Visulization of peroxynitrite variation for accurate diagnosis and assessing treatment response of hepatic fibrosis using a Golgi-targetable ratiometric fluorescent probe.

Hepatic fibrosis (HF) is caused by persistent inflammation, which is closely associated with hepatic oxidative stress. Peroxynitrite (ONOO-) is significantly elevated in HF, which would be regarded as a potential biomarker for the diagnosis of HF. Research has shown that ONOO- in the Golgi apparatus can be overproduced in HF, and it can induce hepatocyte injury by triggering Golgi oxidative stress. Meanwhile, the ONOO- inhibitors could effectively relieve HF by inhibiting Golgi ONOO-, but as yet, no Golgi-targetable fluorescent probe available for diagnosis and assessing treatment response of HF through sensing Golgi ONOO-. To this end, we reported a ratiometric fluorescent probe, Golgi-PER, for diagnosis and assessing treatment response of HF through monitoring the Golgi ONOO-. Golgi-PER displayed satisfactory sensitivity, low detection limit, and exceptional selectivity to ONOO-. Combined with excellent biocompatibility and good Golgi-targeting ability, Golgi-PER was further used for ratiometric monitoring the Golgi ONOO- fluctuations and screening of ONOO- inhibitors from polyphenols in living cells. Meanwhile, using Golgi-PER as a probe, the overexpression of Golgi ONOO- in HF and the treatment response of HF to the screened rosmarinic acid were precisely visualized for the first time. Furthermore, the screened RosA has a remarkable therapeutic effect on HF, which may be a new strategy for HF treatment. These results demonstrated the practicability of Golgi-PER for monitoring the occurrence, development, and personalized treatment response of HF.

Efficacy and safety of endoscopic retrograde cholangiopancreatography in recurrent pancreatitis of pediatric asparaginase-associated pancreatitis.

BACKGROUND: Asparaginase (ASP) is an important drug in combined chemotherapy regimens for pediatric acute lymphoblastic leukemia (ALL); ASP-associated pancreatitis (AAP) is the main adverse reaction of ASP. Recurrent pancreatitis is a complication of AAP, for which medication is ineffective. AIM: To evaluate the efficacy and safety of endoscopic retrograde cholangiopancreatography (ERCP) in treating recurrent pancreatitis due to AAP. METHODS: From May 2018 to August 2021, ten children (five males and five females; age range: 4-13 years) with AAP were treated using ERCP due to recurrent pancreatitis. Clinical data of the ten children were collected, including their sex, age, weight, ALL risk grading, clinical symptoms at the onset of pancreatitis, time from the first pancreatitis onset to ERCP, ERCP operation status, and postoperative complications. The symptomatic relief, weight change, and number of pancreatitis onsets before and after ERCP were compared. RESULTS: The preoperative symptoms were abdominal pain, vomiting, inability to eat, weight loss of 2-7 kg, and 2-9 pancreatitis onsets. After the operation, nine of ten patients did not develop pancreatitis, had no abdominal pain, could eat normally; the remaining patient developed three pancreatitis onsets due to the continuous administration of ASP, but eating was not affected. The postoperative weight gain was 1.5-8 kg. There was one case of post ERCP pancreatitis and two cases of postoperative infections; all recovered after medication. CONCLUSION: ERCP improved clinical symptoms and reduced the incidence of pancreatitis, and was shown to be a safe and effective method for improving the management of recurrent pancreatitis due to AAP.

External use of mirabilite to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis in children: A multicenter randomized controlled trial.

BACKGROUND: Acute pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Currently, there is no suitable treatment for post-ERCP pancreatitis (PEP) prophylaxis. Few studies have prospectively evaluated interventions to prevent PEP in children. AIM: To assess the efficacy and safety of the external use of mirabilite to prevent PEP in children. METHODS: This multicenter, randomized controlled clinical trial enrolled patients with chronic pancreatitis scheduled for ERCP according to eligibility criteria. Patients were randomly divided into the external use of mirabilite group (external use of mirabilite in a bag on the projected abdominal area within 30 min before ERCP) and blank group. The primary outcome was the incidence of PEP. The secondary outcomes included the severity of PEP, abdominal pain scores, levels of serum inflammatory markers [tumor necrosis factor-alpha (TNF-α) and serum interleukin-10 (IL-10)], and intestinal barrier function markers [diamine oxidase (DAO), D-lactic acid, and endotoxin]. Additionally, the side effects of topical mirabilite were investigated. RESULTS: A total of 234 patients were enrolled, including 117 in the external use of mirabilite group and the other 117 in the blank group. The pre-procedure and procedure-related factors were not significantly different between the two groups. The incidence of PEP in the external use of mirabilite group was significantly lower than that in the blank group (7.7% vs 26.5%, P < 0.001). The severity of PEP decreased in the mirabilite group (P = 0.023). At 24 h after the procedure, the visual analog scale score in the external use of mirabilite group was lower than that in the blank group (P = 0.001). Compared with those in the blank group, the TNF-α expressions were significantly lower and the IL-10 expressions were significantly higher at 24 h after the procedure in the external use of mirabilite group (P = 0.032 and P = 0.011, respectively). There were no significant differences in serum DAO, D-lactic acid, and endotoxin levels before and after ERCP between the two groups. No adverse effects of mirabilite were observed. CONCLUSION: External use of mirabilite reduced the PEP occurrence. It significantly alleviated post-procedural pain and reduced inflammatory response. Our results favor the external use of mirabilite to prevent PEP in children.

Influence of Different Pretreatment Steps on the Ratio of Phenolic Compounds to Saccharides in Soluble Polysaccharides Derived from Rice Straw and Their Effect on Ethanol Fermentation.

The complex structure of rice straw is such that its bioconversion requires multiple physical and chemical pretreatment steps. In this study, it was found that a large amount of soluble polysaccharides (SPs) are formed during the pretreatment of straw. The yield of NaOH-based SPs (4.8%) was much larger than that of ball-milled SPs (1.5%) and H2SO4-based SPs (1.1%). For all the pretreatments, the ratio of phenolic compounds to saccharides (P/S) for each type of SPs increased upon increasing the concentration of ethanol in the order of 90% > 70% > 50%. The yield of NaOH-based SPs was much higher than that of acid-based and ball-milled SPs. The changes in the 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric reducing antioxidant power assay (FRAP), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) of SPs follow the same rule, i.e., the higher the P/S ratio, the higher the antioxidant values of the SPs. The flow cytometry and laser scanning microscopy results show that the P/S ratio can significantly influence the effect of SPs on microbial growth and cell membrane permeability. Upon varying the ethanol concentration in the range of 50-90%, the P/S ratio increased from 0.02 to 0.17, resulting in an increase in the promoting effects of the SPs on yeast cell growth. Furthermore, H2O2, NAD+/NADH, and NADP+/NADPH assays indicate that SPs with a high P/S ratio can reduce intracellular H2O2 and change the intracellular redox status.

Recent advances in anti-multidrug resistance for nano-drug delivery system.

Chemotherapy for tumors occasionally results in drug resistance, which is the major reason for the treatment failure. Higher drug doses could improve the therapeutic effect, but higher toxicity limits the further treatment. For overcoming drug resistance, functional nano-drug delivery system (NDDS) has been explored to sensitize the anticancer drugs and decrease its side effects, which are applied in combating multidrug resistance (MDR) via a variety of mechanisms including bypassing drug efflux, controlling drug release, and disturbing metabolism. This review starts with a brief report on the major MDR causes. Furthermore, we searched the papers from NDDS and introduced the recent advances in sensitizing the chemotherapeutic drugs against MDR tumors. Finally, we concluded that the NDDS was based on several mechanisms, and we looked forward to the future in this field.

Endoscopic retrograde cholangiopancreatography in children with symptomatic pancreaticobiliary maljunction: A retrospective multicenter study.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) has been widely used in pediatric patients with cholangiopancreatic diseases. AIM: To evaluate the efficacy, safety, and long-term follow-up results of ERCP in symptomatic pancreaticobiliary maljunction (PBM). METHODS: A multicenter, retrospective study was conducted on 75 pediatric patients who were diagnosed with PBM and underwent therapeutic ERCP at three endoscopy centers between January 2008 and March 2019. They were divided into four PBM groups based on the fluoroscopy in ERCP. Their clinical characteristics, specific ERCP procedures, adverse events, and long-term follow-up results were retrospectively reviewed. RESULTS: Totally, 112 ERCPs were performed on the 75 children with symptomatic PBM. Clinical manifestations included abdominal pain (62/75, 82.7%), vomiting (35/75, 46.7%), acholic stool (4/75, 5.3%), fever (3/75, 4.0%), acute pancreatitis (47/75, 62.7%), hyperbilirubinemia (13/75, 17.3%), and elevated liver enzymes (22/75, 29.3%). ERCP interventions included endoscopic sphincterotomy, endoscopic retrograde biliary or pancreatic drainage, stone extraction, etc. Procedure-related complications were observed in 12 patients and included post-ERCP pancreatitis (9/75, 12.0%), gastrointestinal bleeding (1/75, 1.3%), and infection (2/75, 2.7%). During a mean follow-up period of 46 mo (range: 2 to 134 mo), ERCP therapy alleviated the biliary obstruction and reduced the incidence of pancreatitis. The overall effective rate of ERCP therapy was 82.4%; seven patients (9.3%) were lost to follow-up, eight (11.8%) re-experienced pancreatitis, and eleven (16.2%) underwent radical surgery, known as prophylactic excision of the extrahepatic bile duct and hepaticojejunostomy. CONCLUSION: ERCP is a safe and effective treatment option to relieve biliary or pancreatic obstruction in symptomatic PBM, with the characteristics of minor trauma, fewer complications, and repeatability.

Fecal microbiota transplantation for refractory diarrhea in immunocompromised diseases: a pediatric case report.

BACKGROUND: Immunocompromised (IC) patients have an increased risk of refractory diarrhea. Fecal microbiota transplantation (FMT) is a safe and effective therapy for infection-related diarrhea which are mainly mediated by the loss of the microbial colonization, although there is concern that IC patients may be at higher risk of infectious complications related to FMT. And reports of FMT in IC children are limited. CASE PRESENTATION: We describe two cases of FMT in IC children with refractory diarrhea. One IC child had polyendocrinopathy, enteropathy, X-linked syndrome and the other child had graft-versus-host disease. Both of the children had a long course of diarrhea and no response to traditional treatment. FMT was performed on both patients via nasojejunal tubes under guidance of gastroduodenoscopy. After FMT, the patients achieved remission of symptoms and neither of them had related infectious complications. Microbiota analysis showed that FMT resulted in reconstruction of a diverse microbiota. CONCLUSIONS: Use of FMT is safe and effective in treatment of refractory diarrhea in IC children with a damaged microbiota.

Saccharides in straw hydrolysate decrease cell membrane damage by phenolics by inducing the formation of extracellular matrix in yeast.

The bioconversion of rice straw into ethanol can alleviate the energy crisis and solve problems related to waste treatment. In this study, the effect of soluble polysaccharides (SPs) produced during rice straw saccharification on the formation of extracellular matrices (EMs) by the yeast Saccharomyces cerevisiae was investigated. SPs were characterized by high-performance liquid chromatography (HPLC) and fourier transform infrared spectroscopy (FT-IR). SPs reduced the inhibition of alcohol dehydrogenase activity by phenolic acids (PAs) and regulated the intracellular redox state, resulting in higher ethanol production. The results of flow cytometry, confocal laser scanning microscopy, and atomic force microscopy indicated that PAs changed microbial morphology and caused damage in microbial cell membranes. The protective effect of SPs against cell membrane damage could be attributed to the synthesis of polysaccharide-dependent extracellular matrix, which maintained cellular integrity even under phenolic acid stress. These findings provide new strategies to improve pretreatment and saccharification processes.

Extraction of Flavonoids from the Saccharification of Rice Straw Is an Integrated Process for Straw Utilization.

To date, bioethanol is not economically competitive. One strategy to overcome this limitation is co-producing ethanol and high value-added products as an integrated process. The results of this study demonstrated that flavonoids could be extracted from rice straw, and the flavonoids apigenin and kaempferol were detected by HPLC. Compared with untreated straw, ball-milling slightly increased the total amount of flavonoids and antioxidant activity measured by ABTS, DPPH, and FRAP assays. The saccharification step in the bioconversion of straw strongly affected the extraction of flavonoids from straw. The residue obtained after saccharification of ball-milled straw for glucose production was more suitable for flavonoid extraction than untreated and ball-milled straw. The yield of flavonoids from the residue was 1.51-fold higher than that from untreated straw. The antioxidant activity of flavonoids derived from the residue was similar to that of flavonoid-rich biomasses such as rice bran and wheat bran. More importantly, saccharification may significantly affect the conditions of flavonoid extraction. In this respect, treatment with cellulase may reduce the extraction time from 2.0 to 0.5 h and the extraction temperature from 80 to 30 °C. Therefore, saccharification in the bioconversion of straw may be considered as an enzyme pretreatment step for the efficient extraction of flavonoids from straw, serving as a sustainable process for straw utilization.

Tapping the Bioactivity Potential of Residual Stream from Its Pretreatments May Be a Green Strategy for Low-Cost Bioconversion of Rice Straw.

In this study, it was found that the residual stream from pretreatments of rice straw exhibited high antioxidant activity. Assays based on the Folin-Ciocalteu colorimetric method confirmed that the residual stream contained large amounts of phenolic compounds. Three antioxidant assays were employed to evaluate the bioactivity of the residual stream. Strong linear correlations existed among the release of phenolic compounds, saccharification efficiency, and antioxidant activity. The alkaline pretreatment provided a much greater release of phenolic compounds, especially phenolic acids, compared to the acid pretreatment, and consequently, it had stronger linear correlations than the acid pretreatment. Antibacterial experiments demonstrated the ability of the phenolic compounds in the residual stream to inhibit the growth of microorganisms, indicating the potential of these compounds as antimicrobial agents. To discuss the possibility of the co-production of antimicrobial agents and biofuels/biochemicals, both acid and alkaline pretreatments were optimized using response surface methodology. Under the optimal conditions, 285.7 g glucose could be produced from 1 kg rice straw with the co-production of 3.84 g FA and 6.98 g p-CA after alkaline pretreatment. These results show that the recovery of phenolic compounds from the residual stream could be a green strategy for the low-cost bioconversion of rice straw.

Influence of rice straw-derived dissolved organic matter on lactic acid fermentation by Rhizopus oryzae.

Rice straw can be used as carbon sources for lactic acid fermentation. However, only a small amount of lactic acid is produced even though Rhizopus oryzae can consume glucose in rice straw-derived hydrolysates. This study correlated the inhibitory effect of rice straw with rice straw-derived dissolved organic matter (DOM). Lactic acid fermentations with and without DOM were conducted to investigate the effect of DOM on lactic acid fermentation by R. oryzae. Fermentation using control medium with DOM showed a similar trend to fermentation with rice straw-derived hydrolysates, showing that DOM contained the major inhibitor of rice straw. DOM assay indicated that it mainly consisted of polyphenols and polysaccharides. The addition of polyphenols and polysaccharides derived from rice straw confirmed that lactic acid fermentation was promoted by polysaccharides and significantly inhibited by polyphenols. The removal of polyphenols also improved lactic acid production. However, the loss of polysaccharides during the removal of polyphenols resulted in low glucose consumption. This study is the first to investigate the effects of rice straw-derived DOM on lactic acid fermentation by R. oryzae. The results may provide a theoretical basis for identifying inhibitors and promoters associated with lactic acid fermentation and for establishing suitable pretreatment methods.

Inhibitory effects of phenolic compounds of rice straw formed by saccharification during ethanol fermentation by Pichia stipitis.

In this study, it was found that the type of phenolic acids derived from rice straw was the major factor affecting ethanol fermentation by Pichia stipitis. The aim of this study was to investigate the inhibitory effect of phenolic acids on ethanol fermentation with rice straw. Different cellulases produced different ratios of free phenolic acids to soluble conjugated phenolic acids, resulting in different fermentation efficiencies. Free phenolic acids exhibited much higher inhibitory effect than conjugated phenolic acids. The flow cytometry results indicated that the damage to cell membranes was the primary mechanism of inhibition of ethanol fermentation by phenolic acids. The removal of free phenolic acids from the hydrolysates increased ethanol productivity by 2.0-fold, indicating that the free phenolic acids would be the major inhibitors formed during saccharification. The integrated process for ethanol and phenolic acids may constitute a new strategy for the production of low-cost ethanol.