyses. Survival analysis revealed that CQ and HCQ caused dose-dependent lethality, which was prevented by co-treatment with vinpocetine (100 mg/kg, oral or intraperitoneal). To gain deeper understanding, a dose of 1 g/kg CQ—which did not cause death within the first 24 h after administration—was applied with and without vinpocetine administration (100 mg/kg, intraperitoneal). The CQ vehicle group showed marked cardiotoxicity as evidenced by significant alterations of blood biomarkers including troponione-1, creatine phosphokinase (CPK), creatine kinase-myocardial band (CK-MB), ferritin, and potassium levels. This was confirmed at the tissue level by massive alteration of the heart tissue morphology and coincided with massive oxidative stress. Interestingly, co-administration of vinpocetine strongly ameliorated CQ-induced alterations and restored the antioxidant-defense system of the heart. These data suggest that vinpocetine could be used as an adjuvant therapy together with CQ/HCQ applications.

Vinpocetine (Vin), a synthetic-derivative of the Vinca alkaloid- Vincamine, has been reported to possess a variety of health benefits. We herein investigated the critical role of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant response in the protection of Vin against H2O2 and paracetamol (APAP)-induced liver toxicity. For this purpose, a normal human hepatic cell line (L02 cells) was incubated with cytotoxic concentrations of H2O2 or APAP in the presence or absence of Vin. To evaluate the responses, MTS Cell Viability assay, immunoblotting, biochemical assays, and molecular docking approach were used. Viability analysis showed that treatment of L02 cells with Vin prevented the cytotoxicity induced by H2O2 and APAP. It was evidenced by the fact that Vin dumped H2O2 and APAP cytotoxicity and reactive oxygen species (ROS) generation. The immunoblotting analysis shows that Vin increased Nrf2 expression along with the expression of target protein, heme oxygenase-1 (HO-1), and increased intracellular glutathione (GSH) level. Interestingly, we found that Vin could enhance the thermal stability of Keap1, which indicated the potential interaction between Vin and Keap1. Furthermore, molecular docking revealed that Vin possibly competed with Nrf2 for Keap1-binding site, with hydrogen and stearic interactions. Collectively, Vin effectively protects against H2O2 and APAP -induced hepatotoxicity via executing Nrf2-mediated antioxidative signaling pathway. Meanwhile, Vin interrupts protein-protein interaction between Keap1 and Nrf2 which might also contribute to decrease Nrf2 degradation and stabilize protein expression. Thus, Vin-based adjuvant therapy may represent a smart drug regimen to mitigate drug-induced oxidative stress and liver injuries.