Inulin alleviates perinatal 2-ethylhexyl diphenyl phosphate (EHDPHP) exposure-induced intestinal toxicity by reshaping the gut microbiota and suppressing the enteric-origin LPS/TLR4/NF-κb pathway in dams and pups.

Organophosphorus flame retardants (OPFRs), such as 2-ethylhexyl diphenyl phosphate (EHDPHP), are ubiquitously used, leading to pervasive environmental contamination and human health risks. While associations between EHDPHP and health issues such as disruption of hormones, neurotoxic effects, and toxicity to reproduction have been recognized, exposure to EHDPHP during perinatal life and its implications for the intestinal health of dams and their pups have largely been unexplored. This study investigated the intestinal toxicity of EHDPHP and the potential for which inulin was effective. Dams were administered either an EHDPHP solution or a corn oil control from gestation day 7 (GD7) to postnatal day 21 (PND21), with inulin provided in their drinking water. Our results indicate that inulin supplementation mitigates damage to the intestinal epithelium caused by EHDPHP, restores mucus-secreting cells, suppresses intestinal hyperpermeability, and abates intestinal inflammation by curtailing lipopolysaccharide leakage through reshaping of the gut microbiota. A reduction in LPS levels concurrently inhibited the inflammation-associated TLR4/NF-κB pathway. In conclusion, inulin administration may ameliorate intestinal toxicity caused by EHDPHP in dams and pups by reshaping the gut microbiota and suppressing the LPS/TLR4/NF-κB pathway. These findings underscore the efficacy of inulin as a therapeutic agent for managing health risks linked to EHDPHP exposure.

Maternal inulin supplementation ameliorates prenatal methamphetamine exposure-induced hepatotoxicity and restores gut microbiota in mouse offspring.

Prenatal exposure to methamphetamine (METH) is an issue of global concern due to its adverse effects on offspring, particularly its impact on liver health, an area still not fully understood. Inulin, a recognized prebiotic, is thought to potentially ameliorate these developmental disorders and toxic injuries in progeny. To investigate the effects of prenatal METH exposure on the liver and the role of gut microbiota, we established a murine model, the subjects of which were exposed to METH prenatally and subsequently treated with inulin. Our findings indicate that prenatal METH exposure causes liver damage in offspring, as evidenced by a decreased liver index, histopathological changes, diminished glycogen synthesis, hepatic dysfunction, and alterations in mRNA profiles. Furthermore, it impairs the antioxidant system and induces oxidative stress, possibly due to changes in cecal microbiota and dysregulation of bile acid homeostasis. However, maternal inulin supplementation appears to restore the gut microbiota in offspring and mitigate the hepatotoxic effects induced by prenatal METH exposure. Our study provides definitive evidence of METH's transgenerational hepatotoxicity and suggests that maternal inulin supplementation could be an effective preventive strategy.

Inulin alleviates neuroinflammation and oxidative stress induced by perinatal 2-ethylhexyl diphenyl phosphate (EHDPHP) exposure in female mice and offspring.

Organophosphorus flame retardants (OPFRs), including 2-ethylhexyl diphenyl phosphate (EHDPHP), are prevalent in everyday life due to their broad usage in fields such as healthcare, electronics, industry, and sports. These compounds, added to polymers through physical mixing, can leach into the environment, posing a risk to humans through direct contact or the food chain. Despite known associations with health issues like endocrine disruption, neurotoxicity, and reproductive toxicity, the implications of perinatal EHDPHP exposure on both mothers and offspring are still unclear. This study aimed to investigate the neuroinflammatory effects of EHDPHP and the potential mitigating role of inulin. Pregnant C57 mice were administered either a corn oil control or an EHDPHP solution (300 µg/kg bw/d) from gestation day 7 (GD7) to postnatal day 21 (PND21). Concurrently, mice were provided either regular drinking water or water supplemented with 1% inulin. We found that EHDPHP significantly increased the serum levels of IL-1ß, IL-6, and MDA, but decreased SOD levels in both mothers and pups. These effects were reversed by inulin supplementation. RNA-sequencing revealed that EHDPHP induced inflammation and oxidative stress through the TLR4/NF-κB pathway, which was mitigated by inulin. In conclusion, inulin ameliorated EHDPHP-induced neuroinflammation and oxidative stress in both mothers and offspring, highlighting its potential therapeutic role.

Gestational PCB52 exposure induces hepatotoxicity and intestinal injury by activating inflammation in dam and offspring mice: A maternal and progeny study.

Although Polychlorinated biphenyl (PCB) levels are decreased in the environment, the adverse effects of gestational exposure on the mother and offspring cannot be ignored due to the vulnerability of the fetus. In the present study, pregnant Balb/c mice were administered PCB52 (1 mg/kg BW/day) or corn oil vehicle by gavage until parturition. In the dams, PCB52 caused histopathological changes in the liver, higher serum levels of aminotransferase and alanine aminotransferase, and activated apoptosis and autophagy, suggesting hepatotoxicity. Overexpressed indicators of TLR4 pathway were observed in the liver of PCB52-exposed dams, indicated hepatic inflammation. Moreover, PCB52 exposure weakened the intestinal barrier and triggered inflammatory response, which might contribute to the hepatic inflammation by gut-liver axis. In the pups, prenatal PCB52 exposure affected the sex ratio at birth and reduced birth length and weights. Similar to the dams, prenatal PCB52 exposure induced hepatotoxicity in the pups without gender difference. Consistent with the alteration of gut microbiota, intestinal inflammation was confirmed, accompanying the disruption in the intestinal barrier and the activation of apoptosis and autophagy in the PCB52-exposed pups. Intestinal injury might be responsible for hepatotoxicity at least in part. Taken together, these findings suggested that gestational PCB52 exposure induced hepatic and intestinal injury in both maternal and offspring mice by arousing inflammation.

Corrigendum: Efficacy and Safety of Shenqu Xiaoshi Oral Liquid Compared With Domperidone Syrup in Children With Functional Dyspepsia.

[This corrects the article DOI: 10.3389/fphar.2022.831912.].

Efficacy and Safety of Shenqu Xiaoshi Oral Liquid Compared With Domperidone Syrup in Children With Functional Dyspepsia.

Background: Treatment of functional dyspepsia (FD) in children is generally symptomatic and unsatisfactory. Traditional Chinese medicines, such as Shenqu Xiaoshi Oral Liquid (SXOL), have been recommended to alleviate dyspeptic symptoms. However, evidence of their safety and efficacy remains limited to date. AIM: To assess whether 2 weeks of therapy with SXOL was non-inferior to domperidone syrup in children with FD. Methods: In this randomized, double-blind, double-simulated, non-inferiority, multi-center clinical trial, we recruited children (3-14 years) with FD according to the Rome IV criteria from 17 tertiary medical centers across China. Patients were randomly allocated (1:1) to receive SXOL or domperidone syrup for 2 weeks. We compared the participants' clinical scores from both groups based on the severity and frequency of dyspepsia symptoms according to Rome IV criteria (0, 1, 2, and 4 weeks after randomization). The primary endpoint was the total response rate, which was defined as the proportion of patients with a decrease of 30% or more in the FD symptoms clinical score from baseline, at the end of the 2-weeks treatment. A non-inferiority margin of -10% was set. Secondary endpoints and adverse events were assessed. This trial is registered with www.Chictr.org.cn, number ChiCTR1900022654. Results: Between February 2019 and March 2021, a total of 373 patients were assessed for eligibility, and 356 patients were enrolled and randomized. The clinical response rate at week two was similar for SXOL [118 (83.10%) of 142] and domperidone [128 (81.01%) of 158]; difference 2.09; 95% CI -6.74 to 10.71, thereby establishing non-inferiority. The total FD symptom scores were significantly improved in the two groups at 1-, 2-, and 4-weeks follow-up periods (p < 0.005). The decrease in symptom score compared with the baseline were similar between these two groups. Over the total study period, 10 patients experienced at least one treatment-related adverse event [six (3.37%)] in the SXOL group, four [(2.25%) in the domperidone group], although no serious adverse event was noted. Conclusion: Treatment with SXOL effectively improves dyspeptic symptoms and is well tolerated. In addition, it is not inferior to domperidone syrup and leads to sustained improvement in Chinese children with FD.

Fanconi-Bickel syndrome in an infant with cytomegalovirus infection: A case report and review of the literature.

BACKGROUND: Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder caused by mutation of the SLC2A2 gene, which encodes glucose transporter protein 2 (GLUT2). CASE SUMMARY: We report a 7-mo-old girl with cytomegalovirus infection presenting hepatomegaly, jaundice, liver transaminase elevation, fasting hypoglycemia, hyperglycosuria, proteinuria, hypophosphatemia, rickets, and growth retardation. After prescription of ganciclovir, the levels of bilirubin and alanine aminotransferase decreased to normal, while she still had aggravating hepatomegaly and severe hyperglycosuria. Then, whole exome sequencing was conducted and revealed a homozygous c.416delC mutation in exon 4 of SLC2A2 inherited from her parents, which was predicted to change alanine 139 to valine (p.A139Vfs*3), indicating a diagnosis of FBS. During the follow-up, the entire laboratory test returned to normal with extra supplement of vitamin D and corn starch. Her weight increased to normal range at 3 years old without hepatomegaly. However, she still had short stature. Although there was heterogeneity between phenotype and genotype, Chinese children had typical clinical manifestations. No hot spot mutation or association between severity and mutations was found, but nonsense and missense mutations were more common. Data of long-term follow-up were rare, leading to insufficient assessment of the prognosis in Chinese children. CONCLUSION: FBS is a rare genetic metabolic disease causing impaired glucose liver homeostasis and proximal renal tubular dysfunction. Results of urine and blood testing suggesting abnormal glucose metabolism could be the clues for FBS in neonates and infants. Genetic sequencing is indispensable for diagnosis. Since the diversity of disease severity, early identification and long-term follow-up could help improve patients' quality of life and decrease mortality.

[Clinical effect of alanyl-glutamine-enriched nutritional support in the treatment of children with abdominal Henoch-Schönlein purpura].

OBJECTIVE: To study the clinical effect of alanyl-glutamine-enriched nutritional support in the treatment of children with abdominal Henoch-Schönlein purpura. METHODS: Children with abdominal Henoch-Schönlein purpura who needed nutritional support were enrolled and stratified according to age, sex and the severity of disease, and were randomly divided into a control group (n=118) and an enriched nutritional support group (n=107). The control group was given nutritional support without using alanyl-glutamine, while the enriched nutritional support group was given alanyl-glutamine-enriched nutritional support. Intravenous steroids were used according to the severity of disease in both groups. Other therapies were the same in the two groups. The two groups were compared in terms of the length of hospital stay, the rate and duration of use of intravenous steroids, the recurrence rate of symptoms during hospitalization, the rate of total parenteral nutrition (TPN), the rate of weight loss and the rate of fasting for more than 5 days. All patients were followed up for 3 months after discharge to monitor the recurrence of symptoms. RESULTS: There were no significant differences in the length of hospital stay, the rate of TPN and the rate of fasting for more than 5 days between the two groups (P>0.05). Compared with the enriched nutritional support group, the control group showed significant increases in the rate and duration of use of intravenous steroids, the recurrence rate of symptoms and the rate of weight loss (P<0.05). After the 3-month follow-up, all the children resumed normal diet, and the recurrence rate of digestive symptoms was less than 20% in each group. Abdominal pain was the most common symptom (83.33%, 30/36), followed by vomiting and abdominal distention. No digestive hemorrhage was observed. All the symptoms were relieved after symptomatic treatment. No significant difference was found between the two groups in the recurrence rate of digestive symptoms (P=0.693). CONCLUSIONS: Alanyl-glutamine-enriched nutritional support in the treatment of children with abdominal Henoch-Schönlein purpura can reduce the use of intravenous steroids and weight loss, but without impact on the length of hospital stay and post-discharge recurrence.

Facile total synthesis of lysicamine and the anticancer activities of the RuII, RhIII, MnII and ZnII complexes of lysicamine.

Lysicamine is a natural oxoaporphine alkaloid, which isolated from traditional Chinese medicine (TCM) herbs and has been shown to possess cytotoxicity to hepatocarcinoma cell lines. Reports on its antitumor activity are scarce because lysicamine occurs in plants at a low content. In this work, we demonstrate a facile concise total synthesis of lysicamine from simple raw materials under mild reaction conditions, and the preparation of the Ru(II), Rh(III), Mn(II) and Zn(II) complexes 1-4 of lysicamine (LY). All the compounds were fully characterized by elemental analysis, IR, ESI-MS, 1H and 13C NMR, as well as single-crystal X-ray diffraction analysis. Compared with the free ligand LY, complexes 2 and 3 exhibited superior in vitro cytotoxicity against HepG2 and NCI-H460. Mechanistic studies indicated that 2 and 3 blocked the cell cycle in the S phase by decreasing of cyclins A2/B1/D1/E1, CDK 2/6, and PCNA levels and increasing levels of p21, p27, p53 and CDC25A proteins. In addition, 2 and 3 induced cell apoptosis via both the caspase-dependent mitochondrial pathway and the death receptor pathway. in vivo study showed that 2 inhibited HepG2 tumor growth at 1/3 maximum tolerated dose (MTD) and had a better safety profile than cisplatin.

Ethanol-extracted propolis enhances BBN-initiated urinary bladder carcinogenesis via non-mutagenic mechanisms in rats.

Ethanol-extracted propolis (EEP) is used for medical, dietetic and cosmetic purposes. In this study, the effects of EEP on urinary bladder carcinogenesis, its underlying mechanism and in vivo genotoxicity were investigated. In experiment 1, rats were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 2 or 4 weeks followed by dietary administration of 0.125, 0.25, 0.5 or 1% EEP for 4 or 32 weeks, respectively. At week 6, the mRNA levels of top2a, cyclin D1 and survivin were significantly elevated in the 0.5 and 1% EEP groups. At week 36, the incidence and multiplicity of urothelial carcinomas and total tumors were markedly elevated in all EEP groups. In experiment 2, rats were fed basal diet or the 1% EEP diet for 13 weeks without carcinogen initiation. Increases in urinary precipitate, cell proliferation and incidence of simple hyperplasia were observed in the 1% EEP group. In experiment 3, dietary administration of 2.5% EEP to gpt delta rats for 13 weeks did not induce any obvious mutagenicity in the urinary bladder urothelium. Taken together, EEP enhanced BBN-initiated rat urinary bladder carcinogenesis in a non-genotoxic manner through increasing formation of urinary precipitate, enhancing cell proliferation and inhibiting apoptosis during the early stages of carcinogenesis.

L-Leucine and L-isoleucine enhance growth of BBN-induced urothelial tumors in the rat bladder by modulating expression of amino acid transporters and tumorigenesis-associated genes.

We investigated the underlying mechanisms of L-leucine and L-isoleucine mediated promotion of bladder carcinogenesis using an initiation-promotion model. Rats were administered N-butyl-N-(4-hydroxybutyl) nitrosamine for 4 weeks and then fed AIN-93G basal diet or diet supplemented with L-leucine or L-isoleucine for 8 weeks followed by the basal diet for another 8 weeks. At the end of the experiment, week 20, there was a significant elevation of papillary and nodular (PN) hyperplasia multiplicity in the amino acid groups. L-Leucine and L-isoleucine transporters were up-regulated in PN hyperplasias and/or bladder tumors compared with concomitant normal-appearing bladder urothelium at weeks 12 and/or 20 in all groups. In addition, in normal-appearing bladder urothelium, significantly increased mRNA levels of y+LAT1, LAT2, LAT4, and 4F2hc were observed in the amino acid groups compared with the BBN control group at both weeks 12 and 20, and increased mRNA levels of LAT1 were observed at week 20. Furthermore, up-regulation of TNF-α, c-fos, ß-catenin, p53, p21(Cip1/WAF1), cdk4, cyclin D1 and caspase 3 in the amino acid groups was detected in normal-appearing bladder urothelium. Overall, our results indicate that supplementation with l-leucine or l-isoleucine enhanced growth of bladder urothelial tumors by triggering expression of amino acid transporters and tumorigenesis-associated genes.

Long-term treatment with L-isoleucine or L-leucine in AIN-93G diet has promoting effects on rat bladder carcinogenesis.

In the present study, effects of L-leucine and L-isoleucine on rat bladder carcinogenesis were investigated using AIN-93G and MF basal diet. In Experiment 1, N-butyl-N-(4-hydroxybutyl)-nitrosamine was used as an initiator of bladder carcinogenesis. In the AIN-93G diet groups, a significantly higher incidence and multiplicity of bladder tumors, accompanied by decreased final body weight, was observed in the L-leucine-supplemented group and a significantly higher incidence of papillomas and total tumors was observed in the L-isoleucine-supplemented group. In the MF diet groups, the multiplicity of papillary and nodular hyperplasia was significantly increased in the L-isoleucine-supplemented group. Urinary pH values were not affected by supplementing either type of diet with L-leucine or L-isoleucine. In Experiment 2, the amino acid was administered in the basal diets for 2 weeks without initiator. No pathological lesions were observed in the bladder urothelium in any of the groups, and no significant differences in urinary pH values, microcrystals or aggregates were observed between the amino acid-supplemented groups and their respective control groups. In conclusion, long-term treatment with L-leucine or L-isoleucine has a promoting effect on rat bladder carcinogenesis; therefore, their long-term use as a dietary supplement for bladder cancer patients should be avoided until more is known.

Dammar resin, a non-mutagen, induces [corrected] oxidative stress and metabolic enzymes in the liver of gpt delta transgenic mouse which is different from a mutagen, 2-amino-3-methylimidazo[4,5-f]quinoline.

Dammar resin has long been used in foods as either a clouding or a glazing agent. In a recent study, 2% Dammar resin showed significant hepatocarcinogenicity in a rat 2-year bioassay. Therefore, for an accurate estimate of human risk, it is necessary to understand whether Dammar resin induces liver genotoxicity and the underlying mechanisms of its hepatocarcinogenicity. Modifying effects of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), a typical genotoxic carcinogen produced during cooking of protein-rich foods, was also studied in the present study. Exposure of gpt delta mice to Dammar resin at a dose of 2% for 12 weeks did not induce any obvious mutagenicity in the liver. However, the index of cell proliferation, the level of 8-OHdG, and bax, bcl-2, p53, cyp1a2, cyp2e1, gpx1 and gstm2 gene expression were all significantly increased when compared with the control group. In the IQ treatment group, at a dose of 300ppm, mutagenicity was readily detected, the index of cell proliferation increased, and p53, cyp2e1 and gpx1 gene expression was down-regulated in the liver. Down-regulation of p53, P450s, and gpx1 in the livers of IQ treated mice are consistent with its genotoxic mechanism of carcinogenicity observed in a 675-day study. In contrast, our results using gpt delta mice suggest that Dammar resin is not genotoxic. Instead, the Dammar resin-induced hepatocarcinogenicity seen in our previous 2-year study with rats may have been mediated by non-genotoxic mechanisms, including increased P450 enzyme activity, increased oxidative stress, altered gene expression, and promotion of cell proliferation.

[Effects of soil factors on vegetation community structure in an abandoned subtropical paddy wetland].

Based on the investigation data from a subtropical wetland having been abandoned from paddy agriculture for one year, a redundancy analysis was conducted on the relationships between vegetation community and soil factors in the wetland. It was found that soil moisture regime, available K and P, and pH were the main factors affecting the distribution of plant species. The common plant species could be classified into three groups, i. e., Ludwigia prostrata - Murdannia triquetra group (G1), Hemarthria altissima - Rotala rotundifolia - Lapsana apogonoides group (G2), and Conyza canadensis - Polygonum hydropiper - Paspalum pasaloides group (G3). G1 mainly distributed on the soils with higher available K, G2 mainly distributed in periodically flooded area, while G3 mainly distributed in drainage area and was positively correlated to soil available P and pH. Species diversity and above-ground biomass had significant positive correlations with soil pH and total K, respectively, while evenness index was significantly negatively correlated with soil available N. No significant correlations were observed among other indices.

[Time series analysis of soil water on sloping land in red soil hilly region].

Based on time series analysis, the correlation between soil water and precipitation on the sloping land in red soil hilly region under two land use modes was studied from March to September, 2002-2004. The results showed that precipitation was not an autocorrelation series, while soil water at the depths of 10, 30, 50, 70 and 90 cm was an autocorrelation series with 30-45 days of time correlation range. Precipitation and land use mode were the main factors affecting the correlation of soil water and precipitation. The effect of precipitation weakened gradually with increasing soil depth. This effect lasted 7-8 days in upper soil layers (0-10 and 0-30 cm) , but no marked regularity was observed in deeper soil layers. 2-3 days after raining, precipitation had the most prominent effect on soil water in 0-100 cm soil layer. The correlation time range was 1-3 days shorter in dry season than in wet season. When it didn' t rain more than 5 days, the water content in topsoil would decrease, and even, lead to seasonal drought. Compared with farmland, tea plantation had a weaker correlation between soil water and precipitation in surface soil, but a stronger and more persistent correlation in soil layers below 50 cm.

[Responses of microbial biomass P to the changes of organic C and P in paddy soils under different fertilization systems].

Based on a fifteen years field experiment in double rice-cropping region of subtropical China, the responses of microbial biomass P (MB-P) to organic C and P in red paddy soils under different fertilization systems were investigated. The results indicated that a long-term input of organic carbon sources and the increasing soil organic carbon made soil microbial biomass remain at a high level (MB-C > 800 mg x kg(-1)), being a main reason of the increase of MB-P. Under long-term zero chemical P fertilization, there was a significant decrease in soil total P (P < 0.05), but soil organic P increased by 29.3% on average. The inorganic P forms in deficit were mainly Al-P, Fe-P, Ca-P and O-P, with the lowest content of Al-P (only 0.5 mg x kg(-1) on average). The content of soil MB-P under zero chemical P fertilization was much higher than that of Olsen-P. Correlation analysis showed that there was a significant relationship (P < 0.05) between MB-P and Al-P, from which, it was deduced that the utilization of Al-P, Fe-P, Ca-P and O-P by soil microbes could be the key approach of promoting these P forms transformed into available P. Chemical P fertilization combined with organic nutrient recycling could not only enlarge the soil P pool, but also improve the P availability.

[Clinical effect of garlic plaster on recurrent oral ulcer].

OBJECTIVE: To evaluate the clinical effects of garlic plaster on the recurrent oral ulcer (ROU). METHODS: The garlic powder was made by special method and made into garlic plaster including 0.1% garlicin. The plaster was painted on the surface of ROU to examine its clinical effect. The patients were followed up for 1 to 4 years. RESULTS: Of the 30 patients treated with garlic plaster, the complete effective rate was 83.3%, the partial effective rate was 16.7%, and the total effective rate was 100%. Fourteen patients did not recur 4 years after the treatment (46.7%). CONCLUSION: Garlic has a broad clinical prospect due to its effective treatment on ROU.