Contamination and ecological risk assessment of Cr, As, Cd and Pb in water and sediment of the southeastern Bay of Bengal coast in a developing country.

Safe levels of heavy metals in the surface water and sediment of the eastern Bay of Bengal coast have not been universally established. Current study characterized heavy metals such as arsenic (As), chromium (Cr), cadmium (Cd) and lead (Pb) in surface water and sediments of the most important fishing resource at the eastern Bay of Bengal coast, Bangladesh. Both water and sediment samples were analyzed using inductively coupled plasma mass spectrometer. Considering both of the seasons, the mean concentrations of Cr, As, Cd, and Pb in water samples were 33.25, 8.14, 0.48, and 21.14 µg/L, respectively and in sediment were 30.47, 4.48, 0.20, and 19.98 mg/kg, respectively. Heavy metals concentration in water samples surpassed the acceptable limits of usable water quality, indicating that water from this water resource is not safe for drinking, cooking, bathing, and any other uses. Enrichment factors also directed minor enrichment of heavy metals in sediment of the coast. Other indexes for ecological risk assessment such as pollution load index (PLI), contamination factor (CF), geoaccumulation index (Igeo), modified contamination degree (mCd), and potential ecological risk index (PERI) also indicated that sediment of the coastal watershed was low contamination. In-depth inventorying of heavy metals in both water and sediment of the study area are required to determine ecosystem health for holistic risk assessment and management.

Chinese medicine, Qijudihuang pill, mediates cholesterol metabolism and regulates gut microbiota in high-fat diet-fed mice, implications for age-related macular degeneration.

Background: Traditional Chinese Medicines have been used for thousands of years but without any sound empirical basis. One such preparation is the Qijudihuang pill (QP), a mixture of eight herbs, that has been used in China for the treatment of various conditions including age-related macular degeneration (AMD), the most common cause of blindness in the aged population. In order to explain the mechanism behind the effect of QP, we used an AMD model of high-fat diet (HFD) fed mice to investigate cholesterol homeostasis, oxidative stress, inflammation and gut microbiota. Methods: Mice were randomly divided into three groups, one group was fed with control diet (CD), the other two groups were fed with high-fat-diet (HFD). One HFD group was treated with QP, both CD and the other HFD groups were treated with vehicles. Tissue samples were collected after the treatment. Cholesterol levels in retina, retinal pigment epithelium (RPE), liver and serum were determined using a commercial kit. The expression of enzymes involved in cholesterol metabolism, inflammation and oxidative stress was measured with qRT-PCR. Gut microbiota was analyzed using 16S rRNA sequencing. Results: In the majority of the lipid determinations, analytes were elevated by HFD but this was reversed by QP. Cholesterol metabolism including the enzymes of bile acid (BA) formation was suppressed by HFD but again this was reversed by QP. BAs play a major role in signaling between host and microbiome and this is disrupted by HFD resulting in major changes in the composition of colonic bacterial communities. Associated with these changes are predictions of the metabolic pathway complexity and abundance of individual pathways. These concerned substrate breakdowns, energy production and the biosynthesis of pro-inflammatory factors but were changed back to control characteristics by QP. Conclusion: We propose that the ability of QP to reverse these HFD-induced effects is related to mechanisms acting to lower cholesterol level, oxidative stress and inflammation, and to modulate gut microbiota.

Inhibition of non-receptor tyrosine kinase LCK partially mitigates mixed granulocytic airway inflammation in a murine model of asthma.

Asthma affects millions of people worldwide and is one of the most common inflammatory airway diseases. Asthma phenotypes are quite complex and categorized as eosinophilic, mixed granulocytic (presence of both eosinophils and neutrophils in the airways) and neutrophilic. Mixed granulocytic asthma requires large doses of inhaled corticosteroids, which are often insufficient in controlling airway inflammation. Therefore, there is a medical need to test newer therapies to control granulocytic inflammation. Lymphocyte specific protein tyrosine kinase (LCK) signaling has gained momentum in recent years as a molecular target in inflammatory diseases such as asthma. LCK is expressed in lymphocytes and is required for inflammatory intracellular signaling in response to antigenic stimulation. Therefore, efficacy of LCK inhibitor, A770041 was tested in cockroach (CE)-induced corticosteroid insensitive murine model of asthma. The effect of LCK inhibitor was investigated on granulocytic airway inflammation, mucus production, p-LCK and downstream signaling molecules such as p-PLCγ, GATA3, p-STAT3 in CD4+ T cells. Moreover, its effects were also studied on Th2/Th17 related cytokines and oxidative stress parameters (iNOS/nitrotyrosine) in neutrophils/macrophages. Our study shows that CE-induced p-LCK levels are concomitant with increased neutrophilic/eosinophilic inflammation and mucus hypersecretion which are significantly mitigated by A770041 treatment. A770041 also caused marked attenuation of CE-induced pulmonary levels of IL-17A levels but not completely. However, A770041 in combination with dexamethasone caused complete downregulation of mixed granulocytic airway inflammation as well as Th2/Th17 related immune responses. These results suggest that combination of LCK inhibition along with corticosteroids may be pursued as an alternative strategy to completely treat mixed granulocytic asthma.

Butterbur (Petasites hybridus) Extract Ameliorates Hepatic Damage Induced by Ovalbumin in Mice.

The liver is the most vital organ that could be influenced by inducers of hypersensitivity such as ovalbumin. The current study was carried out to explore the effects of butterbur (Petasites hybridus) extract on the ovalbumin-induced liver hypersensitivity in Swiss albino male mice. Animals were divided into 4 groups, 1st group served as a control group, 2nd group treated with daily oral administration of 75 mg/kg of butterbur extract, 3rd group received single oral dose 100 mg/kg of ovalbumin to induce hypersensitivity, and 4th group treated with oral administration of butterbur extract one-day post to the hypersensitivity induction. Ovalbumin induces a significant increase in the activity of liver enzymes and MDA and decreased the activity of CAT after the ovalbumin treatment. Histopathological investigations revealed marked pathological alterations in liver tissues in the form of hyaline degeneration and fibrosis. Additionally, heavy immune response indicated by immunostaining of MDA and TNF-α could be observed. In contrast, posttreatment with butterbur extract after hypersensitivity induction resulted in a significant decrease of liver enzymes and oxidative stress and reduced the inflammation and fibrosis of liver tissues. These results suggest that butterbur extract is considered as anti-inflammatory and antioxidant therapeutic herb for hypersensitivity treatment of liver.

Inhibition of Bruton's tyrosine kinase and IL-2 inducible T-cell kinase suppresses both neutrophilic and eosinophilic airway inflammation in a cockroach allergen extract-induced mixed granulocytic mouse model of asthma using preventative and therapeutic strategy.

Asthma is a complex airways disease with a wide spectrum which ranges from eosinophilic (Th2 driven) to mixed granulocytic (Th2/Th17 driven) phenotypes. Mixed granulocytic asthma is a cause of concern as corticosteroids often fail to control this phenotype. Different kinases such as Brutons's tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) play a pivotal role in shaping allergic airway inflammation. Ibrutinib is primarily a BTK inhibitor, however it is reported to be an ITK inhibitor as well. In this study, we sought to determine the effect of Ibrutinib on Th1, Th17 and Th2 immune responses in a cockroach allergen extract (CE)-induced mixed granulocytic (eosinophilic and neutrophilic) mouse model in preventative mode. Ibrutinib attenuated neutrophilic inflammation at a much lower doses (25-75 µg/mouse) in CE-induced mixed granulocytic asthma whereas Th2/Th17 immune responses remained unaffected at these doses. However, at a much higher dose, i.e. 250 µg/mouse, Ibrutinib remarkably suppressed both Th17/Th2 and lymphocytic/neutrophilic/eosinophilic airway inflammation. At molecular level, Ibrutinib suppressed phosphorylation of BTK in neutrophils at lower doses and ITK in CD4 + T cells at higher doses in CE-treated mice. Further, effects of Ibrutinib were compared with dexamethasone on CE-induced mixed granulocytic asthma in therapeutic mode. Ibrutinib was able to control granulocytic inflammation along with Th2/Th17 immune response in therapeutic mode whereas dexamethasone limited only Th2/eosinophilic inflammation. Thus, Ibrutinib has the potential to suppress both Th17/Th2 and neutrophilic/eosinophilic inflammation during mixed granulocytic asthma and therefore may be pursued as alternative therapeutic option in difficult-to-treat asthma which is resistant to corticosteroids.

Protective effects of a natural herbal compound quercetin against snake venom-induced hepatic and renal toxicities in rats.

Echis pyramidum is a highly poisonous viper snake. Previous studies have shown acute phase hepatic and renal toxicities of Echis pyramidum venom (EPV) in rats. This study reports the protective effects of a natural herbal compound quercetin (QRC) on EPV-induced hepatic and renal toxicities in rats. A singly injection of EPV (4.76 mg/kg) caused significant increase in serum biomarkers of liver and kidney function. Pre-treatment of QRC (10 mg/kg) significantly reduced the toxic effects of EPV on functional impairment in liver and kidneys of rats. Administration of QRC also reversed EPV-induced increase in lipid peroxidation and decrease in total thiols. The histopathology of liver showed fat accumulation, focal degeneration and cytoplasmic vacuolation of hepatocytes in EPV treated rats. EPV also caused renal tubular dilation and focal atrophy of glomerular tufts in rat kidneys. Administration of QRC prevented EPV-induced structural tissue damage in liver and kidneys of rats. In conclusion, QRC significantly inhibited the acute phase toxic effects of EPV on liver and kidneys of rats by preventing the oxidative stress in these organs. QRC is also known for its anti-inflammatory, anti-edema, anti-hemorrhagic and PLA2-inhibitory properties and therefore may be regarded as a multi-action antidote against snake venom toxicity.

Protective effect of Atriplex suberecta extract against oxidative and apoptotic hepatotoxicity.

Atriplex suberecta I. Verd is a known phytomedicinal species of Atriplex; however, studies into its bioactivity remain inconclusive. The in vitro and in vivo antioxidative and hepatoprotective potential of A. suberecta ethanol-extract (ASEE) was assessed in the present study. 1,1-diphenyl-2-picrylhydrazyl radical scavenging and ß-carotene bleaching assays revealed that ASEE possesses free radical scavenging and anti-lipid peroxidative activities. These results were supported by the in vitro protection of HepG2 hepatoblastoma cells via abating 2,7-dichlorofluorescein-activated oxidative and apoptotic molecules (caspase-3/-7). In carbon tetrachloride-treated rats, the oral administration of ASEE significantly normalized serum biomarkers of liver function (serum glutamate oxaloacetate, serum pyruvate transaminase, alkaline phosphatase, γ-glutamyl transferase and bilirubin) and the lipid profile (total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides and malondialdehyde), including tissue non-protein sulfhydryl and total protein levels. These results were also supported by liver histopathology, which demonstrated that the therapeutic effect of ASEE was comparable to silymarin. Furthermore, phytochemical analysis of ASEE revealed the presence of flavonoids, alkaloids, tannins and saponins. Rutin, an antioxidant flavonoid, was identified using the validated high-performance thin-layer chromatography method. In conclusion, this is the first report on the therapeutic potential of A. suberecta against chemical-induced oxidative stress and liver damage.

Therapeutic efficacy of ethanolic extract of Aerva javanica aerial parts in the amelioration of CCl4-induced hepatotoxicity and oxidative damage in rats.

BACKGROUND: Liver diseases, the fifth most common cause of global death, can be metabolic, toxin-induced, or infective. Though approximately 35 Saudi medicinal plants are traditionally used to treat liver disorders, the hepatoprotective potential of Aerva javanica has not been explored. OBJECTIVE: To investigate the antioxidative and hepatoprotective effect of Aerva javanica. DESIGN: Total ethanol extract of A. javanica aerial parts was prepared and tested on DCFH-toxicated HepG2 cells ex vivo, and in CCl4-injured Wistar rats in vivo. MTT assay was used to determine cell viability and the serum biochemical markers of liver injury as well as histopathology was performed. In vitro 1,1-diphenyl-2-picrylhydrazyl and ß-carotene free-radical scavenging assay and phytochemical screening of the extract were done. Furthermore, A. javanica total extract was standardized and validated by high-performance thin layer chromatographic method. RESULTS: MTT assay showed that, while DCFH-injured cells were recovered to ~56.7% by 100 µg/ml of the extract, a 200 µg/ml dose resulted in hepatocytes recovery by ~90.2%. Oral administration of the extract (100 and 200 mg/kg.bw/day) significantly normalized the serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, gamma-glutamyl transferase, alkaline phosphatase, bilirubin, cholesterol, high-density lipoprotein, low-density lipoprotein, very-low-density lipoprotein, triglyceride, and malondialdehyde levels, including tissue nonprotein sulfhydryl and total protein in CCl4-injured rats. In addition, the histopathology of dissected liver also revealed that A. javanica cured the tissue lesion compared to silymarin treatment. In vitro assays revealed strong free-radical scavenging ability of the extract and presence of alkaloids, flavonoids, tannins, sterols, and saponins where rutin, a well-known antioxidant flavonoid, was identified. CONCLUSIONS: Our findings demonstrate the potential of A. javanica in the attenuation of ex vivo and in vivo hepatotoxicity and oxidative damage. This further suggests its therapeutic value in various liver diseases. However, isolations of the active principles, their mechanisms of action, and other therapeutic contributions remain to be addressed.

Secondary NAD+ deficiency in the inherited defect of glutamine synthetase.

Glutamine synthetase (GS) deficiency is an ultra-rare inborn error of amino acid metabolism that has been described in only three patients so far. The disease is characterized by neonatal onset of severe encephalopathy, low levels of glutamine in blood and cerebrospinal fluid, chronic moderate hyperammonemia, and an overall poor prognosis in the absence of an effective treatment. Recently, enteral glutamine supplementation was shown to be a safe and effective therapy for this disease but there are no data available on the long-term effects of this intervention. The amino acid glutamine, severely lacking in this disorder, is central to many metabolic pathways in the human organism and is involved in the synthesis of nicotinamide adenine dinucleotide (NAD(+)) starting from tryptophan or niacin as nicotinate, but not nicotinamide. Using fibroblasts, leukocytes, and immortalized peripheral blood stem cells (PBSC) from a patient carrying a GLUL gene point mutation associated with impaired GS activity, we tested whether glutamine deficiency in this patient results in NAD(+) depletion and whether it can be rescued by supplementation with glutamine, nicotinamide or nicotinate. The present study shows that congenital GS deficiency is associated with NAD(+) depletion in fibroblasts, leukocytes and PBSC, which may contribute to the severe clinical phenotype of the disease. Furthermore, it shows that NAD(+) depletion can be rescued by nicotinamide supplementation in fibroblasts and leukocytes, which may open up potential therapeutic options for the treatment of this disorder.

Glutamine supplementation in a child with inherited GS deficiency improves the clinical status and partially corrects the peripheral and central amino acid imbalance.

Glutamine synthetase (GS) is ubiquitously expressed in mammalian organisms and is a key enzyme in nitrogen metabolism. It is the only known enzyme capable of synthesising glutamine, an amino acid with many critical roles in the human organism. A defect in GLUL, encoding for GS, leads to congenital systemic glutamine deficiency and has been described in three patients with epileptic encephalopathy. There is no established treatment for this condition.Here, we describe a therapeutic trial consisting of enteral and parenteral glutamine supplementation in a four year old patient with GS deficiency. The patient received increasing doses of glutamine up to 1020 mg/kg/day. The effect of this glutamine supplementation was monitored clinically, biochemically, and by studies of the electroencephalogram (EEG) as well as by brain magnetic resonance imaging and spectroscopy.Treatment was well tolerated and clinical monitoring showed improved alertness. Concentrations of plasma glutamine normalized while levels in cerebrospinal fluid increased but remained below the lower reference range. The EEG showed clear improvement and spectroscopy revealed increasing concentrations of glutamine and glutamate in brain tissue. Concomitantly, there was no worsening of pre-existing chronic hyperammonemia.In conclusion, supplementation of glutamine is a safe therapeutic option for inherited GS deficiency since it corrects the peripheral biochemical phenotype and partially also improves the central biochemical phenotype. There was some clinical improvement but the patient had a long standing severe encephalopathy. Earlier supplementation with glutamine might have prevented some of the neuronal damage.