Atramacrolodes A-D (1-4), Four Undescribed Eudesmane-type Sesquiterpenes from the Rhizome of Atractylodes macrocephala.

Four undescribed sesquiterpenes, atramacrolodes A-D (1-4), along with six known compounds 5-10 were isolated from the rhizome of Atractylodes macrocephala. Compound 3 possessed a new skeleton based on an unprecedented carton-carton connection. Their structures were determined by UV, IR, HRESIMS, NMR spectra, 13C NMR calculation with DP4+ analysis, and the comparison of experimental and calculated ECD spectra. Compounds 5 and 8 showed protective effects against paracetamol-induced liver cell injury.

Hydrangea paniculata coumarins alleviate adriamycin-induced renal lipotoxicity through activating AMPK and inhibiting C/EBPß.

ETHNOPHARMACOLOGICAL RELEVANCE: Throughout Chinese history, Hydrangea paniculata Siebold has been utilized as a traditional medicinal herb to treat a variety of ailments associated to inflammation. In a number of immune-mediated kidney disorders, total coumarins extracted from Hydrangea paniculata (HP) have demonstrated a renal protective effect. AIM OF THE STUDY: To investigate renal beneficial effect of HP on experimental Adriamycin nephropathy (AN), and further clarify whether reversing lipid metabolism abnormalities by HP contributes to its renoprotective effect and find out the underlying critical pathways. MATERIALS AND METHODS: After establishment of rat AN model, HP was orally administrated for 6 weeks. Biochemical indicators related to kidney injury were determined. mRNAs sequencing using kidney tissues were performed to clarify the underlying mechanism. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis, western blot, molecular docking, and drug affinity responsive target stability (DARTS) assay was carried out to further explore and confirm pivotal molecular pathways and possible target by which HP and 7-hydroxylcoumarin (7-HC) played their renal protection effect via modulating lipid metabolism. RESULTS: HP could significantly improve renal function, and restore renal tubular abnormal lipid metabolism and interstitial fibrosis in AN. In vitro study demonstrated that HP and its main metabolite 7-HC could reduce ADR-induced intracellular lipid deposition and fibrosis characteristics in renal tubular cells. Mechanically, HP and 7-HC can activate AMP-activated protein kinase (AMPK) via direct interaction, which contributes to its lipid metabolism modulation effect. Moreover, HP and 7-HC can inhibit fibrosis by inhibiting CCAAT/enhancer binding protein beta (C/EBPß) expression in renal tubular cells. Normalization of lipid metabolism by HP and 7-HC further provided protection of mitochondrial structure integrity and inhibited the nuclear factor kappa-B (NF-κB) pathway. Long-term toxicity using beagle dogs proved the safety of HP after one-month administration. CONCLUSION: Coumarin derivates from HP alleviate adriamycin-induced lipotoxicity and fibrosis in kidney through activating AMPK and inhibiting C/EBPß.

New monoterpene phenol dimers from the fruits of Psoralea corylifolia.

Three new monoterpene phenol dimers, bisbakuchiols V-X (1-3), and two bakuchiol ethers (4 and 5), along with four known compounds (6-9) were isolated from the fruits of Psoralea corylifolia. Their structures were elucidated based on extensive spectral analysis. The absolute configurations of 1, 2, 4, and 5 were specified by quantum chemical calculations of ECD spectra.

[Effects of Straw Returning and Biochar Addition on Greenhouse Gas Emissions from High Nitrate Nitrogen Soil After Flooding in Rice-vegetable Rotation System in Tropical China].

In rice-vegetable rotation systems in tropical areas, a large amount of nitrate nitrogen accumulates after fertilization in the melon and vegetable season, which leads to the leaching of nitrate nitrogen and a large amount of N2O emission after the seasonal flooding of rice, which leads to nitrogen loss and intensification of the greenhouse effect. How to improve the utilization rate of nitrate nitrogen and reduce N2O emissions has become an urgent problem to be solved. Six treatments were set up [200 mg·kg-1 KNO3 (CK); 200 mg·kg-1 KNO3 + 2% biochar addition (B); 200 mg·kg-1 KNO3+1% peanut straw addition (P); 200 mg·kg-1 KNO3 + 2% biochar + 1% peanut straw addition (P+B); 200 mg·kg-1 KNO3 + 1% rice straw addition (R); 200 mg·kg-1 KNO3 + 2% biochar+1% rice straw addition (R+B)] and cultured at 25℃ for 114 d to explore the effects of organic material addition on greenhouse gas emissions and nitrogen use after flooding in high nitrate nitrogen soil. The results showed that compared with that in CK, adding straw or combining straw with biochar significantly increased soil pH (P<0.05). The B and P treatments significantly increased the cumulative N2O emissions by 41.6% and 28.5% (P<0.05), and the P+B, R, and R+B treatments significantly decreased the cumulative N2O emissions by 14.1%, 24.7%, and 36.7% (P<0.05), respectively. The addition of straw increased the net warming potential of greenhouse gases (NGWP). The addition of coir biochar significantly reduced the effect of straw on NGWP (P<0.05). The combined application of straw and biochar decreased NGWP, and P+B significantly decreased NGWP, but that with R+B was not significant (P>0.05). Adding straw or biochar significantly increased soil microbial biomass carbon (MBC) (P<0.05), and that of P+B was the highest (502.26 mg·kg-1). The combined application of straw and biochar increased soil microbial biomass nitrogen (MBN), and that of P+B was the highest. The N2O emission flux was negatively correlated with pH (P<0.01) and positively correlated with NH4+-N and NO3--N (P<0.01). The cumulative emission of N2O was negatively correlated with MBN (P<0.05). There was a significant negative correlation between NO3--N and MBN (P<0.01), indicating that the reduction in NO3--N was likely to be held by microorganisms, and the increase in the microbial hold of NO3--N also reduced N2O emission. In conclusion, the combined application of peanut straw and coconut shell biochar could significantly inhibit N2O emission and increase soil MBC and MBN, which is a reasonable measure to make full use of nitrogen fertilizer, reduce nitrogen loss, and slow down N2O emission after the season of Hainan vegetables.

[Safe Utilization Effect of Passivator on Mild to Moderate Cadmium Contaminated Farmland].

In order to study the safe utilization of acid cadmium （Cd） contaminated soil， light and moderate Cd-contaminated farmland in Shangluo， Shaanxi Province was taken as the research object， and lime， biochar， and calcium magnesium phosphate fertilizer were applied. Through the wheat-maize rotation experiment， the safe utilization effect of different amounts of passivator on Cd-contaminated soil was explored， and the best ratio of passivator was selected. The results showed that： ① the soil quality could be improved to varying degrees by applying the passivator. ② After the application of amendments， the grain yield of wheat and maize increased to different degrees. ③ The lime 2 340 kg·hm-2 （C3） treatment had the best effect， which increased the soil pH of wheat and corn by 1.453 and 1.717 units， respectively， and reduced the available Cd content by 34.38% and 30.20%， respectively. ④ The application of biochar 1 800 kg·hm-2 （B2） treatment had the best effect on reducing the Cd contents in wheat roots， straws， and grains， which were significantly reduced by 53.60%， 38.86%， and 52.96%， respectively， compared with that in CK. The Cd content in wheat grains was reduced to 0.09 mg·kg-1， which was lower than the limit value of wheat Cd （0.1 mg·kg-1） specified in the "National food safety standard food pollutant limit" （GB 2762-2017）. The application of the biochar 1 260 kg·hm-2 （B1） treatment had the best comprehensive effect on reducing the Cd contents of maize roots， straws， and grains， which were significantly reduced by 43.74%， 53.20%， and 94.57%， respectively， compared with that in CK. The Cd content of maize grains was reduced to 0.001 9 mg·kg-1， which was far lower than the limit value of maize Cd （0.1 mg·kg-1） specified in the "National food safety standard food pollutant limit" （GB 2762-2017）. Therefore， under the conditions of the field experiment， considering the influence of various indexes， biochar had the best effect on farmland soil in the wheat-maize rotation area with mild to moderate Cd pollution.

Previously undescribed tetrahydroanthraquinones from Prismatomeris tetrandra (roxb.) K. Schum with antitumor cell proliferation activities.

To find structurally previously undescribed compounds with pharmacological effects from Prismatomeris tetrandra (Roxb.) K. Schum (Rubiaceae), thirteen undescribed tetrahydroanthraquinones (1⎼13) named prisconnatanones J⎼V and seven known anthraquinones (14⎼20) were isolated and characterized. The structures of these compounds were elucidated by detailed spectroscopic analyses, and their absolute configurations were established by modified Mosher's method and ECD calculations. The antitumor cell proliferative activities of prisconnatanones J⎼V were determined. Among them, prisconnatanones J possessed high antitumor cell proliferation in HGC27 cells (IC50, 0.792 µM) by blocking HGC27 cells in the S phase and significantly inducing apoptosis in HGC27 cells. Prisconnatanone J has no cytotoxicity to normal gastric cells line (GES-1) at 10 µM and showed a considerable selectivity for HGC27 cells. Prisconnatanone J can potentially inhibit tumor cell proliferation and should be further investigated.

Chiral separation and bioactivities of six pairs of enantiomeric dilignans from Magnolia officinalis var. biloba.

Six pairs of enantiomeric dilignans, (+)/(-)-magdiligols A-F, have been isolated from an ethanolic extract of the barks of Magnolia officinalis var. biloba. Their chemical structures were elucidated by extensive spectroscopic analyses, NMR calculation with DP4+ analysis, and the electronic circular dichroism spectra calculation. (+)/(-)-1-3 possessed a dihydrobenzopyran ring, while a propyl chain of 1 was linked via ether bond. (+)/(-)-Magdiligols D and E ((+)/(-)-4 and 5) were dilignans possessing a furan ring. (+)-Magdiligol B ((+)/(-)-2), (+)/(-)-magdiligol C ((+)/(-)-3), and racemes 2, 3, and 5 showed potential hepatoprotective effects against APAP-induced HepG2 cell damage, increased the cell viability from 65.4% to 72.7, 78.7.76.6, 73.9, 77.9 and 73.2%, via decreasing the level of the live enzymes ALH and LDH consistently. (+)/(-)-Magdiligols B-D ((+)/(-)-2-4) and (+)/(-)-magdiligol F ((+)/(-)-6) exhibited significant antioxidative activity. (+)/(-)-Magdiligols B-C ((+)/(-)-2 and 3), (-)-magdiligol D ((-)-4), and (+)-magdiligol E ((+)-5) displayed significant PTP1B inhibitory activity with IC50 values 1.41-3.42 µM. (+)/(-)-Magdiligol B ((+)/(-)-2), and its raceme (2) demonstrated α-glucosidase inhibitory activity with the IC50 values 1.47, 2.88 and 1.85 µM, respectively.

Dietary L-carnitine supplementation changes lipid metabolism and glucose utilization of Rhynchocypris lagowskii fed diets with different lipid sources.

The widely available crop oil is an effective alternative to the increasingly scarce marine fish oil. However, simple alternative strategies have led to declining growth and the edible value of farmed fish. It is worthwhile to explore the effects of micro supplements in diets to improve the tolerance of fish to different dietary lipid sources, which finally optimizes the feeding strategies. This study aimed to investigate the regulation of L-carnitine and dietary oil conditions on nutrient composition, lipid metabolism, and glucose regulation of Rhynchocypris lagowskii. Four diets were prepared according to fish oil, fish oil supplemented with L-carnitine, corn oil, and corn oil supplemented with L-carnitine, and FO, LCFO, CO, and LCCO were labeled, respectively. R. lagowskii was fed experimental diets for 8 weeks, and the glucose tolerance test was performed. The CO diet significantly resulted in higher crude lipid content in muscle but a lower level of serum lipid parameters of R. lagowskii than the FO diet. However, dietary L-carnitine supplementation significantly reduced the crude lipid content in the hepatopancreas and muscle of the fish fed with the CO diet yet increased the serum lipid parameters. Additionally, the crude lipid content of muscle was reduced in the fish fed with an FO diet supplemented with L-carnitine. Compared with the FO diet, the CO diet significantly reduced the ratio of n3/n6 polyunsaturated fatty acid in the hepatopancreas and muscle of R.lagowskii. Dietary L-carnitine supplementation significantly reduced the contents of total saturated fatty acids and total monounsaturated fatty acids in hepatopancreas under both dietary lipid sources. The CO diet significantly up-regulated the expression of genes related to lipid uptake and adipogenesis in hepatopancreas, including lipoprotein lipase (lpl), acetyl-coenzyme A carboxylase alpha (accα), and sterol regulatory element binding protein-1 (srebp1), compared with the FO diet. While dietary L-carnitine supplementation significantly down-regulated the expressions of lpl, accα, srebp1, and fatty acid synthase in hepatopancreas and muscle of fish under both dietary lipid sources, along with up-regulated expression of carnitine palmitoyltransferase 1 in hepatopancreas. Moreover, the fish fed with a CO diet significantly increased the expression of glucose uptake and clearance and significantly down-regulated the expressions of glucose regulation-related genes, including glucose transporter 1, glycogen synthase 1, and phosphofructokinase in hepatopancreas and muscle, resulting in slower glucose uptake and clearance than fish fed with FO diet. Nevertheless, dietary L-carnitine supplementation up-regulated the expression of gluconeogenesis-related genes, including glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in the hepatopancreas of R. lagowskii under both dietary lipid sources. In conclusion, a higher dietary n6 PUFA resulted in lipid deposition, decreased serum lipid parameters, and limited serum glucose utilization of R. lagowskii. While the regulatory effect of L-carnitine on lipid metabolism and glucose utilization of R. lagowskii varies with dietary lipid sources and tissues.

ATP6V1A variants are associated with childhood epilepsy with favorable outcome.

PURPOSE: ATP6V1A variants have been identified in patients with highly variable phenotypes such as autosomal dominant epileptic encephalopathy and autosomal recessive cutis laxa. However, the mechanism underlying phenotype variation is unknown. We screened ATP6V1A variants in patients with epilepsy and analyzed the genotype-phenotype correlation to explain the mechanism underlying phenotypic variations. METHODS: We performed trio-based whole-exome sequencing in people with epilepsy without acquired causes. All previously reported ATP6V1A variants were systematically retrieved from the HGMD and PubMed databases. RESULTS: Three novel de novo ATP6V1A variants, including c.749G>C/p.Gly250Ala, c.782A>G/p.Gln261Arg, and c.1103T>C/p.Met368Thr, were identified in three unrelated cases with childhood focal (partial) epilepsy. None of the variants were listed in any public population database and evaluated as likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics (ACMG). All persons showed good responses to anti-seizure medication and psychomotor development was normal. Further analysis showed that monoallelic missense variants were associated with epilepsy with variable severity, whereas biallelic variants resulted in developmental abnormalities of multisystem that may result in early lethality. CONCLUSION: Childhood focal epilepsy with favorable outcome was probably a novel phenotype of ATP6V1A. ATP6V1A variants are associated with a range of phenotypes that correlate with genotypes. The relationship between phenotype severity and the genotype (genetic impairment) of ATP6V1A variants helps explain the phenotypic variations.

DYNC1H1 variants associated with infant-onset epilepsy without neurodevelopmental disorders.

OBJECTIVES: The DYNC1H1 variants are associated with abnormal brain morphology and neuromuscular disorders that are accompanied by epilepsy. This study aimed to explore the relationship between DYNC1H1 variants and epilepsy. MATERIALS AND METHODS: Trios-based whole-exome sequencing was performed on patients with epilepsy. Previously reported epilepsy-related DYNC1H1 variants were systematically reviewed to analyse genotype-phenotype correlation. RESULTS: The DYNC1H1 variants were identified in four unrelated cases of infant-onset epilepsy, including two de novo and two biallelic variants. Two patients harbouring de novo missense variants located in the stem and stalk domains presented with refractory epilepsies, whereas two patients harbouring biallelic variants located in the regions between functional domains had mild epilepsy with infrequent focal seizures and favourable outcomes. One patient presented with pachygyria and neurodevelopmental abnormalities, and the other three patients presented with normal development. These variants have no or low frequencies in the Genome Aggregation Database. All the missense variants were predicted to be damaging using silico tools. Previously reported epilepsy-related variants were monoallelic variants, mainly de novo missense variants, and all the patients presented with severe epileptic phenotypes or developmental delay and malformations of cortical development. Epilepsy-related variants were clustered in the dimerization and stalk domains, and generalized epilepsy-associated variants were distributed in the stem domain. CONCLUSION: This study suggested that DYNC1H1 variants are potentially associated with infant-onset epilepsy without neurodevelopmental disorders, expanding the phenotypic spectrum of DYNC1H1. The genotype-phenotype correlation helps to understand the underlying mechanisms of phenotypic variation.

Osimertinib versus comparator first-generation epidermal growth factor receptor tyrosine kinase inhibitors as first-line treatment in patients with advanced EGFR-mutated non-small cell lung cancer: a Chinese, multicenter, real-world cohort study.

Background: In the phase 3 FLAURA trial, osimertinib was compared with first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as a first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib showed longer progression-free survival (PFS), overall survival (OS), and a similar safety profile. However, more studies demonstrating the effectiveness and safety of osimertinib as a first-line strategy are needed in real-world populations. Methods: We enrolled 1,556 patients with EGFR-mutated stage IIIc-IV NSCLC from the CAPTRA-Lung database. All patients received either osimertinib (n=202) or a first-generation EGFR-TKI (n=1,354) as their initial treatment. To adjust for differences in baseline characteristics between two groups, 1:2 propensity score matching (PSM) was performed. Propensity scores included gender, age, Eastern Cooperative Oncology Group performance status score, smoking history, family history of tumor, pathology, EGFR mutations, and central nervous system (CNS) metastases. The standardized mean differences (SMD) before and after PSM were calculated to examine the balance of covariate distributions between two groups. Results: After PSM, 202 patients receiving osimertinib and 404 patients receiving first-generation EGFR-TKIs were finally identified. SMD of each matched variable is less than 0.10. The median PFS was 19.4 months [95% confidence interval (CI): 14.3-24.4] in the osimertinib arm and 10.9 months (95% CI: 9.3-12.5) in the comparator arm [hazard ratio (HR) for progression, 0.47; 95% CI: 0.38-0.59; P<0.001). The median OS was 40.5 months (95% CI: 27.1-54.0) vs. 34.3 months (95% CI: 30.6-38.0) in two groups, respectively (HR for death, 0.76; 95% CI: 0.58-1.00; P=0.045). The incidence of grade 3 adverse events (AEs) between the two groups was 1% and 4.2%, respectively. No grade 4 AEs and treatment-related deaths were reported in both groups. Conclusions: In real-world settings, osimertinib demonstrates longer PFS and OS, with a similar safety profile to that of comparator EGFR-TKIs when used as a first-line strategy in NSCLC patients.

Application of ArcGIS 3D modeling technology in the study of land use policy decision making in China.

In this paper, a land use management information system based on ArcGIS 3D modeling technology is constructed to process land use policy decisions through ArcSDE spatial data engine and Oracle relational database to realize a land use planning management information system. Using genetic algorithm in order to use for regional land use optimization allocation, the introduction of multi-intelligent body system in this algorithm will be able to enhance the optimization search ability of the algorithm and make the genetic algorithm to obtain land use planning supported. The behavior of the main body of the integrated land use planning decision maker will guide the development of the quantitative structure of land use in terms of spatial layout toward sustainability. The experimental results prove that the target is better than the other three types of scenarios under the integrated benefit model, then it is reduced by 18.67%, 15.98% and 16.61%, and the number of spatially contiguous areas is increased by 9.4%, 13.8% and 0.8%, respectively. The proposed model can reasonably configure the regional land use quantitative results and spatial layout, and coordinate the needs of different land use decision makers.

Factors of parental investment in the home language environment in peri-urban China: A mixed methods study.

The home language environment is a critical point of investment in early language skills. However, few studies have quantitatively measured the home language environment of low-socioeconomic-status households in non-western settings. This mixed methods study describes the home language environment and early child language skills among households in a low-socioeconomic-status, peri-urban district of Chengdu, China, and identifies factors influencing parental investment in the home language environment. Audio recordings were collected from 81 peri-urban households with children ages 18-24 months and analysed using the Language Environment Analysis (LENATM) system. The Mandarin version of the MacArthur-Bates Communicative Development Inventory was administered to each child's primary caregiver. The quantitative results revealed large variation in home language environments and child language skills among the sample, with relatively low average scores when compared to other Chinese samples. Qualitative interviews with a subset of 31 caregivers revealed that many caregivers face constraints on their knowledge of interactive parenting, compounded, in some households, by time constraints due to work or household responsibilities. The findings indicate a need for increased sources of credible parenting information for peri-urban caregivers of young children to promote investment in the home language environment.

Unraveling the parameters and biological mechanisms of CO2 laser therapy for acute pain relief.

Acute pain-related pathology is a significant challenge in clinical practice, and the limitations of traditional pain-relief drugs have made it necessary to explore alternative approaches. Photobiomodulation (PBM) therapy using CO2 laser has emerged as a promising option. In this study, we aimed to identify the optimal parameters of CO2 laser irradiation for acute pain relief through in vivo and in vitro experiments. First, we validated the laser intensity used in this study through bone marrow mesenchymal stem cells (BMSCs) experiments to ensure it will not adversely affect stem cell viability and morphology. Then we conducted a detailed evaluation of the duty cycle and frequency of CO2 laser by the hot plate and formalin test. Results showed a duty cycle of 3% and a frequency of 25 kHz produced the best outcomes. Additionally, we investigated the potential mechanisms underlying the effects of CO2 laser by immunohistochemical staining, and found evidence to suggest that the opioid receptor may be involved in its analgesic effect. In conclusion, this study provides insights into the optimal parameters and underlying mechanisms of CO2 laser therapy for effective pain relief, thereby paving the way for future clinical applications.

Hydrangea paniculata coumarins attenuate experimental membranous nephritis by bidirectional interactions with the gut microbiota.

Coumarins isolated from Hydrangea paniculata (HP) had a renal protective effect in experimental membranous nephritis (MN), but the mechanisms are not clear. Currently, we investigate whether the modulation of gut dysbiosis by HP contributes to its renal protection. Experimental MN rats were treated with HP for six weeks. Fecal 16S rDNA sequencing and metabolomics were performed. Fecal microbiota transplantation (FMT) was used for the evaluation study. The results demonstrate that deteriorated renal function and gut dysbiosis are found in MN rats, as manifested by a higher Firmicutes/Bacteroidetes ratio and reduced diversity and richness, but both changes were reversed by HP treatment. Reduced gut dysbiosis is correlated with improved colonic integrity and lower endotoxemia in HP-treated rats. HP normalized the abnormal level of fecal metabolites by increasing short-chain fatty acid production and hindering the production of uremic toxin precursors. FMT of HP-treated feces to MN animals moderately reduced endotoxemia and albuminuria. Moreover, major coumarins in HP were only biotransformed into more bioactive 7-hydroxycoumarin by gut microbiota, which strengthened the effect of HP in vivo. Depletion of the gut microbiota partially abolished its renal protective effect. In conclusion, the bidirectional interaction between HP and the gut microbiota contributes to its beneficial effect.

Beneficial effects of indigenous Bacillus spp. on growth, antioxidants, immunity and disease resistance of Rhynchocypris lagowskii.

This study aimed to investigate the effect of Bacillus aryabhattai (LSG3-7) and Bacillus mojavensis (LSG3-8) on growth performance, antioxidant capacity, and immune response in Rhynchocypris lagowskii (Dybowski, 1869), at the trial and challenge periods. A 630 healthy fish (10.76 ± 0.05) were randomly divided into six groups: control group (D1) was fed the basal diet, D2 and D3 were supplemented with LSG 3-7 and LSG3-8 (1 × 108 CFU/g) for both of them, whereas D4 was supplemented with a mixture of both bacteria (0.5 × 108 CFU/g each), and D5 was supplemented with LSG3-7 0.75 × 108 CFU/g + LSG3-8 0.25 × 108 CFU/g, and D6 supplemented with LSG3-7 0.25 × 108 CFU/g + LSG3-8 0.75 × 108 CFU/g. After the trial, Aeromonas hydrophila was used in a challenge test for 14 days. Treatments showed significant differences (p < 0.05) in growth performance and antioxidant capacity (CAT, CuZn-SOD, GPX) in the liver and intestine compared to the control. The antioxidant-related genes CAT, CuZn-SOD, GPX, and Nrf2 in the liver and intestine showed upregulation compared with the control group. Serum IgM, LZM, C3, C4, and AKP showed a favorable superiority (p < 0.05) in treatments (D2 - D6) at the trial and challenge test compared to controls. In parallel, immune-related genes (IgM, NF-κB, TLR-1, TLR-2, and MyD88) showed an up-regulated level (p < 0.05) in treatments (D2 - D6) compared to the control. In addition, pro-inflammatory cytokines (IL-1, TNF-α) showed a downregulated level in treatments (D2 - D6). After the challenge test, the immune-related genes in the liver and muscle showed an up-regulated level in treatments compared to the controls. The survival rate showed a significant increase (p < 0.05) in the treatment groups (D2 - D6) compared to the control. Overall, individuals and the bacterial mixture of B. aryabhattai and B. mojavensis could improve the growth performance, antioxidant capacity, immune capacity, and survival rate of R. lagowskii and prevent side effects of A. hydrophila. However, B. mojavensis showed a slight improvement compared to B. aryabhattai without a significant difference between them.

Clinical significance of DNA damage response mutations in stage I and stage IIIa NSCLC.

BACKGROUND: DNA damage response (DDR) pathways are essential to sustain genomic stability and play a critical role in cancer development and progression. Here, we investigated the profile of DDR gene mutations in early-stage non-small cell lung cancer (NSCLC) and their prognostic values. METHODS: We first examined 74 DDR genes involved in seven DDR pathways and then focused on six specific genes: ATM, BRCA1, BRCA2, CHEK1, BARD1, and BRIP1. A total of 179 stage I and IIIa NSCLC patients who received curative resection in Peking Union Medical College Hospital and their corresponding samples were collected for DNA sequencing, immunohistochemistry and survival analysis. RESULTS: A total of 167 eligible patients were finally analyzed. Mutation frequencies were 82% and 26.3% for the selected 74 genes and six genes, respectively. Mismatch repair (MMR) and nucleotide excision repair (NER) alterations were observed more frequently in lung squamous cell carcinoma (LUSC) and smokers were more likely to develop the selected six DDR gene mutations than those who never smoked. Deleterious mutations in the six genes were independent prognostic indicators of significantly longer disease-free survival and overall survival. No association was found between DDR gene status and PD-L1 expression, CD8 positive lymphocyte and tumor-associated macrophage infiltration in tumor area. However, numbers of mutations were significantly increased among patients with DDR alterations. CONCLUSIONS: Deleterious mutations of these six genes were common in resected NSCLC and could serve as prognostic biomarkers.

LA67 Liposome-Loaded Thermo-Sensitive Hydrogel with Active Targeting for Efficient Treatment of Keloid via Peritumoral Injection.

A keloid is a benign tumor manifested as abnormal fibroplasia on the surface of the skin. Curing keloids has become a major clinical challenge, and searching for new treatments and medications has become critical. In this study, we developed a LA67 liposome-loaded thermo-sensitive hydrogel (LA67-RL-Gel) with active targeting for treating keloids via peritumoral injection and explored the anti-keloid mechanism. Firstly, Arg-Gly-Asp (RGD) peptide-modified liposomes (LA67-RL) loaded with LA67 were prepared with a particle size of 105.9 nm and a Zeta potential of -27.4 mV, and an encapsulation efficiency of 89.6 ± 3.7%. We then constructed a thermo-sensitive hydrogel loaded with LA67-RL by poloxamer 407 and 188. The formulation was optimized through the Box-Behnken design, where the impact of the proportion of the ingredients on the quality of the hydrogel was evaluated entirely. The optimal formulation was 20.7% P407 and 2.1% P188, and the gelation time at 37 °C was 9.5 s. LA67-RL-Gel slowly released 92.2 ± 0.8% of LA67 at pH 6.5 PBS for 72 h. LA67-RL-Gel increased adhesion with KF cells; increased uptake; promoted KF cells apoptosis; inhibited cell proliferation; reduced α-SMA content; decreased collagen I, collagen III, and fibronectin deposition; inhibited angiogenesis; and modulated the keloid microenvironment, ultimately exerting anti-keloid effects. In summary, this simple, low-cost, and highly effective anti-keloid liposome hydrogel provides a novel approach for treating keloids and deserves further development.

Brain-specific Pd1 deficiency leads to cortical neurogenesis defects and depressive-like behaviors in mice.

Embryonic neurogenesis is tightly regulated by multiple factors to ensure the precise development of the cortex. Deficiency in neurogenesis may result in behavioral abnormalities. Pd1 is a well-known inhibitory immune molecule, but its function in brain development remains unknown. Here, we find brain specific deletion of Pd1 results in abnormal cortical neurogenesis, including enhanced proliferation of neural progenitors and reduced neuronal differentiation. In addition, neurons in Pd1 knockout mice exhibit abnormal morphology, both the total length and the number of primary dendrites were reduced. Moreover, Pd1cKO mice exhibit depressive-like behaviors, including immobility, despair, and anhedonia. Mechanistically, Pd1 regulates embryonic neurogenesis by targeting Pax3 through the ß-catenin signaling pathway. The constitutive expression of Pax3 partly rescues the deficiency of neurogenesis in the Pd1 deleted embryonic brain. Besides, the administration of ß-catenin inhibitor, XAV939, not only rescues abnormal brain development but also ameliorates depressive-like behaviors in Pd1cKO mice. Simultaneously, Pd1 plays a similar role in human neural progenitor cells (hNPCs) proliferation and differentiation. Taken together, our findings reveal the critical role and regulatory mechanism of Pd1 in embryonic neurogenesis and behavioral modulation, which could contribute to understanding immune molecules in brain development.

A mitotic NADPH upsurge promotes chromosome segregation and tumour progression in aneuploid cancer cells.

Redox metabolites have been observed to fluctuate through the cell cycle in cancer cells, but the functional impacts of such metabolic oscillations remain unknown. Here, we uncover a mitosis-specific nicotinamide adenine dinucleotide phosphate (NADPH) upsurge that is essential for tumour progression. Specifically, NADPH is produced by glucose 6-phosphate dehydrogenase (G6PD) upon mitotic entry, which neutralizes elevated reactive oxygen species (ROS) and prevents ROS-mediated inactivation of mitotic kinases and chromosome missegregation. Mitotic activation of G6PD depends on the phosphorylation of its co-chaperone protein BAG3 at threonine 285, which results in dissociation of inhibitory BAG3. Blocking BAG3T285 phosphorylation induces tumour suppression. A mitotic NADPH upsurge is present in aneuploid cancer cells with high levels of ROS, while nearly unobservable in near-diploid cancer cells. High BAG3T285 phosphorylation is associated with worse prognosis in a cohort of patients with microsatellite-stable colorectal cancer. Our study reveals that aneuploid cancer cells with high levels of ROS depend on a G6PD-mediated NADPH upsurge in mitosis to protect them from ROS-induced chromosome missegregation.