Synthesis and Biological Evaluation of Novel Psidium Meroterpenoid Derivatives against Cisplatin-Induced Acute Kidney Injury.

Cisplatin is a widely used drug for the clinical treatment of tumors. However, nephrotoxicity limits its widespread use. A series of compounds including eight analogs (G3-G10) and 40 simplifiers (G11-G50) were synthesized based on the total synthesis of Psiguamer A and B, which were novel meroterpenoids with unusual skeletons from the leaves of Psidium guajava. Among these compounds, (d)-G8 showed the strongest protective effect on cisplatin-induced acute kidney injury (AKI) in vitro and vivo, and slightly enhanced the antitumor efficacy of cisplatin. A mechanistic study showed that (d)-G8 promoted the efflux of cisplatin via upregulating the copper transporting efflux proteins ATP7A and ATP7B. It enhanced autophagy through the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. (d)-G8 showed no acute toxicity or apparent pathological damage in the healthy mice at a single dose of 1 g/kg. This study provides a promising lead against cisplatin-induced AKI.

[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.

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.

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.

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.

Comparison of Chemotherapy Plus Pembrolizumab vs. Chemotherapy Alone in EGFR-Mutant Non-small-Cell Lung Cancer Patients.

INTRODUCTION: Platinum doublet chemotherapy is the standard of care in patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation who had disease progression after tyrosine kinase inhibitor (TKI). We aimed to assess immune checkpoint inhibitors efficacy in EGFR-mutant advanced NSCLC. MATERIALS AND METHODS: We retrospectively reviewed the data of sensitive EGFR-mutant NSCLC patients who progressed after EGFR-TKIs and received platinum doublet chemotherapy plus immunotherapy between 2015 and 2021. Efficacy outcomes, including overall response rate, progression-free survival, and overall survival, were assessed and compared with those of patients who had received platinum-based doublet chemotherapy. RESULTS: Of the total 869 patients, 82 treated with pembrolizumab and chemotherapy and 82 with only chemotherapy were selected. The median progression-free survival in patients administered pembrolizumab was significantly longer than those not administered pembrolizumab (6.7 months; 95% confidence interval [CI] 5.0-8.5 vs. 4.2 months; 95% CI 3.3-5.0, hazard ratio [HR] 0.64, 95% CI 0.46-0.89, P = .0076). Improved median overall survival was also observed in patients receiving pembrolizumab plus chemotherapy (26.7 [95% CI 22.6-30.8] vs. 13.4 months [95% CI 10.4-16.4], HR, 0.49 [95% CI 0.31-0.75], P = .0052). In addition, the overall response rate was higher in patients treated with than patients treated without pembrolizumab (34.1% and 20.7%, respectively). CONCLUSION: The combination of pembrolizumab with chemotherapy is associated with improved efficacy and survival in patients with EGFR-mutant NSCLC after TKI resistance, but these findings need to be confirmed in further prospective studies.

Unraveling the mechanism of ethyl acetate extract from Prismatomeris connata Y. Z. Ruan root in treating pulmonary fibrosis: insights from bioinformatics, network pharmacology, and experimental validation.

Introduction: Pulmonary fibrosis is a terminal lung disease characterized by fibroblast proliferation, extracellular matrix accumulation, inflammatory damage, and tissue structure destruction. The pathogenesis of this disease, particularly idiopathic pulmonary fibrosis (IPF), remains unknown. Macrophages play major roles in organ fibrosis diseases, including pulmonary fibrosis. The phenotype and polarization of macrophages are closely associated with pulmonary fibrosis. A new direction in research on anti-pulmonary fibrosis is focused on developing drugs that maintain the stability of the pulmonary microenvironment. Methods: We obtained gene sequencing data and clinical information for patients with IPF from the GEO datasets GSE110147, GSE15197, GSE24988, GSE31934, GSE32537, GSE35145, GSE53845, GSE49072, GSE70864, and GSE90010. We performed GO, KEGG enrichment analysis and GSEA analysis, and conducted weighted gene co-expression network analysis. In addition, we performed proteomic analysis of mouse lung tissue. To verify the results of bioinformatics analysis and proteomic analysis, mice were induced by intratracheal instillation of bleomycin (BLM), and gavaged for 14 days after modeling. Respiratory function of mice in different groups was measured. Lung tissues were retained for histopathological examination, Western Blot and real-time quantitative PCR, etc. In addition, lipopolysaccharide, interferon-γ and interleukin-4 were used to induce RAW264.7 cells for 12h in vitro to establish macrophage inflammation and polarization model. At the same time, HG2 intervention was given. The phenotype transformation and cytokine secretion of macrophages were investigated by Western Blot, RT-qPCR and flow cytometry, etc. Results: Through bioinformatics analysis and experiments involving bleomycin-induced pulmonary fibrosis in mice, we confirmed the importance of macrophage polarization in IPF. The analysis revealed that macrophage polarization in IPF involves a change in the phenotypic spectrum. Furthermore, experiments demonstrated high expression of M2-type macrophage-associated biomarkers and inducible nitric oxide synthase, thus indicating an imbalance in M1/M2 polarization of pulmonary macrophages in mice with pulmonary fibrosis. Discussion: Our investigation revealed that the ethyl acetate extract (HG2) obtained from the roots of Prismatomeris connata Y. Z. Ruan exhibits therapeutic efficacy against bleomycin-induced pulmonary fibrosis. HG2 modulates macrophage polarization, alterations in the TGF-ß/Smad pathway, and downstream protein expression in the context of pulmonary fibrosis. On the basis of our findings, we believe that HG2 has potential as a novel traditional Chinese medicine component for treating pulmonary fibrosis.

Design, synthesis and biological evaluation of pyranocarbazole derivatives against Alzheimer's disease, with antioxidant, neuroprotective and cognition enhancing properties.

A series of novel pyranocarbazole alkaloids were designed and synthesized as derivatives of Claulansine F and CZ-7. Some of the compounds showed strong neuroprotective effects and anti-lipid peroxidation capacity. Among these compounds, 10b, introduced leucine at the C-3 position of pyranocarbazole, was the most active in inhibiting the programmed death of SH-SY5Y cells. This compound exhibited stronger free radical scavenging activity than Edaravone. Furthermore, 10b could penetrate the blood-brain barrier (BBB). More importantly, 10b showed a tendency of improvement in learning and memory in the dose range of 10-40 mg/kg. The research on mechanisms indicated that 10b could reduce oxidative stress in the brain of Aß25-35-intoxicated mice, and then improve the cognitive function of Aß25-35-intoxicated mice. Our findings suggest that 10b may be promising for further evaluation as an intervention for Alzheimer's Disease.

Novel nitric oxide-releasing derivatives of pyranocarbazole as antitumor agents: Design, synthesis, biological evaluation, and nitric oxide release studies.

In this study, a series of novel furoxan-based nitric oxide (NO) releasing derivatives of pyranocarbazole alkaloids were designed, synthesized, and biologically evaluated against human cancer cell lines. The derivatives showed considerable antiproliferative activities (IC50 = 0.05-7.55 µM) and most compounds showed higher activity in MDA-MB-231 than H460 and HeLa. Especially, the most active derivative 7a (IC50 = 0.05 µM) against MDA-MB-231 was about 60 times stronger than lead compound, as well as equivalent to positive control taxol, and produced high levels of NO in MDA-MB-231. Furthermore, 7a could significantly inhibit the growth of MDA-MB-231 tumors in vivo with low toxicity and the PI3K/Akt signaling pathway. These results indicated that compound 7a could be a promising lead for further studies.

Formaldehyde gas sensor with extremely high response employing cobalt-doped SnO2 ultrafine nanoparticles.

Formaldehyde is a common carcinogen in daily life and harmful to health. The detection of formaldehyde by a metal oxide semiconductor gas sensor is an important research direction. In this work, cobalt-doped SnO2 nanoparticles (Co-SnO2 NPs) with typical zero-dimensional structure were synthesized by a simple hydrothermal method. At the optimal temperature, the selectivity and response of 0.5% Co-doped SnO2 to formaldehyde are excellent (for 30 ppm formaldehyde, R a/R g = 163 437). Furthermore, the actual minimum detectable concentration of 0.5%Co-SnO2 NPs is as low as 40 ppb, which exceeds the requirements for formaldehyde detection in the World Health Organization (WHO) guidelines. The significant improvement of 0.5%Co-SnO2 NPs gas performance can be attributed to the following aspects: firstly, cobalt doping effectively improves the resistance of SnO2 NPs in the air; moreover, doping creates more defects and oxygen vacancies, which is conducive to the adsorption and desorption of gases. In addition, the crystal size of SnO2 NPs is vastly small and has unique physical and chemical properties of zero-dimensional materials. At the same time, compared with other gases tested, formaldehyde has a strong reducibility, so that it can be selectively detected at a lower temperature.

Safety and efficacy of immune checkpoint inhibitors in non-small cell lung cancer patients with preexisting antinuclear antibodies: a retrospective cohort study.

Background: Antinuclear antibodies (ANAs) predicting the safety and efficacy of patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) are still a matter of debate considering previous studies showed quite different results based on different ANA cut-off values. Thus, we investigated the associations between different ANA titers and the safety and efficacy of ICIs. Moreover, we also briefly discussed the effects of anti-thyroglobulin (ATG) and anti-thyroid peroxidase (ATPO) on the safety of ICIs. Methods: A total of 159 Chinese patients confirmed to have locally-advanced or metastatic NSCLC given ICIs or chemoimmunotherapy in Peking Union Medical College Hospital from January 2015 to December 2020 were analyzed retrospectively and were followed up until December 2020 or death or loss to follow-up. Patients' characteristics were retrieved from medical records. ANAs were detected by the indirect immunofluorescence assay, ATG and ATPO by the electrochemiluminescence immunoassay. The severity of immune-related adverse events (irAEs) was graded according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0) and the efficacy was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Results: The incidence of irAEs, median progression-free survival (mPFS) of the ANA negative and positive groups were 26.0% vs. 31.4% (P=0.457), 17.7 vs. 10 months (P=0.603) for the cut-off value of 1:80; 26.2% vs. 33.9% (P=0.305), 11.9 vs. 10.6 months (P=0.957) for 1:160; and 25.9% vs. 45.8% (P=0.047), and 11.9 vs. 7.7 months (P=0.471) for 1:320, separately. Besides, ANA titer ≥1:320 was associated with irAEs [odds ratio (OR) =4.9, 95% confidence interval (CI): 1.45-16.52, P=0.01] and the incidence of adverse skin reactions differed greatly between the negative and positive groups (9.7% vs. 32%, P=0.003). Moreover, a total of 52 out of 159 patients were tested for ATG and ATPO. 46 patients were negative and 6 were positive, with the incidence of abnormal thyroid function being 4.3% vs. 50% (P=0.005), respectively. Conclusions: Preexisting ANAs may not correlate with the clinical benefit of immunotherapy in patients with NSCLC but may be associated with adverse skin reactions. Besides, ATG or ATPO has the potential to predict thyroid dysfunction.

[Blocking Adenosine/A2AR Pathway for Cancer Therapy].

Adenosine is a metabolite produced abundantly in the tumor microenvironment, dampening immune response in inflamed tissues via adenosine A2A receptor (A2AR) which is widely expressed on immune cells, inhibiting anti-tumor immune response accordingly. Therefore, blocking adenosine signaling pathway is of potential to promote anti-tumor immunity. This review briefly introduces adenosine signaling pathway, describes its role in regulating tumor immunity and highlights A2AR blockade in cancer therapy. Prospective anti-tumor activity of adenosine/A2AR inhibition has been revealed by preclinical data, and a number of clinical trials of A2AR antagonists are under way. Primary results from clinical trials suggest that A2AR antagonists are well tolerated in cancer patients and are effective both as monotherapy and in combination with other therapies. In the future, finding predictive biomarkers are critical to identify patients most likely to benefit from adenosine pathway blockade, and further researches are needed to rationally combine A2AR antagonists with other anti-tumor therapies.
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Clinical characteristics and outcomes of immune checkpoint inhibitor-induced diabetes mellitus.

OBJECTIVE: To better understand immune checkpoint inhibitor (ICI)-induced diabetes mellitus (DM) in cancer patients. DESIGN AND METHOD: We present a case of ICI-induced diabetic ketoacidosis (DKA) and conduct a systematic review of the PubMed and Web of Science databases up to September 2021 to identify all published cases of ICI-induced diabetes. RESULTS: In addition to our case, a total of 171 published cases were identified during the literature search. Summary and statistical analyzes were conducted for all 172 cases. The median onset time from ICI initiation to DM diagnosis was 12 weeks (range: 0-122). DKA was present in 67.4% (116/172) of the cases, and low C-peptide levels were detected in 91.8% (123/134), indicating an acute onset of diabetes. Patients with positive glutamic acid decarboxylase antibodies (GADA) had an earlier onset of ICI-induced diabetes (median time 7 weeks vs. 16 weeks for GADA-negative patients, p < 0.001) and a higher frequency of DKA development (82.8 vs. 62.1%, p = 0.006). All but two patients developed insulin-dependent diabetes permanently. Immunotherapy rechallenge was reported in 53 cases after glycemia was well controlled. CONCLUSION: ICI-induced DM is a serious adverse event that often presents with life-threatening ketoacidosis. GADA positivity is related to an earlier onset of ICI-induced diabetes and a higher frequency of DKA development. Close monitoring of glucose levels is needed in patients receiving ICI treatment. ICI-induced DM is usually insulin-dependent since damage to ß cells is irreversible. On the premise of well-controlled glycemia, immunotherapy rechallenge is feasible.

The immuneoreaction and antioxidant status of Chinese mitten crab (Eriocheir sinensis) involve protein metabolism and the response of mTOR signaling pathway to dietary methionine levels.

To study the effects of dietary methionine on growth performance, immunity, antioxidant capacity, protein metabolism, inflammatory response and apoptosis factors in Chinese mitten crabs (Eriocheir sinensis). Five diets with different methionine levels (0.63%, 0.85%, 1.06%, 1.25% and 1.47%) were fed to E. sinensis for 8 weeks. Results showed that in the 1.25% Met group, both growth performance and feed utilization were significantly increased. The crude protein content of crab muscle in the 1.06% and 1.25% Met groups was significantly higher than that in the control group. The immune and antioxidant enzyme activities, as well as gene expression levels of anti-lipopolysaccharide factor 1 (ALF1), Crustin-1, prophenoloxidase (proPO), cap 'n' collar isoform C (CncC) in 1.25% Met group were significantly higher than other groups. The activities of adenosine deaminase (ADA) and glutamate transaminase (GPT) in serum decreased first and then increased with the increase of methionine content, while the changes of ADA and GPT in hepatopancreas increased first and then decreased. 1.25% Met group exhibited significantly increased levels of GOT, GPT, and ADA compared to the control group. 1.25% Met diet group significantly up-regulated protein synthesis and anti-apoptotic factors, and significantly down-regulated inflammatory and pro-apoptotic factors in hepatopancreas. At 1.25% in the diet, methionine was found to boost E. sinensis growth, muscle protein deposition and immunity, as well as its antioxidant capacity. Combined with the above results, based on the expression of factors involved in the mammalian target of rapamycin (mTOR) signaling pathway and the mitogen-activated protein kinase (MAPK) signaling pathway, it is proved that methionine can not only promote protein metabolism, improve feed utilization, but also alleviate the inflammatory response and apoptosis caused by oxidative stress in the body.

The effect of adding Bacillus amyloliquefaciens LSG2-8 in diets on the growth, immune function, antioxidant capacity, and disease resistance of Rhynchocypris lagowskii.

The purpose of this study was to investigate the effect of Bacillus amyloliquefaciens LSG2-8 on the growth performance, immune function, antioxidant capacity, and disease resistance of Rhynchocypris lagowskii. Fish were fed with the feed containing five levels such as 0, 1.0 × 106, 1.0 × 107, 1.0 × 108, and 1.0 × 109 CFU/g of the B. amyloliquefaciens LSG2-8 for 56 days. After 56 days of feeding, twenty four fish were randomly selected to test various growth, immune and antioxidant parameters. Ten fish were challenged with Aeromonas hydrophila for 14 days; the mortality rate was recorded 14 days after infection. The results showed that B. amyloliquefaciens LSG2-8 could significantly increase the growth parameters of R. lagowskii's, such as final body weight, weight gain rate, specific growth rate, and feed efficiency (p < 0.05). Further examination revealed the activity of antioxidant enzymes, Nrf-2 mRNA, and Keap-1 mRNA gene expression in the intestine and liver, and the serum immune index of R. lagowskii in the 1.0 × 108 CFU/g were all significantly higher compared to the other groups. Furthermore, fish fed a diet supplemented with B. amyloliquefaciens LSG2-8 had a significantly lower (p < 0.05) post-challenge mortality rate than the control fish. In summary, the research results showed that B. amyloliquefaciens LSG2-8 could improve the growth performance, immune function, antioxidant capacity, and disease resistance of R. lagowskii and be used in aquaculture.

Ferrous Bisglycinate Supplementation Modulates Intestinal Antioxidant Capacity via the AMPK/FOXO Pathway and Reconstitutes Gut Microbiota and Bile Acid Profiles in Pigs.

Multi-omics were applied to compare the risks and benefits of ferrous sulfate (FeSO4) and ferrous bisglycinate (FebisGly) in pigs in the current study. The FebisGly group showed reduced triglyceride (TG) and triglyceride/total cholesterol (TG/CHOL) values in the serum and reduced malondialdehyde (MDA) and increased glutathione (GSH) levels in the duodenum. Transcriptome analysis revealed that differentially expressed genes in the duodenum were enriched in oxidative phosphorylation, AMPK, and FOXO signaling pathways between FeSO4 and FebisGly groups. AMPK phosphorylation and FOXO3 protein expressions were significantly increased in the FebisGly group. Bacterial 16S rRNA gene sequence analysis revealed significantly reduced alpha diversity in the FeSO4 group and increased Firmicutes, reduced Bacteroidetes, and Proteobacteria abundances in the FebisGly group. Targeted metabolome revealed notably increased lithocholic acid (LCA), glycolithocholic acid (GLCA), hyodeoxycholic acid (HDCA), ursodeoxycholic acid (UDCA), and glycoursodeoxycholic acid (GUDCA) in the FebisGly group. RDA analysis indicated that Fusobacteria was positively correlated with TG and TG/high-density lipoprotein in the FeSO4 group while Christensenellaceae_R-7_group, Ruminococcaceae_UCG-002, and Ruminococcaceae_UCG-005 were positively correlated with UDCA and GLCA in the FebisGly group. According to the current study, FebisGly improves serum lipid metabolism, modulates intestinal antioxidant capacity via the AMPK/FOXO pathway, and reconstitutes gut microbiota and bile acid profiles in pigs.