A new treatment step of bioelectrochemically treated leachate using natural clay adsorption towards sustainable leachate treatment.

Standalone and combined leachate treatment mechanisms suffer from low treatment efficiencies due to leachate's complex, toxic, and recalcitrant nature. Bioelectrochemical system (BES) was used for the first time to investigate the treatment of leachate mixed wastewater (WW) (i.e., diluted leachate, DL) (DL ≈ L:WW = 1:4) to minimize these complexities. A natural clay (palygorskite) was used as adsorbent material for further treatment on the BES effluent (EBES) while using two different masses and sizes (i.e., 3 g and 6 g of raw crushed clay (RCC) and 75 µ of sieved clay (75 µSC)). According to bioelectrochemical performance, BES, when operated with low external resistance (Rext = 1 Ω) (BES 1), showed a high removal of COD and NH3-N with 28% and 36%, respectively. On the other hand, a high Rext (100 Ω, BES 100) resulted in low removal of NH3-N with 10% but revealed high COD removal by 78.26%. Moreover, the 6 g doses of 75 µSC and RCC showed the maximum COD removals of 62% and 38% and showed the maximum removal of NH3-N with an average range of 40% for both sizes. After efficient desorption, both clay sizes resulted in regeneration performance which was observed with high COD (75%) and NH3-N (34%) on EBES. Therefore, when BES and clay adsorption technique sequentially treated and achieved with combined removal of ~ 98% for COD and ~ 80% of NH3-N, it demonstrated an efficient treatment method for DL treatment.

Modelling the significance of health values, beliefs and norms on the intention to consume and the consumption of organic foods.

The present research aims to extend the value-belief-norm model by including health values, health consciousness, healthy eating beliefs, and trust in organic food as the impelling factors. This study empirically tested the holistic framework to understand the important factors in consumers' decision-making processes concerning organic food consumption. A web-based survey was performed to collect data from a convenience sample of 571 organic food consuming university students in China. The hypotheses were tested using partial least square structural equation modelling (PLS-SEM). Based on the findings, health values and health consciousness had substantial impacts on healthy eating beliefs, which in turn positively affected personal norms and awareness of consequences. Additionally, awareness of consequences and ascription of responsibility had major effects on personal norms. Likewise, personal norms and trust in organic food had a profound influence on the intention to consume organic foods, which in turn significantly induced actual consumption. The findings not only provide novel insights for researchers to understand the aspects of organic food consumption but present a guideline for marketers to develop appropriate marketing tactics to grow the organic food business. This study recommends that policymakers should focus on increasing the awareness and knowledge of organic food, encouraging organic food production, and prioritising campaigns showcasing the unique health benefits of organic food to stimulate increased consumption.

Pharmacoinformatics and molecular dynamics simulation approach to identify anti-diarrheal potentials of Centella asiatica (L.) Urb. against Vibrio cholerae.

Vibrio cholerae, the etiological agent of cholera, causes dehydration and severe diarrhea with the production of cholera toxin. Due to the acquired antibiotic resistance, V. cholerae has drawn attention to the establishment of novel medications to counteract the virulence and viability of the pathogen. Centella asiatica is a medicinal herb native to Bangladesh that has a wide range of medicinal and ethnobotanical applications including anti-bacterial properties. In the present investigation, a total of 25 bioactive phytochemicals of C. asiatica have been screened virtually through molecular docking, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analyses, and molecular dynamics simulation. Our results revealed four lead compounds as Viridiflorol (-8.7 Kcal/mol), Luteolin (-8.1 Kcal/mol), Quercetin (-8.0 Kcal/mol) and, Geranyl acetate (-7.1 Kcal/mol) against V. cholerae Toxin co-regulated pilus virulence regulatory protein (ToxT). All the lead compounds have been found to possess favorable pharmacokinetic, pharmacodynamics, and molecular dynamics properties. Toxicity analysis revealed satisfactory results with no major side effects. Molecular dynamics simulation was performed for 100 ns that revealed noteworthy conformational stability and structural compactness for all the lead compounds, especially for Quercetin. Target class prediction unveiled enzymes in most of the cases and some experimental and investigational drugs were found as structurally similar analogs of the lead compounds. These findings could aid in the development of novel therapeutics targeting Cholera disease and we strongly recommend in vitro trials of our experimental findings.Communicated by Ramaswamy H. Sarma.

Investigating Polyphenol Nanoformulations for Therapeutic Targets against Diabetes Mellitus.

Diabetes mellitus (DM) is a fatal metabolic disorder, and its prevalence has escalated in recent decades to a greater extent. Since the incidence and severity of the disease are constantly increasing, plenty of therapeutic approaches are being considered as a promising solution. Many dietary polyphenols have been reported to be effective against diabetes along with its accompanying vascular consequences by targeting multiple therapeutic targets. Additionally, the biocompatibility of these polyphenols raises questions about their use as pharmacological mediators. Nevertheless, the pharmacokinetic and biopharmaceutical properties of these polyphenols limit their clinical benefit as therapeutics. Pharmaceutical industries have attempted to improve compliance and therapeutic effects. However, nanotechnological approaches to overcome the pharmacokinetic and biopharmaceutical barriers associated with polyphenols as antidiabetic medications have been shown to be effective to improve clinical compliance and efficacy. Therefore, this review highlighted a comprehensive and up-to-date assessment of polyphenol nanoformulations in the treatment of diabetes and vascular consequences.

Chemotherapeutic potential of hesperetin for cancer treatment, with mechanistic insights: A comprehensive review.

BACKGROUND: Cancer has become a significant concern in the medical sector with increasing disease complexity. Although some available conventional treatments are still a blessing for cancer patients, short-and long-term adverse effects and poor efficiency make it more difficult to treat cancer patients, demonstrating the need for new potent and selective anticancer drugs. In search of potent anticancer agents, naturally occurring compounds have always been admired due to their structural diversity, where Hesperetin (HSP) may be one of the potent candidates. PURPOSE: We aimed to summarize all sources, pharmacological properties, anticancer activities of HSP against numerous cancers types through targeting multiple pathological processes, mechanism of HSP on sensitizing the current anti-cancer agents and other phytochemicals, overcoming resistance pattern and determining absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox). METHODS: Information was retrieved from PubMed, Science Direct, and Google Scholar based on some key points like Hesperetin, cancer name, anticancer resistance, nanoformulation, and ADME/Tox was determined by in silico approaches. RESULT: HSP is a phytoestrogen present in citrus fruits in a high concentration (several hundred mg/kg) and exhibited anti-cancer activities through interfering at several pathways. HSP can suppress tumor formation by targeting several cellular proteins such as cell cycle regulatory, apoptosis, metastatic, tyrosine kinase, growth factor receptor, estrogen metabolism, and antioxidant-related protein.HSP has shown remarkable synergistic properties in combination therapy and has been reported to overcome multidrug cancer resistance drugs, leading to an improved defensive mechanism. These anticancer activities of HSP may be due to proper structural chemistry. CONCLUSION: Overall, HSP showed potential anticancer activities against all cancer and possess better pharmacokinetic properties. So this phytochemical alone or combination with other agents can be an effective alternative drug for cancer treatment.

Pharmacological Properties to Pharmacological Insight of Sesamin in Breast Cancer Treatment: A Literature-Based Review Study.

The use of dietary phytochemical rather than conventional therapies to treat numerous cancers is now a well-known approach in medical science. Easily available and less toxic dietary phytochemicals present in plants should be introduced in the list of phytochemical-based treatment areas. Sesamin, a natural phytochemical, may be a promising chemopreventive agent aiming to manage breast cancer. In this study, we discussed the pharmacological properties of sesamin that determine its therapeutics opportunity to be used in breast cancer treatment and other diseases. Sesamin is available in medicinal plants, especially in Sesamum indicum, and is easily metabolized by the liver. To better understand the antibreast cancer consequence of sesamin, we postulate some putative pathways related to the antibreast cancer mechanism: (1) regulation of estrogen receptor (ER-α and ER-ß) activities, (2) suppressing programmed death-ligand 1 (PD-L1) overexpression, (3) growth factor receptor inhibition, and (4) some tyrosine kinase pathways. Targeting these pathways, sesamin can modulate cell proliferation, cell cycle arrest, cell growth and viability, metastasis, angiogenesis, apoptosis, and oncogene inactivation in various in vitro and animal models. Although the actual tumor intrinsic signaling mechanism targeted by sesamin in cancer treatment is still unknown, this review summarized that this phytoestrogen suppressed NF-κB, STAT, MAPK, and PIK/AKT signaling pathways and activated some tumor suppressor protein in numerous breast cancer models. Cotreatment with γ-tocotrienol, conventional drugs, and several drug carriers systems increased the anticancer potentiality of sesamin. Furthermore, sesamin exhibited promising pharmacokinetics properties with less toxicity in the bodies. Overall, the shreds of evidence highlight that sesamin can be a potent candidate to design drugs against breast cancer. So, like other phytochemicals, sesamin can be consumed for better therapeutic advantages due to having the ability to target a plethora of molecular pathways until clinically trialed standard drugs are not available in pharma markets.

Investigations of AGEs' inhibitory and nephroprotective potential of ursolic acid towards reduction of diabetic complications.

In diabetes, interactions between AGEs (advanced glycation end products) and RAGEs (receptors of AGEs) are responsible for chronic complications and the current work reports the potential of ursolic acid as a RAGE inhibitor. The three-dimensional crystal structure of RAGE was first docked with target molecules by 'AutodockVina' using GROMOS 96 4381 parameters. Druggability and pharmacokinetic properties were calculated from the SwissADME server. In vitro bovine serum albumin (BSA)-glucose fluorescence and BSA-methylglyoxal fluorescence assays were also performed. Finally, alloxan-induced diabetic mice were administered ursolic acid and metformin standards (at 1, 50, 100 mg/kg) for 50 days. Blood glucose levels, several blood parameters, blood lipid profiles, supernatants of homogenized kidney and plasma of mice were examined. In the computational study, ursolic acid showed greater binding affinity (-7.5 kcal/mol) for RAGE with an ADMET profiles and lead-likeness compared to metformin as a standard antidiabetic. In the in vitro fluorescence assays, the IC50 value for ursolic acid was much less than that of metformin standard. During the in vivo study, significant reduction in the levels of blood glucose, HbA1C (glycated hemoglobin), creatinine, uric acid, BUN (blood urea nitrogen), AST (aspartate aminotransferase), ALT (alanine aminotransferase), ALP (alkaline phosphatase) were observed in the ursolic acid and metformin-treated mice. Substantial inhibition of AGEs' formation in the plasma and kidney were also detected. Finally, the histopathological examinations of the kidney revealed reversal of cellular necrosis. Hence, ursolic acid is proved to be a potent AGE inhibitory agent in managing the diabetic complications.

Determining the effect of aging, recovery time, and post-stroke memantine treatment on delayed thalamic gliosis after cortical infarct.

Secondary injury following cortical stroke includes delayed gliosis and eventual neuronal loss in the thalamus. However, the effects of aging and the potential to ameliorate this gliosis with NMDA receptor (NMDAR) antagonism are not established. We used the permanent distal middle cerebral artery stroke model (pdMCAO) to examine secondary thalamic injury in young and aged mice. At 3 days post-stroke (PSD3), slight microgliosis (IBA-1) and astrogliosis (GFAP) was evident in thalamus, but no infarct. Gliosis increased dramatically through PSD14, at which point degenerating neurons were detected. Flow cytometry demonstrated a significant increase in CD11b+/CD45int microglia (MG) in the ipsilateral thalamus at PSD14. CCR2-RFP reporter mouse further demonstrated that influx of peripheral monocytes contributed to the MG/Mϕ population. Aged mice demonstrated reduced microgliosis and astrogliosis compared with young mice. Interestingly, astrogliosis demonstrated glial scar-like characteristics at two years post-stroke, but not by 6 weeks. Lastly, treatment with memantine (NMDAR antagonist) at 4 and 24 h after stroke significantly reduced gliosis at PSD14. These findings expand our understanding of gliosis in the thalamus following cortical stroke and demonstrate age-dependency of this secondary injury. Additionally, these findings indicate that delayed treatment with memantine (an FDA approved drug) provides significant reduction in thalamic gliosis.

Dissolution and Vertical Transport of Uranium from Stable Mineral Forms by Plants as Influenced by the Co-occurrence of Uranium with Phosphorus.

Plants could mobilize (dissolution followed by vertical transport) uranium (U) from mineral forms that are otherwise stable. However, the variability of this plant-mediated mobilization of U as a function of the presence of various essential plant nutrients contained in these minerals remains unknown. A series of column experiments were conducted using Andropogon virginicus to quantify the vertical transport of U from stable mineral forms as influenced by the chemical and physical coexistence of U with the essential nutrient, phosphorus (P). The presence of plants significantly increased the vertical migration of U only when U was precipitated with P (UO2HPO4·4H2O; chernikovite) but not from UO2 (uraninite) that lacks any essential plant nutrient. The U dissolution was further increased when chernikovite co-occurred with a sparingly available form of P (FePO4) under P-limited growing conditions. Similarly, A. virginicus accumulated the highest amount of U from chernikovite (0.05 mg/g) in the presence of FePO4 compared to that of uraninite (no-P) and chernikovite supplemented with KH2PO4. These results signify an increased plant-mediated dissolution, uptake, and leaching of radioactive contaminants in soils that are nutrient deficient, a key factor that should be considered in management at legacy contamination sites.

Bone mineral density in children with relapsing nephrotic syndrome: A hospital-based study.

This cross-sectional analytical study was conducted from January 2012 to November 2014 in the Department of Pediatric Nephrology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh, to evaluate the bone mineral density (BMD) values in children with relapsing nephrotic syndrome (NS). Thirty relapsing nephrotic patients were enrolled in this study. They were divided into two groups: Group I - Frequent Relapse (FR) with 21 patients and Group II - Infrequent Relapse (IFR) with nine patients. Children included were both males and females aged between four and 15 years with relapsing NS with normal renal function. Steroid-resistant NS or those with abnormal renal functions or who were on cyclosporine and calcium supplement with Vitamin D or children with secondary NS were excluded from the study. All the study population underwent dual-energy X-ray absorptiometry scan to see the BMD value. Mean age of the patients of Group I (8.43 ± 2.61 years) was lower than that of Group II (9.41 ± 2.94 years (P = 0.4043). Mean BMD Z-scores of Group I was significantly lower than that of Group II (-2.70 ± 1.28 vs. -1.30 ± 1.54, respectively; P = 0.0317). A significantly higher cumulative dose of prednisolone was administered to Group I compared with Group II (P = 0.00003). On multivariate analysis, the total dose of prednisolone (P = 0.03693), body mass index (BMI) (P = 0.00703), and age of onset of disease (P = 0.03465) had a linear relationship with dependent variable BMD Z-score. On univariate regression analysis, statistically significant inverse relationship was observed between cumulative dose of prednisolone (in grams) (P = 0.049) and BMI (P = 0.00) with BMD Z-score, but no relation was observed with duration of illness. Children with relapsing NS, especially those receiving higher doses of steroids, were at risk for low BMD.

Nootropic and Anti-Alzheimer's Actions of Medicinal Plants: Molecular Insight into Therapeutic Potential to Alleviate Alzheimer's Neuropathology.

Medicinal plants are the backbone of modern medicine. In recent times, there is a great urge to discover nootropic medicinal plants to reverse cognitive dysfunction owing to their less adverse effects. Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the inevitable loss of cognitive function, memory and language impairment, and behavioral disturbances, which turn into gradually more severe. Alzheimer's has no current cure, but symptomatic treatments are available and research continues. The number of patients suffering from AD continues to rise and today, there is a worldwide effort under study to find better ways to alleviate Alzheimer's pathogenesis. In this review, the nootropic and anti-Alzheimer's potentials of 6 medicinal plants (i.e., Centella asiatica, Clitoria ternatea, Crocus sativus, Terminalia chebula, Withania somnifera, and Asparagus racemosus) were explored through literature review. This appraisal focused on available information about neuroprotective and anti-Alzheimer's use of these plants and their respective bioactive compounds/metabolites and associated effects in animal models and consequences of its use in human as well as proposed molecular mechanisms. This review progresses our existing knowledge to reveal the promising linkage of traditional medicine to halt AD pathogenesis. This analysis also avowed a new insight to search the promising anti-Alzheimer's drugs.

Effect of dietary n-3 fatty acids supplementation on fatty acid metabolism in atorvastatin-administered SHR.Cg-Leprcp/NDmcr rats, a metabolic syndrome model.

The effects of cholesterol-lowering statins, which substantially benefit future cardiovascular events, on fatty acid metabolism have remained largely obscured. In this study, we investigated the effects of atorvastatin on fatty acid metabolism together with the effects of TAK-085 containing highly purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ethyl ester on atorvastatin-induced n-3 polyunsaturated fatty acid lowering in SHR.Cg-Leprcp/NDmcr (SHRcp) rats, as a metabolic syndrome model. Supplementation with 10mg/kg body weight/day of atorvastatin for 17 weeks significantly decreased plasma total cholesterol and very low density lipoprotein cholesterol. Atorvastatin alone caused a subtle change in fatty acid composition particularly of EPA and DHA in the plasma, liver or erythrocyte membranes. However, the TAK-085 consistently increased both the levels of EPA and DHA in the plasma, liver and erythrocyte membranes. After confirming the reduction of plasma total cholesterol, 300mg/kg body weight/day of TAK-085 was continuously administered for another 6 weeks. Supplementation with TAK-085 did not decrease plasma total cholesterol but significantly increased the EPA and DHA levels in both the plasma and liver compared with rats administered atorvastatin only. Supplementation with atorvastatin alone significantly decreased sterol regulatory element-binding protein-1c, Δ5- and Δ6-desaturases, elongase-5, and stearoyl-coenzyme A (CoA) desaturase-2 levels and increased 3-hydroxy-3-methylglutaryl-CoA reductase mRNA expression in the liver compared with control rats. TAK-085 supplementation significantly increased stearoyl-CoA desaturase-2 mRNA expression. These results suggest that long-term supplementation with atorvastatin decreases the EPA and DHA levels by inhibiting the desaturation and elongation of n-3 fatty acid metabolism, while TAK-085 supplementation effectively replenishes this effect in SHRcp rat liver.

The effect of zinc supplementation on body composition and hormone levels related to adiposity among children: a systematic review.

OBJECTIVE: To provide a comprehensive synthesis of the effects of Zn supplementation on childhood body composition and adiposity-related hormone levels. DESIGN: Five electronic databases were searched for randomized controlled trials of Zn supplementation studies published before 28 February 2015. No statistical pooling of results was carried out due to diversity in study designs. SETTING: Community- or hospital-based, from fourteen developing and developed countries. SUBJECTS: Children and adolescents aged 0 to 10 years. RESULTS: Seven of the fourteen studies reported an overall or subgroup effect of Zn supplementation on at least one parameter of body composition, when determined by anthropometric measurements (increased mid upper-arm circumference, triceps skinfold, subscapular skinfold and mid upper-arm muscle area, and decreased BMI). Three out of the fourteen studies reported increased mean value of total body water estimated by bio-impedance analysis and increased fat-free mass estimated by dual energy X-ray absorptiometry and by total body water. Zn supplementation was associated with increased fat-free mass among stunted children. One study found supplementation decreased leptin and insulin concentrations. CONCLUSIONS: Due to the use of anthropometry when determining body composition, a majority of the studies could not accurately address whether alterations in the fat and/or fat-free mass components of the body were responsible for the observed changes in body composition. The effect of Zn supplementation on body composition is not consistent but may modify fat-free mass among children with pre-existing growth failure.

Household and personal factors are sources of heterogenity in intestinal parasite clearance among Mexican children 6-15 months of age supplemented with vitamin A and zinc.

A randomised, double-blind, placebo-controlled trial was carried out among Mexico children aged 6-15 months to determine how household characteristics modify vitamin A and zinc supplementation efficacy on Ascaris lumbricoides, Giardia intestinalis and Entamoeba histolytica/E. dispar infection durations. Children assigned to receive vitamin A every 2 months, a daily zinc supplement, a combined vitamin A-zinc supplement or a placebo were followed for 1 year. Parametric hazard models were fit to infection durations stratified by personal and household factors. Children supplemented with vitamin A and zinc combined from households lacking piped water and children in all three treatment arms from households with dirt floors had longer G. intestinalis and A. lumbricoides infection durations than their counterparts, respectively. Shorter E. histolytica/E.dispar durations were found among zinc-supplemented children of mothers who had <6 years of education and no indoor bathrooms. Heterogeneity in supplementation efficacy among children may reflect differences in exposure risk and baseline immune responses.

Exploring new pharmacology and toxicological screening and safety evaluation of one widely used formulation of Nidrakar Bati from South Asia region.

BACKGROUND: Nidrakar Bati (NKB) is an herbal remedy consisted with seven medicinal herbs widely used to cure Somnifacient (sleeping aid) in South Asia as Ayurvedic medicinal system. In the present study, pharmacological and toxicological effects of this medicine was investigated in mice to validate the safety and efficacy of the herb. METHODS: Organic solvent extracts NKB were prepared using maceration method. Effect of extracts on the central nervous system was evaluated using hypnotic activity assay. Effect of the extracts on metabolic activity, assessing involvement of thyroid was conducted using hypoxia test. analgesic and anti-inflammatory activities were assessed in mice using acetic acid induced writhing, formalin induced paw edema, xylene induced ear edema assays. Anxiolytic activity was performed using plus maze, climbing out and forced swimming tests. Effect of the extracts on psychopharmacological effect was carried out using locomotor activity tests (open field, Hole-board and Hole-cross tests). Neuropharmacological effect of the extracts was performed using motor coordination (rotarod test). Toxicological potential of the extract was evaluated using gastro-intestinal activity (gastric emptying and gastrointestinal motility tests). RESULTS: The studied formulation reduced the CNS stimulant effects dose independently. In the hypoxia test, only a dose of 100 mg/kg of NKB decreased the survival time. Orally administration of the NKB (200 and 400 mg/kg) produced significant inhibition (P < 0.01) of the acetic acid-induced writhing in mice and suppressed xylene induced ear edema and formalin-induced licking response of animals in both phases of the test. NKB showed locomotor activity (p < 0.05) both in higher and lower doses (100 and 400 mg/kg). NKB increased the total ambulation dose dependently (p < 0.05). NKB, at all tested doses (100, 200 and 400 mg/kg) increased some locomotion activity parameters (ambulation, head dipping and emotional defecation) in hole board test. At higher doses (200 and 400 mg/kg), NKB showed a significant increase in hole cross test. NKB showed an increase in the time on the open arms of the maze at low to medium doses (100 and 200 mg/kg). When using the Rotarod method, NKB showed a considerable increase on motor coordination of the mice. NKB produced marked gastric emptying effect and decreased gastrointestinal motility in mice at low dose. CONCLUSIONS: NKB demonstrated various pharmacological effects and toxicological effects due to presence of several herbs in the formulation those are not closely fit for the effect of CNS depressants.

Medicinal value of asiaticoside for Alzheimer's disease as assessed using single-molecule-detection fluorescence correlation spectroscopy, laser-scanning microscopy, transmission electron microscopy, and in silico docking.

BACKGROUND: Identifying agents that inhibit amyloid beta peptide (Aß) aggregation is the ultimate goal for slowing Alzheimer's disease (AD) progression. This study investigated whether the glycoside asiaticoside inhibits Aß1-42 fibrillation in vitro. METHODS: Fluorescence correlation spectroscopy (FCS), evaluating the Brownian diffusion times of moving particles in a small confocal volume at the single-molecule level, was used. If asiaticoside inhibits early Aß1-42 fibrillation steps, more Aßs would remain free and rapidly diffuse in the confocal volume. In contrast, "weaker or no inhibition" permits a greater number of Aßs to polymerize into oligomers, leading to fibers and gives rise to slow diffusion times in the solution. Trace amounts of 5-carboxytetramethylrhodamine (TAMRA)-labeled Aß1-42 in the presence of excess unlabeled Aß1-42 (10 µM) was used as a fluorescent probe. Steady-state and kinetic-Thioflavin T (ThT) fluorospectroscopy, laser-scanning fluorescence microscopy (LSM), and transmission electron microscopy (TEM) were also used to monitor fibrillation. Binding of asiaticoside with Aß1-42 at the atomic level was computationally examined using the Molegro Virtual Docker and PatchDock. RESULTS: With 1 h of incubation time for aggregation, FCS data analysis revealed that the diffusion time of TAMRA-Aß1-42 was 208 ± 4 µs, which decreased to 164 ± 8.0 µs in the presence of asiaticoside, clearly indicating that asiaticoside inhibited the early stages Aß1-42 of fibrillation, leaving more free Aßs in the solution and permitting their rapid diffusion in the confocal volume. The inhibitory effects were also evidenced by reduced fiber formation as assessed by steady-state and kinetic ThT fluorospectroscopy, LSM, and TEM. Asiaticoside elongated the lag phase of Aß1-42 fibrillation, indicating the formation of smaller amyloid species were impaired in the presence of asiaticoside. Molecular docking revealed that asiaticoside binds with amyloid intra- and inter-molecular amino acid residues, which are responsible for ß-sheet formation and longitudinal extension of fibrils. CONCLUSION: Finally, asiaticoside prevents amyloidogenesis that precedes neurodegeneration in patients with Alzheimer's disease.

Association of n-3 polyunsaturated fatty acids and inflammatory indicators with renal function decline in type 2 diabetes.

BACKGROUND & AIMS: The n-3 polyunsaturated fatty acids (PUFAs) and the inflammatory indicator, interleukin-6 (IL-6), have been implied in the development of renal dysfunction. This longitudinal study examined the effect of n-3 PUFAs and IL-6 on the risk of renal function decline and explored whether n-3 PUFAs modify the effect of inflammatory indicators on renal dysfunction risk in type 2 diabetes. METHODS: Studying 676 type 2 diabetic patients, we analyzed erythrocyte fatty acids and inflammatory markers in 2008 and estimated glomerular filtration rate (eGFR) in 2008 and 2012. Renal function decline was defined as an eGFR decline of ≥25% over a 4-year period. RESULTS: Multivariable logistic regression revealed erythrocyte total PUFAs, n-3 PUFAs, and n-3/n-6 PUFA ratio correlated negatively with risk of renal function decline (OR = 0.75, 0.78, and 0.61, respectively, all p < 0.01), while n-6 PUFAs did not. IL-6 independently predicted risk of renal dysfunction (OR = 1.18, p = 0.015). Stratifying erythrocyte PUFAs into low (<50(th) percentile) or high group (≥50(th) percentile), we found a positive association between IL-6 and risk of renal dysfunction only in the low n-3 PUFA (OR = 1.27, p = 0.035), low n-3/n-6 PUFA (OR = 1.27, p = 0.034), and low total PUFA groups (OR = 1.36, p = 0.005), but not in the high groups. CONCLUSIONS: High PUFA concentrations, especially n-3 or higher n-3/n-6 PUFA ratio, may exert protective effects against renal function impairment in type 2 diabetic patients. Whether the effect is mediated via modification of inflammatory biomarker such as IL-6 by high n-3 PUFA status warrants further investigation.

Omega-3 fatty acids protect renal functions by increasing docosahexaenoic acid-derived metabolite levels in SHR.Cg-Lepr(cp)/NDmcr rats, a metabolic syndrome model.

The omega-3 polyunsaturated fatty acids (ω-3 PUFAs) docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA) protect against diabetic nephropathy by inhibiting inflammation. The aim of this study was to assess the effects of highly purified DHA and EPA or EPA only administration on renal function and renal eicosanoid and docosanoid levels in an animal model of metabolic syndrome, SHR.Cg-Lepr(cp)/NDmcr (SHRcp) rats. Male SHRcp rats were divided into 3 groups. Control (5% arabic gum), TAK-085 (300 mg/kg/day, containing 467 mg/g EPA and 365 mg/g DHA), or EPA (300 mg/kg/day) was orally administered for 20 weeks. The urinary albumin to creatinine ratio in the TAK-085-administered group was significantly lower than that in other groups. The glomerular sclerosis score in the TAK-085-administered group was significantly lower than that in the other groups. Although DHA levels were increased in total kidney fatty acids, the levels of nonesterified DHA were not significantly different among the 3 groups, whereas the levels of protectin D1, resolvin D1, and resolvin D2 were significantly increased in the TAK-085-administered group. The results show that the use of combination therapy with DHA and EPA in SHRcp rats improved or prevented renal failure associate with metabolic syndrome with decreasing triglyceride levels and increasing ω-3 PUFA lipid mediators.

Vitamin A modifies the intestinal chemokine and cytokine responses to norovirus infection in Mexican children.

Vitamin A supplementation is associated with divergent clinical norovirus (NoV) outcomes in Mexican children. Fecal cytokine concentrations following NoV genogroup infections among 127 Mexican children 5-15 mo old enrolled in a randomized, double-blind, placebo-controlled, vitamin A supplementation trial were determined to clarify the role the gut immune response plays in these associations. Stools collected from supplemented children [20,000 IU retinol (3.3 IU = 1 µg retinol) for children < 12 mo of age; 45,000 iu for children ≥ 12 mo] or children in the placebo group were screened for NoV genogroups I (GI) and II (GII). Monocyte chemoattractant protein-1 (MCP-1), TNFα, IL-5, IL-6, IL-8, IL-4, IFNγ, and IL-10 fecal concentrations were also determined. Differences in cytokine levels between the 2 groups following GI and GII infections were determined using ordered logistic regression models. MCP-1 and IL-8 levels were greater among GI- and GII-infected children, respectively, compared with uninfected children, whereas IL-5 levels were greater following both genogroup infections. MCP-1, IL-8, and IL-6 fecal levels were reduced among supplemented children with GII-associated diarrhea compared with the placebo group. Vitamin A-supplemented, GII-infected children had reduced MCP-1 and TNFα levels compared with GII-infected children in the placebo group (P-interaction = 0.02 and 0.03, respectively). Supplemented children with GI-associated diarrhea had higher TNFα and IL-4 levels compared with children in the placebo group with diarrhea (P-interaction = 0.02 and 0.02, respectively). The divergent effects of supplementation on NoV outcomes may result from the different effects vitamin A has on the genogroup-specific immune responses.

Vitamin A supplementation modifies the association between mucosal innate and adaptive immune responses and resolution of enteric pathogen infections.

BACKGROUND: The efficacy of vitamin A supplementation on diarrheal disease morbidity may reflect the divergent effects that supplementation has on pathogen-specific immune responses and pathogen-specific outcomes. OBJECTIVE: We examined how vitamin A supplementation modified associations between gut-cytokine immune responses and the resolution of different diarrheal pathogen infections. DESIGN: Stools collected from 127 Mexican children who were 5-15 mo old and enrolled in a randomized, placebo-controlled vitamin A supplementation trial were screened for enteropathogenic Escherichia coli (EPEC), enterotoxigenic E. coli (ETEC), and Giardia lamblia. Fecal concentrations of interleukin (IL)-6, IL-8, IL-4, IL-5, IL-10, monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were measured by using an enzyme-linked immunosorbent assay. Hazard models that incorporated categorized cytokine variables (ie, nondetectable, less than the median of detectable concentrations, and at least the median of detectable concentrations) were fit to the length of pathogen infections stratified by treatment group. RESULTS: Vitamin A-supplemented children with fecal MCP-1 or IL-8 concentrations less than the median of detectable concentrations and IL-10 concentrations of at least median concentrations had longer durations of EPEC infection than did children in the placebo group. In supplemented children, detectable fecal TNF-α or IL-6 concentrations were associated with shorter ETEC infection durations, whereas MCP-1 concentrations of at least the median were associated with longer infection durations. Children in this group who had IL-4, IL-5, or IFN-γ concentrations of at least median detectable concentrations had shorter durations of G. lamblia infection. CONCLUSION: The effect of supplementation on associations between fecal cytokine concentrations and pathogen infection resolution depends on the role of inflammatory immune responses in resolving specific pathogen infections.