Metabolome evidence of CKDu risks after chronic exposure to simulated Sri Lanka drinking water in zebrafish.

It is still a serious public health issue that chronic kidney disease of uncertain etiology (CKDu) in Sri Lanka poses challenges in identification, prevention, and treatment. What environmental factors in drinking water cause kidney damage remains unclear. This study aimed to investigate the risks of various environmental factors that may induce CKDu, including water hardness, fluoride (HF), heavy metals (HM), microcystin-LR (MC-LR), and their combined exposure (HFMM). The research focused on comprehensive metabolome analysis, and correlation with transcriptomic and gut microbiota changes. Results revealed that chronic exposure led to kidney damage and pancreatic toxicity in adult zebrafish. Metabolomics profiling showed significant alterations in biochemical processes, with enriched metabolic pathways of oxidative phosphorylation, folate biosynthesis, arachidonic acid metabolism, FoxO signaling pathway, lysosome, pyruvate metabolism, and purine metabolism. The network analysis revealed significant changes in metabolites associated with renal function and diseases, including 20-Hydroxy-LTE4, PS(18:0/22:2(13Z,16Z)), Neuromedin N, 20-Oxo-Leukotriene E4, and phenol sulfate, which are involved in the fatty acyls and glycerophospholipids class. These metabolites were closely associated with the disrupted gut bacteria of g_ZOR0006, g_Pseudomonas, g_Tsukamurella, g_Cetobacterium, g_Flavobacterium, which belonged to dominant phyla of Firmicutes and Proteobacteria, etc., and differentially expressed genes (DEGs) such as egln3, ca2, jun, slc2a1b, and gls2b in zebrafish. Exploratory omics analyses revealed the shared significantly changed pathways in transcriptome and metabolome like calcium signaling and necroptosis, suggesting potential biomarkers for assessing kidney disease.

Assessing food security performance from the One Health concept: an evaluation tool based on the Global One Health Index.

BACKGROUND: Food systems instantiate the complex interdependencies across humans, physical environments, and other organisms. Applying One Health approaches for agri-food system transformation, which adopts integrated and unifying approaches to optimize the overall health of humans, animals, plants, and environments, is crucial to enhance the sustainability of food systems. This study develops a potential assessment tool, named the global One Health index-Food Security (GOHI-FS), aiming to evaluate food security performance across countries/territories from One Health perspective and identify relevant gaps that need to be improved for sustainable food systems. METHODS: We comprehensively reviewed existing frameworks and elements of food security. The indicator framework of GOHI-FS was conceptualized following the structure-process-outcome model and confirmed by expert advisory. Publicly available data in 2020 was collected for each indicator. The weighting strategy was determined by the Fuzzy Analytical Hierarchy Process. The data for each indicator was normalized and aggregated by weighted arithmetic mean. Linear regressions were performed to evaluate the associations of GOHI-FS with health and social-economic indicators. RESULTS: The GOHI-FS includes 5 first-level indicators, 19 second-level indicators and 45 third-level indicators. There were 146 countries/territories enrolled for evaluation. The highest average score of first-level indicators was Nutrition (69.8) and the lowest was Government Support and Response (31.3). There was regional heterogeneity of GOHI-FS scores. Higher median scores with interquartile range (IQR) were shown in North America (median: 76.1, IQR: 75.5-76.7), followed by Europe and Central Asia (median: 66.9, IQR: 60.1-74.3), East Asia and the Pacific (median: 60.6, IQR: 55.5-68.7), Latin America and the Caribbean (median: 60.2, IQR: 57.8-65.0), Middle East and North Africa (median: 56.6, IQR: 52.0-62.8), South Asia (median: 51.1, IQR: 46.7-53.8), and sub-Saharan Africa (median: 41.4, IQR: 37.2-46.5). We also found significant associations between GOHI-FS and GDP per capita, socio-demographic index, health expenditure and life expectancy. CONCLUSIONS: GOHI-FS is a potential assessment tool to understand the gaps in food security across countries/territories under the One Health concept. The pilot findings suggest notable gaps for sub-Saharan Africa in numerous aspects. Broad actions are needed globally to promote government support and response for food security.

Multi-omics reveal mechanisms underlying chronic kidney disease of unknown etiology (CKDu) pathogenesis using zebrafish.

Chronic kidney disease of unknown etiology (CKDu) is an endemic disease in the dry zone of farming communities, Sri Lanka. The drinking water in a CKDu prevalent area contains a high concentration of F-, hardness and other environmental pollutants, including heavy metals and microcystin, which are considered possible etiology of CKDu in these areas. Here, multi-omics data with host transcriptome, metabolome and gut microbiomes were obtained using simulated local drinking water of Sri Lanka after their exposure to adult zebrafish. Based on an integrated multi-omics analysis in the context of host physiology in the kidney injury samples with different pathologic grades, two common pathways necroptosis and purine metabolism were identified as potentially important pathways that affect kidney injury. The key metabolite acetyl adenylate in the purine metabolism pathway was significantly positively correlated with Comamonas (rho = 0.72) and significantly negatively correlated with Plesiomonas (rho = -0.58). This crucial metabolite and two key gut bacteria genera may not only be potential markers but also potential therapeutic targets in the uric acid metabolic pathway, which is an important factor in the pathogenesis of acute kidney injury (AKI) in general, as well as of chronic kidney disease (CKD). Based on this, we revealed the urea metabolism pathway of kidney injury in zebrafish and provided a new avenue for the treatment of CKDu in Sri Lanka.

Probiotics mitigate kidney damage after exposure to Sri Lanka's local groundwater from chronic kidney disease with uncertain etiology (CKDu) prevalent area in zebrafish.

Groundwater in Sri Lanka, contaminated with environmental toxins, is suspected to potentially induce chronic kidney disease of uncertain etiology (CKDu) in humans. This study aims to elucidate the potential mitigating effects of probiotics on kidney damage induced by exposure to this local groundwater (LW) in zebrafish. We used zebrafish as a model organism and exposed them to local groundwater to evaluate the risk of CKDu. Probiotics were then added at a concentration of 108 colony-forming units per milliliter (CFU/mL). Our findings revealed that exposure to local groundwater resulted in abnormalities, such as tail deletion and spinal curvature in zebrafish larvae. However, the addition of probiotics mitigated these effects, improving the hatching rate, heart rate, length, weight, deformity rate, survival rate, and abnormal behavior of zebrafish. It also positively influenced the differential expression levels of kidney development and immunity-related genes (dync2h1, foxj1, pkd2, gata3, slc20a1, il1ß, and lyso). Furthermore, exposure to LW decreased both the diversity and abundance of microbiota in zebrafish larvae. However, treatment with probiotics, such as L. plantarum and L. rhamnosus partially restored the disrupted gut microbiota and significantly impacted the cellular process pathways of the microbial community, as determined by KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis. In conclusion, this study highlights the risks associated with Sri Lanka's local groundwater from a CKDu prevalent area and confirms the beneficial effects of different probiotics. These findings may provide new insights into bacterial function in host kidney health.

Elucidating environmental factors and their combined effects on CKDu in Sri Lanka using zebrafish.

Chronic kidney disease with uncertain etiology (CKDu) in Sri Lanka has attracted much attention as a global health issue. However, how environmental factors in local drinking water induce kidney damage in organisms is still elusive. We investigated multiple environmental factors including water hardness and fluoride (HF), heavy metals (HM), microcystin-LR (MC-LR), and their combined exposure (HFMM) to elucidate their toxic effects on CKDu risk in zebrafish. Acute exposure affected renal development and inhibited the fluorescence of Na, K-ATPase alpha1A4:GFP zebrafish kidney. Chronic exposure influenced the body weight of both genders of adult fish and induced kidney damage by histopathological analyses. Furthermore, the exposure significantly disturbed differential expression genes (DEGs), diversity and richness of gut microbiota, and critical metabolites related to renal functions. The transcriptomic analysis revealed that kidney-related DEGs were linked with renal cell carcinoma, proximal tubule bicarbonate reclamation, calcium signaling pathway, and HIF-1 signaling pathway. The significantly disrupted intestinal microbiota was closely related to the environmental factors and H&E score, which demonstrated the mechanisms of kidney risks. Notably, the Spearman correlation analysis indicated that the changed bacteria such as Pseudomonas, Paracoccus, and ZOR0006, etc were significantly connected to the DEGs and metabolites. Therefore, the assessment of multiple environmental factors provided new insights on "bio-markers" as potential therapies of the target signaling pathways, metabolites, and gut bacteria to monitor or protect residents from CKDu.

Exposure to Sri Lanka's local groundwater in a CKDu prevalent area causes kidney damage in zebrafish.

How local groundwater induces chronic kidney disease of unknown etiology (CKDu) in Sri Lanka is still elusive. This study aims to elucidate the impacts of Sri Lanka's local groundwater in a CKDu prevalent area and reveal the possible pathogenic mechanism of CKDu using zebrafish models. The drinking water from the local underground well in Vavuniya was sampled and the water quality parameters including Na+, Mg2+, K+, Ca2+, Cl-, NO3-, SO42-, and F- were analyzed. Then, local groundwater exposure to zebrafish larvae and 293T cells was performed, and water with high hardness and fluoride was prepared as parallel groups. Our result showed that exposure to Sri Lanka's local groundwater caused developmental toxicity, kidney damage, and pronephric duct obstruction as well as abnormal behavior in zebrafish. Similar results were also found after exposure to water with high hardness and fluoride in zebrafish. Further, the expression levels of marker genes related to renal development and functions (foxj1a, dync2h1, pkd2, gata3, and slc20a1) were significantly altered, which is also confirmed in the 293T cells. Taken together, those results indicated that Sri Lanka's local groundwater in a CKDu prevalent area could cause kidney damage, implying that high water hardness and fluorine might be the inducible environmental factors for the etiological cause of CKDu.

[Analysis of schistosomiasis endemic status of national surveillance sites in Yunnan Province, 2014].

OBJECTIVE: To master the dynamic endemic status and influencing factors of schistosomiasis in Yunnan Province, so as to provide the evidence for making the control and prevention measures. METHODS: Four villages of four schistosomiasis heavy endemic counties were selected as survey sites. Then, the serological screening and etiological tests were carried out in the residents, and the basic situations of the survey sites were investigated. The infection status of the livestock and relevant information of Oncomelania hupensis snails were surveyed. All the results were analyzed statistically. RESULTS: Totally 4310 residents were surveyed by the indirect hemagglutination assay with the examination rate of 79.68% and serum positive rate of 8.40%. The positive rate reached upwards 12.53% in Qiandian Village of Eryuan County. The serum positive rate of the female was higher than that of the male, and the positive rates of the 30 years and older age groups were higher than those of the other age groups. The serum positive rates of the peasants, migrant labourers and residents with the junior high school education level were higher. No positive feces were found. A total of 24 advanced cases were reported. No positive livestock and snails were found, and the average density of living snails was 0.023 3-0.056 6/0.1 m2. CONCLUSION: Right now, the schistosomiasis is at a low prevalence status in Yunnan Province, and the endemic situation has been effectively controlled.

Pharmacokinetic study of single and multiple oral dose administration of antofloxacin hydrochloride in healthy male volunteers.

BACKGROUND: A new fluroquinolone antibacterial agent, antofloxacin hydrochloride, developed in China, is an 8-NH(2) derivant of levofloxacin. The purpose of the study was to evaluate the pharmacokinetic characteristics of single and multiple oral doses of antofloxacin hydrochloride in Chinese healthy male volunteers. METHODS: An open-label, non-randomized, single and multiple dose clinical trial was conducted. In single dose study, 12 subjects took 200 mg antofloxacin hydrochloride. In multiple dose study, 12 subjects took antofloxacin hydrochloride 400 mg once on day 1 and 200 mg once daily from day 2 to day 7. HPLC was used to assay the serum and urinary concentrations of antofloxacin. RESULTS: In single dose study, the maximum concentration of drug in serum (C(max)), the time to reach C(max) (T(max)), and the area under the serum concentration-time curve (AUC (0-∞)) of antofloxacin were (1.89 ± 0.65) mg/L, (1.29 ± 0.26) hours, and (25.24 ± 7.26) mg×h(-1)×L(-1), respectively. Accumulating elimination rate of antoflocaxin from urine within 120 hours was 39.1%. In multiple dose study, blood concentration of antofloxiacin achieved stable state on day 2 after dosing. The minimum concentration drug in serum (C(min)), AUCss, mean concentration of drug in serum (C(av)), and degree of fluctuation (DF) were (0.73 ± 0.18) mg/L, (47.59 ± 7.85) mg×h(-1)×L(-1), (1.98 ± 0.33) mg/L, and 1.74 ± 0.60, respectively. On day 7 after dosing, T(max), C(max), and AUC (0-∞) was (1.14 ± 0.50) hours, (2.52 ± 0.38) mg/L, and (48.77 ± 8.44) mg×h(-1)×L(-1), respectively. Accumulating elimination rate of antofloxaxin from urine within 120 hours after the last dosing was 60.06%. CONCLUSIONS: The regimen of 400 mg loading dose given on the first treatment day and then 200 mg dose once daily results in satisfactory serum drug concentration.

Pharmacokinetics of multiple intravenous instillation of levofloxacin in Chinese healthy subjects.

AIM: To study the pharmacokinetics of multiple doses intravenous infusion of levofloxacin instillation in Chinese healthy volunteers. METHODS: Intravenous infusion of levofloxacin instillation 200 mg within 60 min was given to 10 male healthy volunteers for 7 d, on d 1 and d 7, once-daily, from 2-6 d twice-daily dosing. The concentrations of levofloxacin in serum and urine were assayed by HPLC. RESULTS: The main pharmacokinetic parameters af ter the first dosing were as follows: Cmax was (2.4+/-0.4) mg/L; AUC0- was (16.1 +/- 1.4) mg . h . L-1; T1/2beta was (6.3 +/- 0.3) h. The concentration in serum reached steady state within 72 h. The main parameters after the last dosing were as follows: Cssmax was (2.9 +/- 0.4) mg/L; Cssmin was (0.71 +/- 0.19) mg/L; Cav was (1.40 +/- 0.29) mg/L; AUCss0-12 was (17 +/- 3) mg . h . L-1; T1/2beta was (6.2 +/- 0.8) h. The 24-h cumulative urinary excretion rate was (88 +/- 5) %. From the calculation, the cumulative rate was 1.20; the fluctuation index was 1.30. The difference of T1/2beta and AUC between the first dosing and the last dosing was not significant, and the elimination rate of levofloxacin was not changed after multiple dosing. No clear adverse events were noted during this study. CONCLUSION: There was no accumulation of drug after the repeated intravenous infusion with 200 mg levofloxacin instillation for 7 d.