05) as well transcriptional level of RAGE (

 < 0.05) and pro-inflammatory cytokines (

 < 0.05). Chemical analysis of

extracts using High Resolution Liquid Chromatograph Mass Spectrometer (HR-LCMS) and Gas Chromatograph with high resolution Mass Spectrometer (GC-HRMS) suggested some potential active phytochemical compounds. The results from this study may provide possible alternative treatment for prevention and/or therapy of neurodegenerative disorders by targeting the above-mentioned pathways. The role of the phytochemical active ingredient (s) in inhibiting the AGEs-triggered signaling inflammatory pathway should be investigated in future study.

Medicinal plants produce a variety of chemical substances with varied physiological effects. They are a huge reservoir of various chemical substances with potential therapeutic properties. Allophylus spicatus is a shrub that belong to the Sapindaceae family. In this study, male albino wistar rats (18) were used for acute toxicity test. Animals were divided into six groups of three rats each. Group A served as the control group while the other groups were dosed orally with 200, 500, 1000, 2000 and 5000 mg/kg body weight of extract and were observed for 14 days. Swiss albino mice (42) were used for the antimalarial study; five groups of six infected mice per group (Groups C-G) were respectively dosed orally with 25 mg chloroquine/kg bw, 200 mg of extract/kg bw, 400 mg/kg bw of extract, 25 mg chl./kg bw + 200 mg/kg bw of extract and 25 mg chl./kg bw + 400 mg/kg bw extract with three groups serving as the control (Groups A-C) for three days. Acute toxicity test and histology analysis on the liver tissue confirmed the safety of the extract at concentrations less than 1000 mg/kg b/w. Antimalarial studies showed the highest activity in the group administered with 400 mg/kg + 25 mg chl./kg b/w. In conclusion, A. spicatus was non-toxic at doses less than 1000 mg/kg and significantly reduced parasitemia count in P. berghei infected mice, thus validating its folkloric usage.

The online version contains supplementary material available at 10.1007/s43188-020-00070-1.

The online version contains supplementary material available at 10.1007/s43188-020-00070-1.This study aimed to obtain necessary toxicological data using experimental and computational methods for the calculation of a common permitted daily exposure (PDE) which can be relevant for nicotinic acid and its esters and nicotinamide according to European Medicines Agency Guideline on setting health-based exposure limits. PDE calculation is mainly based on critical toxicological endpoints. During this procedure, critical toxicological endpoints data of an active pharmaceutical ingredient (API) may not be able to find satisfactorily. Hence, using toxicological data for another API that has a similar chemical structure can be a useful way. In this study, toxicological endpoints of nicotinic acid and its esters and nicotinamide were evaluated. Then, the data gaps in the toxicological endpoints were filledusing the read-across approach. Based on the current existing data, nicotinic acid and its esters and also nicotinamide are not genotoxic and do not have skin sensitization potential. These compounds do not present a concern for carcinogenicity and developmental/reproductive toxicity. Based on these critical endpoints and available experimental data, the final PDE of 10 mg/day was calculated for all category members. Our study showed the utility of the read-across for PDE calculation of APIs with experimental toxicological data gap.This study investigated the effect of high doses of monosodium glutamate (MSG), a known food additive on hepatic, memory and locomotor functions in mice, and the ameliorative potentials of Jobelyn® (JB), a unique dietary supplement. Twenty four male Swiss mice divided into 4 groups (n = 6) were given MSG (2, 4 and 8 g/kg) or normal saline (10 mL/kg) orally for 14 days. In the intervention study, another set of 30 male Swiss mice distributed into 5 groups (n = 6) received normal saline, MSG (8 g/kg) alone or in combination with JB (5, 10 and 20 mg/kg) orally, for 14 days. Memory and locomotor functions as well as brain oxido-nitrergic stress biomarkers were then assessed in both studies. The hepatic oxido-nitrergic stress biomarkers, liver enzymes functions and histomorphology of the liver were also assessed. MSG (2, 4 and 8 g/kg) produced memory dysfunction, hyperlocomotion, increased malondialdehyde and nitrite levels accompanied by decreased antioxidant status in the brain and hepatic tissues. MSG-treated mice had increased hepatic enzyme activities (alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase) and distorted cyto-architectural integrity of the liver. These findings further suggest that MSG compromised hepatic functioning, which might also contribute to its neurotoxicity. However, JB (5, 10 and 20 mg/kg, p.o) attenuated the memory deficit, hyperlocomotion, increased oxido-nitrergic stress responses in the brain and hepatic tissues induced by MSG (8 g/kg, p.o). JB also normalized hepatic enzymes activities and histomorphological changes in MSG-treated mice. Taken together, JB mitigated MSG-induced toxicity through mechanisms relating to enhancement of cellular antioxidant-machineries and normalization of hepatic enzymatic functions.Methylmercury (MeHg) intoxication is associated with hypertension, hypercholesterolemia, and atherosclerosis by mechanisms that are not yet fully understood. We investigated the effects of MeHg intoxication in atherosclerosis-prone (ApoE-KO) and resistant C57BL/6 mice. Mice were submitted to carotid stenosis surgery (to induce atherosclerosis faster) and received water or MeHg solution (20 mg/L) for 15 days. Tail plethysmography was performed before and after MeHg exposure. Food and MeHg solution intakes were monitored weekly. On the 15th day, mice were submitted to intravital fluorescence microscopy of mesenteric vasculature to observe in vivo leukocyte rolling and adhesion. Results showed that despite the high hair and liver Hg concentrations in the MeHg group, food and water (or MeHg solution) consumption and liver function marker levels were similar to those in controls. MeHg exposure increased total cholesterol, the atherogenic (non-HDL) fraction and systolic and diastolic blood pressure. MeHg exposure also induced inflammation, as seen by the increased rolling and adhered leukocytes in the mesenteric vasculature. Atherosclerosis lesions were more extensive in the aorta and carotid sites of MeHg-ApoE knockout mice. Surprisingly, MeHg exposure also induced atherosclerosis lesions in C57BL/6 mice, which are resistant to atherosclerosis formation. We concluded that MeHg intoxication might represent a risk for cardiovascular diseases since it accelerates atherogenesis by exacerbating several independent risk factors.Epithelial-mesenchymal transition (EMT), a biological process through which epithelial cells transdifferentiate into mesenchymal cells, is involved in several pathological events, such as cancer progression and organ fibrosis. So far, we have found that methotrexate (MTX), an anticancer drug, induced EMT in the human A549 alveolar adenocarcinoma cell line. However, the relationship between EMT and the cytotoxicity induced by MTX remains unclear. In this study, we compared the processes of MTX-induced EMT and apoptosis in A549 cells. Q-VD-Oph, a caspase inhibitor, suppressed MTX-induced apoptosis, but not the increase in mRNA expression of α-smooth muscle actin (SMA), a representative EMT marker. In addition, SB431542, an EMT inhibitor, did not inhibit MTX-induced apoptosis. By using isolated clonal cells from wild-type A549 cells, the induction of EMT and apoptosis by MTX in each clone was analyzed, and no significant correlation was observed between the MTX-induced increase in α-SMA mRNA expression and the proportion of cells undergoing apoptosis. Furthermore, the increase in the mRNA expression of α-SMA was well correlated with cyclin-dependent kinase inhibitor 1A, a cell cycle arrest marker, but not with BCL-2 binding component 3 and Fas cell surface death receptor, which are both pro-apoptotic factors, indicating that the MTX-induced EMT may be related to cell cycle arrest, but not to apoptosis. These findings suggested that different mechanisms were involved in the MTX-induced EMT and apoptosis.Microsomal epoxide hydrolase/epoxide hydrolase 1 (mEH/EPHX1) works in conjunction with cytochromes P450 to metabolize a variety of compounds, including xenobiotics, pharmaceuticals and endogenous lipids. mEH has been most widely studied for its role in metabolism of xenobiotic and pharmaceutical compounds where it converts hydrophobic and reactive epoxides to hydrophilic diols that are more readily excreted. Inhibition or genetic disruption of mEH can be deleterious in the face of many industrial, environmental or pharmaceutical exposures and EPHX1 polymorphisms are associated with the development of exposure-related cancers. The role of mEH in endogenous epoxy-fatty acid (EpFA) metabolism has been less well studied. In vitro, mEH metabolizes most EpFAs at a far slower rate than soluble epoxide hydrolase (sEH) and has thus been generally considered to exert a minor role in EpFA metabolism in vivo. Indeed, sEH inhibitors or sEH-deficiency increase EpFA levels and are protective in animal models of cardiovascular disease. Recently, however, mEH was found to have a previously unrecognized and substantial role in EpFA metabolism in vivo. While few studies have examined the role of mEH in cardiovascular homeostasis, there is now substantial evidence that mEH can regulate cardiovascular function through regulation of EpFA metabolism. The discovery of a prominent role for mEH in epoxyeicosatrienoic acid (EET) metabolism, in particular, suggests that additional studies on the role of mEH in cardiovascular biology are warranted.Arboleda-Tham syndrome (OMIM#616268) is a newly named neurodevelopmental disorder, which is an autosomal dominant hereditary disease characterized by genetic variants. The clinical manifestations include global developmental delay, primary microcephaly, and craniofacial dysmorphism, as well as more varied features such as feeding difficulties, cardiac defects, and ocular anomalies. Currently, due to restricted knowledge of Arboleda-Tham syndrome and less specific pathological manifestations, it is difficult to diagnose at the early stages of the disease. Here, we present a case with obvious growth retardation and intellectual disability, accompanied by other manifestations including dysmorphic features of the ears, facial dysmorphism, right cryptorchidism, and inguinal hernia. Routine laboratory tests including blood-urine tandem mass spectrometry, urine gas chromatographic mass spectrometry, karyotype, echocardiography, automatic auditory brainstem responses, serum levels of calcium, phosphorus, vitamin D, creatine kinase (CK), and CK isoenzyme (CK-MB), and brain magnetic resonance imaging showed negative results. A de novo heterozygous variant in KAT6A, c.57delA (p.Val20*), was detected by trio-based whole exome sequencing and subsequent validation by Sanger sequencing in the patient, which was absent in both the parents. The patient received rehabilitation and nutritional intervention. The testis reduction and orchiopexy was scheduled when he was 1 year old. Our report extends the phenotype-genotype map of Arboleda-Tham syndrome, and also expands the mutant spectrum of the KAT6A gene. Moreover, this case emphasizes the timely conduction of whole exome sequencing for the early diagnosis of Arboleda-Tham syndrome, and spares patients from meaningless examinations and ineffective treatments.