Bacteroides fragilis alleviates necrotizing enterocolitis through restoring bile acid metabolism balance using bile salt hydrolase and inhibiting FXR-NLRP3 signaling pathway.

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants with no specific treatments available. We aimed to identify the molecular mechanisms underlying NEC and investigate the therapeutic effects of Bacteroides fragilis on NEC. Clinical samples of infant feces, bile acid-targeted metabolomics, pathological staining, bioinformatics analysis, NEC rat model, and co-immunoprecipitation were used to explore the pathogenesis of NEC. Taxonomic characterization of the bile salt hydrolase (bsh) gene, enzyme activity assays, 16S rRNA sequencing, and organoids were used to explore the therapeutic effects of B. fragilis on NEC-related intestinal damage. Clinical samples, NEC rat models, and in vitro experiments revealed that total bile acid increased in the blood but decreased in feces. Moreover, the levels of FXR and other bile acid metabolism-related genes were abnormal, resulting in disordered bile acid metabolism in NEC. Taurochenodeoxycholic acid accelerated NEC pathogenesis and taurodeoxycholate alleviated NEC. B. fragilis displayed bsh genes and enzyme activity and alleviated intestinal damage by restoring gut microbiota dysbiosis and bile acid metabolism abnormalities by inhibiting the FXR-NLRP3 signaling pathway. Our results provide valuable insights into the therapeutic role of B. fragilis in NEC. Administering B. fragilis may substantially alleviate intestinal damage in NEC.

Substrate-Controlled Divergent Synthesis of Benzimidazole-Fused Quinolines and Spirocyclic Benzimidazole-Fused Isoindoles.

A Rh(III)-catalyzed annulation of 2-arylbenzimidazoles with α-diazo carbonyl compounds via C-H activation/carbene insertion/intramolecular cyclization is explored. The switchable product selectivity is achieved by the use of distinct α-diazo carbonyl compounds. Benzimidazole-fused quinolines are obtained through [4 + 2] annulation exclusively when 2-diazocyclohexane-1,3-diones are used, where they act as a C2 synthon. Alternatively, diazonaphthalen-1(2H)-ones merely function as a one-carbon unit synthon to generate a quaternary center through [4 + 1] cyclization to afford spirocyclic benzimidazole-fused isoindole naphthalen-2-ones. A thorough mechanistic study reveals the course of the reaction.

Gut microbiota dynamics and fecal SCFAs after colonoscopy: accelerating microbiome stabilization by Clostridium butyricum.

BACKGROUND: Colonoscopy is a classic diagnostic method with possible complications including abdominal pain and diarrhoea. In this study, gut microbiota dynamics and related metabolic products during and after colonoscopy were explored to accelerate gut microbiome balance through probiotics. METHODS: The gut microbiota and fecal short-chain fatty acids (SCFAs) were analyzed in four healthy subjects before and after colonoscopy, along with seven individuals supplemented with Clostridium butyricum. We employed 16S rRNA sequencing and GC-MS to investigate these changes. We also conducted bioinformatic analysis to explore the buk gene, encoding butyrate kinase, across C. butyricum strains from the human gut. RESULTS: The gut microbiota and fecal short-chain fatty acids (SCFAs) of four healthy subjects were recovered on the 7th day after colonoscopy. We found that Clostridium and other bacteria might have efficient butyric acid production through bioinformatic analysis of the buk and assessment of the transcriptional level of the buk. Supplementation of seven healthy subjects with Clostridium butyricum after colonoscopy resulted in a quicker recovery and stabilization of gut microbiota and fecal SCFAs on the third day. CONCLUSION: We suggest that supplementation of Clostridium butyricum after colonoscopy should be considered in future routine clinical practice.

Weizmannia coagulans BCF-01: a novel gastrogenic probiotic for Helicobacter pylori infection control.

The widespread prevalence of Helicobacter pylori infection, particularly in China, contributes to the development of gastrointestinal diseases. Antibiotics have limitations, including adverse reactions and increased antibiotic resistance. Therefore, identification of novel gastrogenic probiotics capable of surviving the acidic gastric environment and effectively combating H. pylori infection has potential in restoring gastric microbiota homeostasis. Five novel strains of human gastrogenic Weizmannia coagulans (BCF-01-05) were isolated from healthy gastric mucosa and characterized using 16S rDNA identification. Acid resistance, H. pylori inhibition, and adherence to gastric epithelial cells were evaluated in in-vitro experiments and the molecular mechanism explored in in-vivo experiments. Among the gastric-derived W. coagulans strains, BCF-01 exhibited the strongest adhesion and H. pylori inhibition, warranting further in-vivo safety evaluation. Through 16S rRNA sequencing of a mouse model, BCF-01 was determined to significantly restore H. pylori-associated gastric dysbiosis and increase the abundance of potential probiotic bacteria. Furthermore, BCF-01 enhanced mucosal tight junction protein expression and inhibited the TLR4-NFκB-pyroptosis signaling pathway in macrophages, as demonstrated by qRT-PCR and western blotting.These findings highlight the potential of BCF-01 in the prevention and control of H. pylori infection. Specifically, treatment with BCF-01 effectively restored gastric microecology and improved H. pylori-mediated mucosal barrier destruction while reducing inflammation through inhibition of the TLR4-NFκB-pyroptosis signaling pathway in macrophages. BCF-01 is a promising alternative to traditional triple therapy for H. pylori infections, offering minimal side effects with high suitability for high-risk individuals.

Rh(III)-Catalyzed Switchable [4 + 1] and [4 + 2] Annulation of N-Aryl Pyrazolones with Maleimides: An Access to Spiro Pyrazolo[1,2-a]indazole-pyrrolidine and Fused Pyrazolopyrrolo Cinnolines.

A rhodium(III)-catalyzed controllable [4 + 1] and [4 + 2] annulation of N-aryl pyrazolones with maleimides as C1 and C2 synthon has been explored for the synthesis of spiro[pyrazolo[1,2-a]indazole-pyrrolidines] and fused pyrazolopyrrolo cinnolines. The product selectivity was achieved through time-dependent annulation. The [4 + 1] annulation reaction involves sequential Rh(III)-catalyzed C-H alkenylation of N-aryl pyrazolone, followed by an intramolecular spirocyclization via aza-Michael-type addition to afford spiro[pyrazolo[1,2-a]indazole-pyrrolidine]. However, prolonged reaction time converts in situ formed spiro[pyrazolo[1,2-a]indazole-pyrrolidine] into fused pyrazolopyrrolocinnoline. This unique product formation switch proceeds via strain-driven ring expansion through a 1,2-shift of the C-C bond.

Lactobacillus casei SYF-08 Protects Against Pb-Induced Injury in Young Mice by Regulating Bile Acid Metabolism and Increasing Pb Excretion.

Pb poisoning affects infant growth and development. However, dimercaptosuccinic acid (DMSA) as the current therapy for Pb poisoning exerts relatively significant toxic side effects in infants. Therefore, identifying a non-toxic treatment in this regard is particularly important. In this study, we aimed to investigate the therapeutic effect of an infant feces-derived probiotic strain, Lactobacillus casei SYF-08 (SYF-08), on Pb poisoning in young mice. The Pb levels in the organisms were detected via inductively coupled plasma mass spectrometry, while the therapeutic effect of SYF-08 on Pb-induced neural system damage was explored via the Morris water maze test, hematoxylin-eosin staining, and immunohistochemistry. Additionally, the molecular mechanisms underlying the protective effects of SYF-08 against Pb-induced intestinal damage were also explored via histological staining, 16S rRNA sequencing, untargeted metabolomics, qRT-PCR, and western blotting. In vivo experiments revealed that SYF-08 reduced blood and bone Pb levels and increased urinary Pb excretion. Additionally, SYF-08 alleviated Pb-induced pathological damage to the brain and ultimately improved the learning and cognitive abilities of the young mice. This treatment also restored intestinal microflora dysbiosis, regulated bile acid metabolism, and inhibited the FXR-NLRP3 signaling pathway. It also resulted in fewer adverse events than the DMSA treatment. In conclusion, our results provided valuable insights into the therapeutic role of SYF-08 in Pb poisoning and also suggested that its administration can significantly alleviate the Pb-induced damage.

Lactobacillus plantarum WSJ-06 alleviates neurobehavioral injury induced by lead in mice through the gut microbiota.

Chronic lead exposure can result in cognitive dysfunction and behavioral disorders. However, the current treatments for alleviating lead poisoning have many side effects. Previous studies have suggested that probiotics may have the potential to ameliorate neurotoxicity caused by lead exposure. This study determines the alleviating effects of Lactobacillus plantarum WSJ-06 on neurological disorders induced by chronic lead exposure from the perspective of the gut microbiota and serum metabolites. The results showed that treatment with Lactobacillus plantarum WSJ-06 alleviated memory dysfunction and reduced the levels of inflammatory cytokines in the serum and hippocampus induced by lead exposure. In addition, Lactobacillus plantarum WSJ-06 partially restored the lead-induced gut microbiota dysbiosis. It also increased the proportion of some beneficial metabolites in the serum, such as arachidonic acid, tryptophan hydroxylase, serotonin, vitamin B12, trehalose, and kynurenic acid, and decreased some metabolites in the serum, such as LPS 20:5 and L-kynurenine. A correlation analysis further indicated that lead-induced neurobehavioral disorders were related to intestinal microbiota (the [Eubacterium]_siraeum_group, Roseburia, Lactobacillus, etc) and serum metabolites (LPS 20:5, serotonin, vitamin B12, etc). In conclusion, Lactobacillus plantarum WSJ-06 alleviated neuroinflammation and memory impairment caused by lead exposure by modulating the gut microbiota and metabolites in the serum.

Intrahepatic Cholestasis of Pregnancy Increases Inflammatory Susceptibility in Neonatal Offspring by Modulating Gut Microbiota.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that is characterized by increased bile acid levels in maternal serum. Studies have shown that cholestatic pregnancy can result in long-term metabolic disturbances in the offspring. However, how ICP shapes the offspring's immunity and predisposition to inflammatory disorders at an early stage is unknown. In this study, we investigated the effect of maternal cholestasis on neonatal offspring metabolism and immune function. We compared 71 neonates with ICP mothers and 63 neonates with healthy mothers and found that the incidence of jaundice and infection was significantly higher in ICP offspring. Maternal serum total bile acid level was associated with blood cell counts in full-term ICP offspring. In animal experiments, a compensatory activation of hepatic and ileal farnesoid X receptor (FXR) and altered gut microbiota in the first week were found in ICP offspring. We also investigated lipopolysaccharide (LPS)-induced inflammatory responses in neonatal rats and found that ICP offspring were more susceptible to inflammation. To understand the correlation between congenital abnormal FXR activation and tissue immunity dysregulation, we assessed the effects of the FXR agonist GW4064 and FXR antagonist E/Z-GS in ICP offspring after LPS exposure. The expression of several pro-inflammatory cytokines significantly decreased after treatment with E/Z-GS but increased after treatment with GW4064. Treatment with the probiotic Lactobacillus rhamnosus LRX01 that inhibits FXR expression in the ileum reduced susceptibility to LPS exposure in ICP offspring. The current study indicated that cholestatic pregnancy may increase the susceptibility of the offspring to inflammation by altering bile acid metabolism and gut microbiota at an early stage. We suggest that supplementation with Lactobacillus rhamnosus LRX01, which inhibits FXR expression in the ileum, may improve intestinal immunity in ICP offspring.

Brightly luminescent (NH4)xCs1-xPbBr3 quantum dots for in vitro imaging and efficient photothermal ablation therapy.

Herein, we report for the first time a facile strategy for the highly efficient (NH4)xCs1-xPbBr3 quantum dots (QDs). By modulating the amount of ammonium, (NH4)xCs1-xPbBr3 QDs with different photoluminescence (PL) quantum yields (QY) were synthesized. The results of X-ray diffraction and X-ray photoelectron spectroscopy showed that the crystal structure of (NH4)xCs1-xPbBr3 was altered by incorporation of NH4+ cations into the CsPbBr3 lattice. The (NH4)xCs1-xPbBr3 QDs showed enhanced PL QY, higher photostability, and long-term storage stability compared to CsPbBr3 QDs. Furthermore, (NH4)xCs1-xPbBr3 QDs could be conjugated with a photothermal dye (IR780) via a one-pot reaction using poly(styrene-co-maleic anhydride) and IR780-MPTS. To the best of our knowledge, the present work is the first attempt integrating perovskite QDs and phototherapeutic molecules into one system (abbreviated as PQD-IR780), demonstrating good water dispersibility and high photothermal conversion efficiency of 57.85%. In vitro experiments performed to examine subcellular uptake showed high fluorescence brightness was observed in HeLa, B16F1, and HepG2 cancer cells cultured with PQD-IR780. The results indicate that the internalization mechanism for uptaking of PQD-IR780 inside HeLa cells is energy-dependent and caveolin-mediated endocytosis. The in vitro cell viability assays and photothermal therapy revealed that PQD-IR780 showed good biocompatibility and can induce hyperthermia upon laser irradiation.

Photosensitizer-conjugated Cu-In-S heterostructured nanorods for cancer targeted photothermal/photodynamic synergistic therapy.

Photo-activated therapy is a non-invasive and promising medical technology for the treatment of cancers. Herein, we present Ce6-HA-CIS phototherapeutic nanohybrids composed of Cu-In-S (CIS) heterostructured nanorod (HS-rod), chlorin e6 (Ce6), and hyaluronic acid (HA) for the use in targeted photodynamic/photothermal therapy (PDT/PTT). In the Ce6-HA-CIS nanohybrids, the CIS HS-rod was investigated as a PTT agent to convert light into thermal energy, with Ce6 acting as a PDT agent to generate singlet oxygen (1O2). HA encapsulated the surface of the CIS HS-rod and aided the hydrophobic CIS HS-rod in achieving aqueous solubility. HA also acts as a tumor-specific targeting vector of cancer cells bearing the cluster determinant 44 receptor. Under light irradiation, the fabricated Ce6-HA-CIS nanohybrids exhibited high photothermal conversion efficiency, good photo-stability, and satisfactory photodynamic activity. In vitro and in vivo experiments demonstrated that Ce6-HA-CIS showed low cytotoxicity and synergistic photodynamic and photothermal cancer cell killing effects as compared to PTT or PDT agents alone. Therefore, these phototherapeutic nanohybrids may enhance cancer therapy in future clinical applications.

Role of cyclooxygenase-2 inhibitors in the survival outcome of colorectal cancer patients: A population-based cohort study.

The aim of this study is to investigate whether use of cyclooxygenase-2 (COX-2) inhibitors as auxiliary drug in colorectal cancer (CRC) patients will lead to better survival outcome. This population-based retrospective cohort study was conducted using the Taiwan National Health Insurance Research Database. The cohort consisted of newly diagnosed CRC adult patients during 2003-2010 with at least one prescription of nonsteroidal anti-inflammation drugs. Analysis groups were defined as users or nonusers of COX-2 inhibitors based on their usage prior to or 1 year after diagnosis of CRC. The outcome measurement was overall survival. The application of propensity scores through the inverse probability of treatment weighting (IPTW) was applied to the study groups. Subgroup analyses included stratification of different cancer site, treatment modalities, and first chemotherapy regimens. Kaplan-Meier estimates and Cox regressions were used to compare survival outcome. We identified 14,688 patients with newly diagnosed CRC. The adjusted hazard ratio (HR) with IPTW was 0.91 [95% confidence interval (CI), 0.86-0.96] in patients using COX-2 inhibitors in before and after diagnosis groups, and statistical significance was not reached for usages at only prior to or only after diagnosis. In subgroup analyses, patients with rectal cancer (adjusted HR with IPTW=0.86; 95% CI, 0.79-0.94) who received surgery followed by chemoradiation (adjusted HR with IPTW=0.57; 95% CI, 0.47-0.77) and with adjuvant chemotherapy of FOLFOX regimen (adjusted HR with IPTW=0.81; 95% CI, 0.67-0.99) had survival benefits in using COX-2 inhibitors both prior to and after diagnosis. Use of COX-2 inhibitors was found to be associated with reduction in mortality for CRC patients when taken both prior to and after cancer diagnosis.

Use of lithium and cancer risk in patients with bipolar disorder: population-based cohort study.

BACKGROUND: Lithium inhibits glycogen synthase kinase-3, which is an enzyme involved in the pathogenesis of cancer. AIMS: To investigate the association between lithium and cancer risk in patients with bipolar disorder. METHOD: A retrospective cohort study was designed using the National Health Insurance Research Database (NHIRD) in Taiwan. Patients using lithium comprised the index drug group and patients using anticonvulsants only comprised the control group. Time-dependent Cox regression was used to evaluate the hazard ratios (HRs) for risk of cancer. RESULTS: Compared with anticonvulsant-only exposure, lithium exposure was associated with significantly lower cancer risk (HR = 0.735, 95% CI 0.554-0.974). The hazard ratios for the first, second and third tertiles of the cumulative defined daily dose were 0.762 (95% CI 0.516-1.125), 0.919 (95% CI 0.640-1.318) and 0.552 (95% CI 0.367-0.831), respectively. CONCLUSIONS: Lithium is associated with reduced overall cancer risk in patients with bipolar disorder. A dose-response relationship for cancer risk reduction was observed.

Ultracompact wavelength and polarization splitters in periodic dielectric waveguides.

A wavelength splitter and a polarization splitter with high compactness and extremely simple structures are designed for optical communication wavelengths. Operation principle of the devices is based on directional coupling in two parallel periodic dielectric waveguides. The device performances have been evaluated by the finite-difference time-domain simulations. The wavelength splitter with a coupling region length of 5 mum can route 1.31 and 1.55 mum wavelengths to corresponding outputs with a transmittance of more than 93%, while the polarization splitter with a coupling region length of 4.6 mum can divide lightwaves in TM and TE polarizations with a degree of polarization higher than 90% at 1.55 mum.