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Elagolix sodium is a gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits endogenous GnRH signaling by competitively binding to GnRH receptors in the pituitary gland to treat moderate to severe pain associated with endometriosis. To keep the safety and quality of the drug, a fast quantitative method by reversed-phase ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry has been developed and validated for the identification, assay and estimation of potential genotoxic impurities trimethyl phosphate and triisopropyl phosphate in commercial batches of this active pharmaceutical ingredient in accordance with International Conference on Harmonization guidelines Q2 and M7. The method was validated by assessing specificity, sensitivity, linearity, the limit of quantification and detection, accuracy, precision and robustness for above analytes at a very low concentration, whose quantification and detection limits reached to 24 and 4.8 pg/ml, respectively, and the total run time for a single injection was 6 min.

Chronic pelvic pain (CPP) affects 2.1-24% of women, causing physical and psychological damage to women around the world. Based on the efficacy of gabapentin in the treatment of chronic pain, we conducted this study to evaluate the efficacy and safety of gabapentin in reducing pain in women with CPP.Systematic searches were performed in the electronic databases of PubMed, Embase, Web of Science, Scopus, Cochrane, and Clinicalkey databases. Studies focused on comparing the efficacy of gabapentin and placebo in the treatment of female CPP patients were included. RevMan 5.4 was used to analyze the results and risk of bias. Two investigators independently selected eligible studies and extracted related pain scores and side effects for meta-analysis.In total, 4 RCTs were enrolled in the meta-analysis, totaling 425 patients. Among patients receiving gabapentin, the average pain scores in 3 and 6 months were significantly lower than those in the placebo group(p0.00001). The results showed that there was no statistical difference between gabapentin and placebo in the reduction of pain scores from baseline(p = 0.41). The incidence of side effects in the gabapentin group was significantly higher than that in the placebo group (p0.00001).This systematic review and meta-analysis demonstrated that for women with CPP, gabapentin was significantly different from placebo in average pain scores at 3 and 6 months. However, the two drugs did not differ in the reduction in pain scores from baseline. Gabapentin can bring more significant side effects, whether they are common side effects or serious side effects.

Soy whey (SW) is generated as process waste while preparing soy protein isolates (SPI), and causing severe environmental pollution. Therefore, its value-added utilization is of prime importance for transforming and upgrading traditional industry. This study aims to utilize SW as a substrate for the growth of probiotics and produce a SW based synbiotics. By a series of trials, the effect of the dietary supplementation with this fermented SW (FSW) was analyzed on ICR mice's body weight, metabolites, and intestinal microbiota in 4 weeks. The results showed that, when SW was concentrated 15 times, the count of viable Lactobacillus casei reached 3.4 × 109 CFU/mL by liquid fermentation method, which was the highest viable cell count among all test strains. In this FSW, the protein, amino acid, total dietary fibre, soluble dietary fibre, and oligosaccharide were 2.10%, 1.63%, 0.52%, 0.51% and 0.79%, respectively. Compared to two control group, the total yields of the short chain fatty acids (SCFAs) were significantly improved (75%–125% at average), while the SCFAs structure was also significantly changed (especially acetic acid and butyrate) in the faeces of mice fed FSW. Meanwhile, FSW dietary addition was associated with the diversity and richness of the intestinal microbiota. Obviously, with mice's body weight loss, Firmicutes/Bacteroides ratio reduced accordingly (< 1.21), and the abundance of Akkermansia muciniphila was significantly increased (the maximum amount was about 0.013%). In summary, our results indicated that the dietary supplementation of FSW affected mice's intestinal microbiota and metabolism and improved their health profile.

Probiotics are widely used for various fields, such as agriculture, food, and treatment and so on. Akkermansia muciniphila, the candidate for next‐generation probiotics, is an intestinal bacterium that was isolated from a human fecal sample. It has been proved that A. muciniphila is closely related to multiple disease and metabolic disorders. What's more, its functions are not limited to intestinal diseases only, and even affect aging and cognition. Therefore, we would like to summarize the related research progress on A. muciniphila though this review, which help us to learn its role in the microbial networks, as well as to understand its positive impacts on the health of animals and human.

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been proven to improve the survival rate of gastric cancer and reduce peritoneal recurrence. We aimed to evaluate the effectiveness and safety of prophylacticHIPEC after radical gastric cancer surgery in this study. Methods: Researchers searched for studies published in PubMed, Embase, Web of science, Scopus, Cochrane, Clinicalkey databases and Microsoft Academic databases to identify studies that examine the impact of prophylactic HIPEC on the survival, recurrence and adverse events of patients undergoing radical gastric cancer surgery. RevMan 5.3 was used to analyze the results and risk of bias. The primary outcome of this review is the overall survival at 3 years follow-up. The secondary outcomes are the overall survival at 1- and 5-years follow-up, recurrence rate, complications and deaths due to recurrence after surgery. The PROSERO registration number is CRD42021262016. Findings: This meta-analysis included 19 studies with a total of 2097 patients, 12 of which are RCTs. The results showed that the 1-,3- and 5-year overall survival rate was significantly favorable to HIPEC (OR=5.10,2.47,1.96 respectively). Compared with the control group, the overall recurrence rate and peritoneal recurrence rate of the HIEPC group were significantly lower (OR=0.43,0.26 respectively). Significantly favorable to the control group in terms of renal dysfunction and pulmonary dysfunction complications (OR=2.44,6.03 respectively). Regarding the causes of death due to postoperative recurrence: liver recurrence, lymph node and local recurrence and peritoneal recurrence, the overall effect is not significantly different (OR=0.81,1.19,0.37 respectively). Interpretation: 1-,3-and 5-year overall survival follow-up can be incremented by the prophylactic HIPEC, and which can significantly reduce the overall recurrence rate and peritoneal recurrence rate. HIPEC can cause significant pulmonary dysfunction and renal dysfunction complications. No difference has been found in the deaths due to recurrence after surgery. Funding: None to declare. Declaration of Interest: None to declare.

1. S-EPA is a sulfur-substitution analog of epacadostat (EPA), an effective small molecule indoleamine 2,3-dioxgenase1 (IDO) inhibitor. By in vitro and in vivo experiments, pharmacokinetic differences of two closely related analogs, S-EPA and EPA was investigated in this study. 2. Liver microsomes clearance experiments showed S-EPA had comparable metabolic stability with EPA in rat and human liver microsomes. The whole blood distribution experiments showed the distribution ratio of S-EPA in blood cells to plasma in mice, rats, dogs and monkey was 1.2, 4.8, 2.2 and 40.6, respectively. While the distribution ratio of EPA ranged from 0.94 to 1.30 in mice, rats, dogs and was 3.1 in monkeys. 3. The pharmacokinetic study in rats showed the exposure (AUC

Aim: Tryptophan (Trp) and kynurnine (Kyn) are a pair of biomarkers for indoleamine 2,3-dioxygenase which closely related to the tumor immune escape. To evaluate the effect of drugs on the indoleamine 2,3-dioxygenase activity, the specific and accurate LC–MS/MS methods were developed and validated for simultaneous determination Kyn and Trp in mouse plasma and tumor tissues using surrogate analytes Kyn-d4 and Trp-d5 calibrators. Results: Plasma and tumor homogenates samples were pretreated with the solid phase extraction which assured the method having high recovery (>90% in plasma and >80% in tumor) and no matrix effect. The methods were validated for specificity, linearity, accuracy and precision, recovery, matrix effect and stability using surrogate analytes Kyn-d4 and Trp-d5 in authentic matrices. Conclusion: The validated methods have been successfully applied to the pharmacodynamic study of INCB024360 in CT26 tumor bearing mice after single dose and multiple dosing.

Rice bran polysaccharides (RBPSs) are the major active constituents of rice bran (RB). In this study, we utilized intracellular enzymes from Grifola frondosa to modify RBPSs, which were extracted from RB using ultrasound. To enhance the effect on natural killer (NK) cell cytotoxicity of modified polysaccharides (mRBPSs) generated from RBPSs, an orthogonal test (L9 [3]4 ) was employed to optimize the modification conditions. Based on the results of a single-factor test, the enzyme to polysaccharide ratio, reaction temperature, reaction pH, and reaction time were the main factors affecting mRBPSs-enhanced NK-cell cytotoxicity. The best conditions were determined to be an enzyme to polysaccharide ratio of 1:5, a reaction temperature of 40 °C, a reaction pH of 4, and a reaction time of 4 hr. By optimizing the conditions, the NK-cell cytotoxicity induced by mRBPSs6 was the highest, increasing by 12.01% ± 0.08%. Gas chromatographic analysis revealed that mRBPSs6 consists of rhamnose, arabinose, xylose, mannose, glucose, and galactose at a molar ratio of 7:21:6:5:53:48, which was 8:13:8:5:44:44 before modification. High-performance liquid chromatography results indicated molecular weights for the RBPSs of approximately 106 Da, which decreased to 104 to 105 Da after modification. Antioxidant activity tests revealed high capacity of mRBPSs6 for scavenging 1,1-diphenyl-2-picrylhydrazyl radicals and hydroxyl free radicals at 1.0 mg/mL. Practical application Rice bran polysaccharides (RBPSs) contain compounds with many biological activities. However, these polysaccharides difficult to absorb due to high molecular weights and unexposed active sites, which are the main factors that limit their use in functional foods. The results of this study demonstrate that modification of RBPSs using intracellular enzymes from an edible fungus alters the molecular weights and monosaccharide composition of RBPSs. In addition, immune and antioxidant activities of RBPSs were increased. The findings provide a new and beneficial application for rice bran.

Spinosad, a member of polyketide-derived macrolides produced in the actinomycete Saccharopolyspora spinosa, has been developed as a broad-spectrum and effective insecticide. The β-oxidation pathway could be an important source of building blocks for the biosynthesis of spinosad, thus the effect of vegetable oils on the production of spinosad in a high-yield strain was investigated. The spinosad production increased significantly with the addition of strawberry seed oil (511.64 mg/L) and camellia oil (520.07 mg/L) compared to the control group without oil (285.76 mg/L) and soybean oil group (398.11 mg/L). It also revealed that the addition of oils would affect the expression of genes involved in fatty acid metabolism, precursor supply, and oxidative stress. The genetically engineered strain, in which fadD1 and fadE genes of Streptomyces coelicolor were inserted, produced spinosad up to 784.72 mg/L in the medium containing camellia oil, while a higher spinosad production level (843.40 mg/L) was detected with the addition of 0.01 mM of thiourea.

Rice bran polysaccharides (RBPSs) are valuable compounds with many biological activities. In this work, a fungus called Grifola frondosa, was selected to ferment defatted rice bran water extracts and modify the RBPSs, which were then isolated by ethanol precipitation and deproteinization. GC analysis of fermented products suggested they are composed of glucose, arabinose, galactose, mannose, and xylose at a molar ratio of 9:5:8:2:5, which was 32:4:6:2:5 before fermentation. HPLC analysis revealed that the molecular weight of unfermented RBPS was distributed mainly from 103 to 104 Da, and it changed to 102 to 103 Da after fermentation. Antioxidant activities and effects on the production of NO were analyzed and it indicated that the scavenging ratios of hydroxyl and DPPH radicals by the fermented products were significantly enhanced compared to the unfermented ones, and also the products fermented for 9 days exhibited two-way adjusting effects on the production of NO in macrophages.

Prebiotics, which can serve as substrates for beneficial gut bacteria, have been shown to suppress harmful intestinal bacteria, regulate balance of gut microbial, and thus promote human and animal health. Cereal grains such as corn, wheat, rice, barley, and oats are potential economic sources to further develop new classes of prebiotics. In this chapter, prebiotic compounds, mostly polysaccharide components of the cereal grains, are discussed with respect to their occurrences, extraction, and enrichments, in the context of grain processing and by-product utilization. Results of in vitro and in vivo studies are also discussed in terms of use of the cereal grain fractions as prebiotics, their responses to foodborne pathogens, feeding amendments, and limiting colonization in the gastrointestinal tract. Economic and market opportunities as well as future research need are also included as topics of discussion.

Spinosad, a member of polyketide-derived macrolides produced in the actinomycete Saccharopolyspora spinosa, has been developed as a broad-spectrum and effective insecticide. The β-oxidation pathway could be an important source of building blocks for the biosynthesis of spinosad, thus the effect of vegetable oils on the production of spinosad in a high-yield strain was investigated. The spinosad production increased significantly with the addition of strawberry seed oil (511.64 mg/L) and camellia oil (520.07 mg/L) compared to the control group without oil (285.76 mg/L) and soybean oil group (398.11 mg/L). It also revealed that the addition of oils would affect the expression of genes involved in fatty acid metabolism, precursor supply, and oxidative stress. The genetically engineered strain, in which fadD1 and fadE genes of Streptomyces coelicolor were inserted, produced spinosad up to 784.72 mg/L in the medium containing camellia oil, while a higher spinosad production level (843.40 mg/L) was detected with the addition of 0.01 mM of thiourea.

Rice bran polysaccharides (RBPSs) are the major active constituents of rice bran (RB). In this study, we utilized intracellular enzymes from Grifola frondosa to modify RBPSs, which were extracted from RB using ultrasound. To enhance the effect on natural killer (NK) cell cytotoxicity of modified polysaccharides (mRBPSs) generated from RBPSs, an orthogonal test (LRice bran polysaccharides (RBPSs) contain compounds with many biological activities. However, these polysaccharides difficult to absorb due to high molecular weights and unexposed active sites, which are the main factors that limit their use in functional foods. The results of this study demonstrate that modification of RBPSs using intracellular enzymes from an edible fungus alters the molecular weights and monosaccharide composition of RBPSs. In addition, immune and antioxidant activities of RBPSs were increased. The findings provide a new and beneficial application for rice bran.

The photoinduced processes of phytochromes have received great research interest for their important biological functions. Phytochromobilin (PΦB), one of the most important phytochrome chromophores, was selected as the prototype to study its photoinduced isomerization. The nonadiabatic dynamics of PΦB from the Pr configuration in the gas phase was investigated by the surface hopping method at the OM2/MRCI level. In the excited state, isolated PΦB does not display the rotation of the two terminal five-membered rings (ring A and ring D), which is assumed to govern the Pr → Pfr process in the protein. Instead, two S1/S0 conical intersection seams (CI01α and CI01β) characterized by the rotation of the two central rings (ring B and ring C) were proven to play essential roles for the photoisomerization of PΦB in the gas phase. These two conical intersections (CI01α and CI01β) are accessible by the twisting motions of the C9-C10 and C10-C11 bonds, respectively. The CI01α and CI01β seams, instead of their minimum-energy points, are responsible for the nonadiabatic dynamics. For both channels, the trajectories may propagate forward to the isomerization products or backward to the original Pr configuration after the S1 → S0 hops.

Dimethylnitramine (DMNA) is a prototype system used in the investigation of the unimolecular decomposition mechanism of the nitramine-compound family. The photoinduced excited-state nonadiabatic processes and successive unimolecular dissociation of DMNA were investigated by trajectory surface-hopping dynamics at the semiempirical OM2/MRCI level. Two S-1/S-0 conical intersections (CI01 alpha and CI01 beta) were found to play essential roles in the nonadiabatic decay dynamics of DMNA. After the S-1 -> S-0 decay, the excess kinetic energy finally results in the cleavage of the N-N bond in the ground electronic state. The two reaction channels through CI01 alpha and CI01 beta show differences in molecular motions and decay features. The trajectories passing CI01 alpha can hop one or several times, and the intramolecular vibrational energy transfer in the ground state takes place before dissociation, whereas trajectories following the CI01 beta channel mainly dissociate directly after only one S-1 -> S-0 hop.

A newly developed reductive ring closure methodology to heteroacenes bearing a dihydropyrrolo[3,2-b]pyrrole core was systematically studied for its scope and limitation. The methodology involves (i) the cyclization of an o-aminobenzoic acid ester derivative to give an eight-membered cyclic dilactam, and (ii) the conversion of the dilactams into the corresponding diimidoyl chloride, which undergoes (iii) reductive ring closure to install the dihydropyrrolo[3,2-b]pyrrole core. The first step of the methodology plays the key role due to its substrate limitation, which suffers from the competition of oligomerization and hydrolysis. All the dilactams could successfully convert to the corresponding diimidoyl chlorides, most of which succeeded to give the dihydropyrrolo[3,2-b]pyrrole core. The influence of the substituents and the elongation of conjugated length on the photophysical properties of the obtained heteroacenes were then investigated systematically using UV-vis spectroscopy and cyclic voltammetry. It was found that chlorination and fluorination had quite a different effect on the photophysical properties of the heteroacene, and the ring fusing pattern also had a drastic influence on the band gap of the heteroacene. The successful preparation of a series of heteroacenes bearing a dihydropyrrolo[3,2-b]pyrrole core would provide a wide variety of candidates for further fabrication of organic field-effect transistor devices.

1,4-Diazapentalene heteroacenes are potential n-type semiconductors that could be used as a new type of material for organic field-effect transistors (OFETs), but their synthesis is still challenging due to their antiaromaticity. The study on their structure-stability relationship should provide useful guidance to the design of stable diazapentalenes. We examined the stability of several types of heteroacenes bearing the 1,4-diazapentalene core using NICS(1)zz calculations. The influence of the fusion pattern, the introduction of substituents, and the incorporation of other heterocycles on the antiaromaticity of the central 1,4-diazapentalene core was systematically studied. It was found that the linear fusion of aromatic rings to the antiaromatic core increases the stability of the heteroacene. The fusion of electron-poor heterocyclic rings also enhances the stability effectively, whereas the fusion of electron-rich heterocyclic rings destabilizes the system. In addition, the combination of the linear fusion pattern or introduction of electron-poor heterocyclic rings to the antiaromatic core reduces the reorganization energy for electron transport, suggesting a way to achieve better n-type semiconductors.

A stable unsubstituted 4nπ-electron acene with an antiaromatic 1,4-diazapentalene core was prepared via an unprecedented mild oxidation. Further investigation showed that the stability of such acenes was dependent on the fusion patterns of the peripheryl benzene rings to the centre core.