An ultra-long-acting L-asparaginase synergizes with an immune checkpoint inhibitor in starvation-immunotherapy of metastatic solid tumors.

Metastasis stands as the primary contributor to mortality associated with tumors. Chemotherapy and immunotherapy are frequently utilized in the management of metastatic solid tumors. Nevertheless, these therapeutic modalities are linked to serious adverse effects and limited effectiveness in preventing metastasis. Here, we report a novel therapeutic strategy named starvation-immunotherapy, wherein an immune checkpoint inhibitor is combined with an ultra-long-acting L-asparaginase that is a fusion protein comprising L-asparaginase (ASNase) and an elastin-like polypeptide (ELP), termed ASNase-ELP. ASNase-ELP's thermosensitivity enables it to generate an in-situ depot following an intratumoral injection, yielding increased dose tolerance, improved pharmacokinetics, sustained release, optimized biodistribution, and augmented tumor retention compared to free ASNase. As a result, in murine models of oral cancer, melanoma, and cervical cancer, the antitumor efficacy of ASNase-ELP by selectively and sustainably depleting L-asparagine essential for tumor cell survival was substantially superior to that of ASNase or Cisplatin, a first-line anti-solid tumor medicine, without any observable adverse effects. Furthermore, the combination of ASNase-ELP and an immune checkpoint inhibitor was more effective than either therapy alone in impeding melanoma metastasis. Overall, the synergistic strategy of starvation-immunotherapy holds excellent promise in reshaping the therapeutic landscape of refractory metastatic tumors and offering a new alternative for next-generation oncology treatments.

Significant spatiotemporal pattern of nitrous oxide emission and its influencing factors from a shallow eutropic lake in Inner Mongolia, China.

Eutrophic shallow lakes are generally considered as a contributor to the emission of nitrous oxide (N2O), while regional and global estimates have remained imprecise. This due to a lack of data and insufficient understanding of the multiple contributing factors. This study characterized the spatiotemporal variability in N2O concentrations and N2O diffusive fluxes and the contributing factors in Lake Wuliangsuhai, a typical shallow eutrophic and seasonally frozen lake in Inner Mongolia with cold and arid climate. Dissolved N2O concentrations of the lake exhibited a range of 4.5 to 101.2 nmol/L, displaying significant spatiotemporal variations. The lowest and highest concentrations were measured in summer and winter, respectively. The spatial distribution of N2O flux was consistent with that of N2O concentrations. Additionally, the hotspots of N2O emissions were detected within close to the main inflow of lake. The wide spatial and temporal variation in N2O emissions indicate the complexity and its relative importance of factors influencing emissions. N2O emissions in different lake zones and seasons were regulated by diverse factors. Factors influencing the spatial and temporal distribution of N2O concentrations and fluxes were identified as WT, WD, DO, Chl-a, SD and COD. Interestingly, the same factor demonstrated opposing effects on N2O emission in various seasons or zones. This research improves our understanding of N2O emissions in shallow eutrophic lakes in cold and arid areas.

[Research progress on C_(20)-diterpenoid alkaloids and their bioactivities in Ranunculaceae].

C_(20)-diterpenoid alkaloids are mainly distributed in plants of genus Aconitum, Delphinium, and Consolida in the Ranunculaceae. Their chemical structures are mainly categorized into nine types such as atisines, denudatines, hetidines, and hetisines. Bioactivity studies have shown that C_(20)-diterpenoid alkaloids have exhibited superior anti-tumor, analgesic, antiarrhythmic, and anti-inflammatory effects. In this review, the chemical structures and biological activities of 190 C_(20)-diterpenoid alkaloids reported in the Ranunculaceae from 2002 to the present were summarized, so as to provide a reference for the subsequent research on C_(20)-diterpenoid alkaloids in plants of Ranunculaceae.

Preoperative gut microbiota of POCD patients induces pre- and postoperative cognitive impairment and systemic inflammation in rats.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is common following surgery in elderly patients. The role of the preoperative gut microbiota in POCD has attracted increasing attention, but the potential underlying mechanisms remain unclear. This research aimed to investigate the impact of the preoperative gut microbiota on POCD. METHODS: Herein, we analyzed the preoperative gut microbiota of POCD patients through a prospective specimen collection and retrospective blinded evaluation study. Then, we transferred the preoperative gut microbiota of POCD patients to antibiotic-treated rats and established POCD model by abdominal surgery to explore the impact of the preoperative gut microbiota on pre- and postoperative cognitive function and systemic inflammation. The gut microbiota was analyzed using 16S rRNA sequencing analysis. The Morris water maze test was performed to evaluate learning and memory abilities. The inflammatory cytokines TNF-α, IL-1ß and IL-6 in the serum and hippocampus were measured by ELISA. Microglia were examined by immunofluorescence staining for Iba-1. RESULTS: Based on the decrease in the postoperative MMSE score, 24 patients were identified as having POCD and were matched with 24 control patients. Compared with control patients, POCD patients exhibited higher BMI and lower preoperative MMSE score. The preoperative gut microbiota of POCD patients had lower bacterial richness but a larger distribution, decreased abundance of Firmicutes and increased abundance of Proteobacteria than did that of control patients. Compared with rats that received preoperative fecal samples of control patients, rats that received preoperative fecal samples of POCD patients presented an increased abundance of Desulfobacterota, decreased cognitive function, increased levels of TNF-α and IL-1ß in the serum, increased levels of TNF-α and greater microglial activation in the hippocampus. Additionally, correlation analysis revealed a positive association between the abundance of Desulfobacterota and the level of serum TNF-α in rats. Then, we performed abdominal surgery to investigate the impact of the preoperative gut microbiota on postoperative conditions, and the surgery did indeed cause POCD and inflammatory response. Notably, compared with rats that received preoperative fecal samples of control patients, rats that received preoperative fecal samples of POCD patients displayed exacerbated cognitive impairment; increased levels of TNF-α, IL-1ß and IL-6 in the serum and hippocampus; and increased activation of microglia in the hippocampus. CONCLUSIONS: Our findings suggest that the preoperative gut microbiota of POCD patients can induce preoperative and aggravate postoperative cognitive impairment and systemic inflammation in rats. Modulating inflammation by targeting the gut microbiota might be a promising approach for preventing POCD.

Diagnostic value of microRNA-200 expression in peripheral blood-derived extracellular vesicles in early-stage non-small cell lung cancer.

OBJECTIVE: This study assessed the diagnostic value of microRNA-200 (miR-200) expression in peripheral blood-derived extracellular vesicles (EVs) in early-stage non-small cell lung cancer (NSCLC). METHODS: This study retrospectively analyzed 100 healthy volunteers (the control group) receiving physical examinations, 168 early-stage NSCLC patients (the NSCLC group), and 128 patients with benign lung nodules (the benign group). The basic and clinical data of participants were obtained, including age, sex, smoking history, carbohydrate antigen 242 (CA242), carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), forced expiratory volume in 1 s, maximal voluntary ventilation, forced vital capacity, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and miR-200 expression. The correlation of miR-200 expression in peripheral blood-derived EVs with CA242, CEA, and CA199 was analyzed, and the diagnostic value of peripheral blood-derived EV miR-200 for early-stage NSCLC was assessed. The risk factors of early-stage NSCLC development were also determined. RESULTS: Age, the percentage of patients with smoking history, CA242, CEA, CA199, IL-6, and TNF-α levels, and miR-200 expression in peripheral blood-derived EVs were significantly higher in the NSCLC group than in the benign and control groups. Lung disease patients with high miR-200 expression in peripheral blood-derived EVs comprised a higher percentage of patients with smoking history and mixed lesions and had higher CA242, CEA, CA199, and TNF-α levels than those with low miR-200 expression in peripheral blood-derived EVs. In lung diseases, miR-200 expression in peripheral blood-derived EVs was significantly and positively correlated with CA242, CEA, and CA199. Peripheral blood-derived EV miR-200 combined with CA242, CEA and CA199 had higher diagnostic value (area under the curve = 0.942) than single detection, along with higher specificity, and high expression of peripheral blood-derived EV miR-200 was an independent risk factor for early-stage NSCLC. CONCLUSION: Peripheral blood-derived EV miR-200 expression in patients with lung diseases is closely correlated with CA242, CEA, and CA199, and high expression of peripheral blood-derived EV miR-200 is an independent risk factor for early-stage NSCLC and is of high clinical diagnostic value for early-stage NSCLC.

Influence of autonomic nervous dysfunction on eating during hemodialysis sessions: An observational study.

Although some studies have indicated that eating during hemodialysis may induce hypotension and cardiovascular events, some patients still consume food during their treatment. This prospective study was conducted to determine whether the need to eat during hemodialysis treatment was related to abnormal glucose metabolism and autonomic nerve dysfunction. Seventy patients were enrolled in this study, and their demographic features and various laboratory parameters were analyzed. At each routine hemodialysis visit, predialysis, intradialysis, and postdialysis blood pressure measurements were systematically conducted. A 24-hour ambulatory electrocardiogram (ECG) was performed during the hemodialysis interval, and heart rate variability (HRV) values were calculated. Additionally, whether the patients ate during the hemodialysis treatments was recorded. Another 20 people who underwent physical examinations during the same period and were matched for sex and age were included in the control group. The HRV values of the hemodialysis patients were generally lower than those of the control group. Univariate analysis revealed significant differences in sex, age, calcium antagonist use, blood calcium levels, insulin levels, diastolic blood pressure (DBP) measurements, and HRV indices between hemodialysis patients who ate and those who did not eat during hemodialysis (P < .05), whereas there were no significant differences in diabetes status or in the hemoglobin, albumin, blood glucose and C-peptide levels (P > .05). Multivariate analysis revealed that low values for very low frequency (VLF) and postdialysis DBP were risk factors for fasting intolerance during hemodialysis treatments. Autonomic dysfunction may affect whether hemodialysis patients tolerate fasting during dialysis. VLF evaluation may provide information that can be used to develop a more reasonable intradialytic nutritional supplementation method.

Effect of health literacy on hospital readmission among patients with heart failure: A protocol for systematic review and meta-analysis.

BACKGROUND: Patients with heart failure have a high rate of health literacy deficiency, and their hospital readmission is a great burden. Whether health literacy affects hospital readmission remains controversial. OBJECTIVE: To investigate the impact of health literacy on hospital readmission among heart failure patients. METHOD: Relevant keywords were used to search for Chinese and English literature from Web of Science, PubMed, Cochrane Library, China National Knowledge Infrastructure, VIP Database for Chinese Technical Periodicals, Digital Journal of Wanfang Data, and Chinese BioMedical Literature Database. Newcastle-Ottawa Scale was used to assess the quality of the studies. Statistical analysis was performed using Stata 15.0, the fixed effect model was used to calculate the pooled effect estimate, and Begg's and Egger's tests were applied to assess the presence of publication bias. RESULTS: Nine studies, involving 4093 heart failure patients, were included in this study. The overall rate of inadequate health literacy was 40.3%. Among these articles, 6 were included in the meta-analysis to calculate the pooled effect. The results indicated that, when compared with patients with adequate health literacy, those with inadequate health literacy had a relative risk of hospital readmission of 1.01, which increased to 1.14 after adjusting for follow-up time, the result was not significant (P = .09). CONCLUSIONS: About 2 out of 5 heart failure patients had inadequate health literacy, and there was no statistical association between health literacy and hospital readmission among these patients. This finding should be carefully considered and confirmed in further studies.

Photoinduced Radical Annulations of Tetrahydroisoquinoline Derivatives with 2-Benzothiazolimines: Highly Diastereoselective Synthesis of Fused Hexahydroimidazo[2,1-a]isoquinolines.

We report herein a photoinduced radical 1,3-dipolar cycloaddition between the 2-benzothiazolimines and tetrahydroisoquinoline derivatives with an organo-photocatalyst. A variety of benzothiazole-based hexahydroimidazo[2,1-a]isoquinoline architectures with great synthetic value were conveniently and efficiently constructed in moderate to good yields and excellent diastereoselectivities with highly tolerant functional groups. Moreover, the practicality and utility of this protocol were demonstrated by scale-up synthesis and facile elaboration. Preliminary mechanistic investigations indicated that the reaction proceeded via a visible-light-induced radical 1,3-dipolar cycloaddition pathway. This finding is expected to stimulate a more extensive exploration of the green and concise synthesis of structurally diverse heterocyclic molecules in the synthetic community.

Interactions of Potential Endocrine-Disrupting Chemicals with Whole Human Proteome Predicted by AlphaFold2 Using an In Silico Approach.

Binding with proteins is a critical molecular initiating event through which environmental pollutants exert toxic effects in humans. Previous studies have been limited by the availability of three-dimensional (3D) protein structures and have focused on only a small set of environmental contaminants. Using the highly accurate 3D protein structure predicted by AlphaFold2, this study explored over 60 million interactions obtained through molecular docking between 20,503 human proteins and 1251 potential endocrine-disrupting chemicals. A total of 66,613,773 docking results were obtained, 1.2% of which were considered to be high binding, as their docking scores were lower than -7. Monocyte to macrophage differentiation factor 2 (MMD2) was predicted to interact with the highest number of environmental pollutants (526), with polychlorinated biphenyls and polychlorinated dibenzofurans accounting for a significant proportion. Dimension reduction and clustering analysis revealed distinct protein profiles characterized by high binding affinities for perfluoroalkyl and polyfluoroalkyl substances (PFAS), phthalate-like chemicals, and other pollutants, consistent with their uniquely enriched pathways. Further structural analysis indicated that binding pockets with a high proportion of charged amino acid residues, relatively low α-helix content, and high ß-sheet content were more likely to bind to PFAS than others. This study provides insights into the toxicity pathways of various pollutants impacting human health and offers novel perspectives for the establishment and expansion of adverse outcome pathway-based models.

Promising strategies in natural products treatments of psoriasis-update.

Psoriasis is a chronic, relapsing, inflammatory skin disease and has been increasing year by year. It is linked to other serious illnesses, such as psoriatic arthritis, cardiometabolic syndrome, and depression, resulting in a notable decrease in the quality of life for patients. Existing therapies merely alleviate symptoms, rather than providing a cure. An in-depth under-standing of the pathogenesis of psoriasis is helpful to discover new therapeutic targets and develop effective novel therapeutic agents, so it has important clinical significance. This article reviews the new progress in the study of pathogenesis and natural products of psoriasis in recent years. These natural products were summarized, mainly classified as terpenoids, polyphenols and alkaloids. However, the translation of experimental results to the clinic takes a long way to go.

Chloride-Ion-Enriched Solid Electrolyte Interphase with Rapid Na+ Migration toward High-Performance Sodium-Ion Batteries.

Sodium-ion batteries (SIBs) have emerged as potential alternatives to lithium-ion batteries (LIBs), particularly for large-scale applications. Alloy-type anode materials for sodium-ion batteries are esteemed as prospective candidate materials for sodium-ion anodes, owing to their elevated theoretical capacity, heightened utilization efficiency, and minimal production of insulating byproducts. However, the severe volume changes and sluggish ion diffusion kinetics can lead to irreversible particle fragmentation and reaggregation phenomena, ultimately resulting in electrode degradation. Additionally, repetitive volume changes can cause an unstable solid electrolyte interphase (SEI). This study presents the synthesis of chloride-ion-modulated bimetallic SnSb/C nanoparticle anode materials, highlighting the following advantages: (i) Designing a bimetallic SnSb alloy structure serves to buffer the structural stresses generated during sodium insertion/extraction processes, effectively mitigating particle fracture phenomena induced by electrode material expansion/contraction. (ii) Nanostructuring both alloy materials enables the full utilization of active materials and shortens diffusion pathways, thereby significantly enhancing the diffusion rate of sodium ions. (iii) Introducing a carbonaceous matrix serves to alleviate self-agglomeration phenomena of the material during charge/discharge cycles, enhancing the material's conductivity and structural stability. (iv) Utilizing chloride-ion interface modification to achieve a chloride-rich solid-electrolyte interphase (SEI) enhances battery performance.

Promoting Cathodic Kinetics and Anodic Stability in Practical Room-Temperature Sodium-Sulfur Batteries with Bifunctional Electrolytes.

The development of room-temperature (RT) sodium-sulfur (Na-S) batteries is severely hindered due to the slow kinetics of the S cathode and the instability of the Na-metal anode. To overcome this, we introduced a dual-functional electrolyte cosolvent, trifluoromethanesulfonamide (TFMSA). Short-chain Na2Sx (1 ≤ x ≤ 2) can be effectively dissolved due to the strong H-S bond interaction between TFMSA and sulfides, which changes the S conversion process, thereby effectively enhancing the conversion kinetics of the cathode. Meanwhile, TFMSA can generate a stable solid electrolyte interphase on the Na-metal surface to protect it from soluble polysulfide attack. Therefore, the RT Na-S batteries using the ether electrolyte show a high initial discharge capacity of 896.6 mAh g-1 and a capacity retention rate of 73% after 150 cycles at 0.2C, and the pouch cell also demonstrates its practical performance. This work proposes a dual-functional electrolyte cosolvent selection principle to inspire the practical application of high-performance RT Na-S batteries.

Fluorine Doping Mediated Epitaxial Growth of NaREF4 on TiO2 for Boosting NIR Light Utilization in Bioimaging and Photodynamic Therapy.

By integrating TiO2 with rare earth upconversion nanocrystals (NaREF4), efficient energy transfer can be achieved between the two subunits under near-infrared (NIR) excitation, which hold tremendous potential in the fields of photocatalysis, photodynamic therapy (PDT), etc. However, in the previous studies, the combination of TiO2 with NaREF4 is a non-epitaxial random blending mode, resulting in a diminished energy transfer efficiency between the NaREF4 and TiO2. Herein, we present a fluorine doping-mediated epitaxial growth strategy for the synthesis of TiO2-NaREF4 heteronanocrystals (HNCs). Due to the epitaxial growth connection, NaREF4 can transfer energy through phonon-assisted pathway to TiO2, which is more efficient than the traditional indirect secondary photon excitation. Additionally, F doping brings oxygen vacancies in the TiO2 subunit, which further introduces new impurity energy levels in the intrinsic band gap of TiO2 subunit, and facilitates the energy transfer through phonon-assisted method from NaREF4 to TiO2. As a proof of concept, TiO2-NaGdF4 : Yb,Tm@NaYF4@NaGdF4 : Nd@NaYF4 HNCs were rationally constructed. Taking advantage of the dual-model up- and downconversion luminescence of the delicately designed multi-shell structured NaREF4 subunit, highly efficient photo-response capability of the F-doped TiO2 subunit and the efficient phonon-assisted energy transfer between them, the prepared HNCs provide a distinctive nanoplatform for bioimaging-guided NIR-triggered PDT.

MRDPDA: A multi-Laplacian regularized deepFM model for predicting piRNA-disease associations.

PIWI-interacting RNAs (piRNAs) are a typical class of small non-coding RNAs, which are essential for gene regulation, genome stability and so on. Accumulating studies have revealed that piRNAs have significant potential as biomarkers and therapeutic targets for a variety of diseases. However current computational methods face the challenge in effectively capturing piRNA-disease associations (PDAs) from limited data. In this study, we propose a novel method, MRDPDA, for predicting PDAs based on limited data from multiple sources. Specifically, MRDPDA integrates a deep factorization machine (deepFM) model with regularizations derived from multiple yet limited datasets, utilizing separate Laplacians instead of a simple average similarity network. Moreover, a unified objective function to combine embedding loss about similarities is proposed to ensure that the embedding is suitable for the prediction task. In addition, a balanced benchmark dataset based on piRPheno is constructed and a deep autoencoder is applied for creating reliable negative set from the unlabeled dataset. Compared with three latest methods, MRDPDA achieves the best performance on the pirpheno dataset in terms of the five-fold cross validation test and independent test set, and case studies further demonstrate the effectiveness of MRDPDA.

Discovery and Evaluation of TLR-Targeted Immune Agonists.

Toll-like receptor (TLR) activation converts immunologically inactive tumors into immunologically active tumors by activating tumor residing antigen-presenting cells and recruitment of cytotoxic T lymphocytes. Targeted immune agonists (TIAs) are antibody drug conjugates with small-molecule TLR agonist payloads. The mechanism of action of TIAs involves tumor antigen recognition, Fcγ-receptor-dependent phagocytosis, and TLR-mediated activation to drive tumor killing by myeloid cells. Several new low DAR anti-HER2 TIAs conjugated with novel TLR7 or dual-TLR7/8 agonists with cleavable and noncleavable linkers were synthesized and profiled. In vitro studies demonstrated that these TIAs activate myeloid cells only in the presence of antigen-expressing cancer cells. Evaluation in ELISpot-based assays confirmed the low immunogenicity of these constructs. Systemic administration of the novel TIAs in tumor-bearing mice resulted in tumor reduction at low doses. These results provide a strong rationale for further development of the TIAs as a novel class of immunotherapeutics.

Role of ASC, a key component of the inflammasome in the antimicrobial process in black rockfish (Sebastes schlegelii).

Apoptosis-associated speck-like protein containing a CARD (ASC) serves as a pivotal component within the inflammasome complex, playing a critical role in the activation of the innate immune response against pathogenic infection. However, the functional significance of inflammasome ASC in teleosts remains unclear. In this study, the coding sequence (CDS) region of ASC gene of Sebastes schlegelii (SsASC) was cloned, and we observed a high conservation of SsASC with teleosts through comprehensive bioinformatics analysis. SsASC and SsCaspase-1 were found to be highly expressed in immune tissues such as spleen and head kidney. Furthermore, our findings revealed that SsASC interacts with SsCaspase-1 through CARD-CARD interactions to generate oligomeric speck-like structures, whereas the PYD structural domain of SsASC forms only filamentous structures. To further understand the role of SsASC in combating Edwardsiella piscicida (E. piscicida) infection, we developed a SsASC knockdown model using in vivo siRNA injection and E. piscicida challenge via intraperitoneal injection. The model demonstrated that E. piscicida infection up-regulated SsASC expression, which was markedly reduced upon SsASC knockdown. Concurrently, E. piscicida colonization was significantly enhanced in the knockdown group, accompanied by a suppression of inflammatory factor expression. These findings confirm the pivotal antibacterial and anti-infective role of SsASC in the Sebastes schlegelii immune response upon E. piscicida stimulation. Our study highlights the significance of SsASC in the innate immune defense mechanism of teleosts against bacterial pathogens.

Identification of N-linked glycans recognized by WGA in saliva from patients with non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths. Saliva diagnosis is an essential approach for clinical applications owing to its noninvasive and material-rich features. The purpose of this study was to investigate differences in wheat germ agglutinin (WGA)-based recognition of salivary protein N-linked glycan profiles to distinguish non-small cell lung cancer (NSCLC) patients from controls. We used WGA-magnetic particle conjugates to isolate glycoproteins in the pooled saliva of healthy volunteers (HV, n = 35), patients with benign pulmonary disease (BPD, n = 35), lung adenocarcinoma (ADC, n = 35), and squamous cell carcinoma (SCC, n = 35), following to release the N-linked glycans from the isolated proteins with PNGase F, and further identified and annotated the released glycans by MALDI-TOF/TOF-MS, respectively. The results showed that 34, 35, 39, and 44 N-glycans recognized by WGA were identified and annotated from pooled saliva samples of HV, BPD, ADC, and SCC, respectively. Furthermore, the proportion of N-glycans recognized by WGA in BPD (81.2 %), ADC (90.1 %), and SCC (88.7 %), increased compared to HV (71.9 %). Two N-glycan peaks (m/z 2286.799, and 3399.211) specifically recognized by WGA were present only in NSCLC. These findings suggest that altered salivary glycopatterns such as sialic acids and GlcNAc containing N-glycans recognized by WGA might serve as potential personalized biomarkers for the diagnosis of NSCLC patients.

Association between processed red meat intake and cardiovascular risk factors in patients with type 2 diabetes: a cross-sectional study from China.

Aim: To explore the association between Processed red meat (PRM) consumption and cardiovascular risk factors in Chinese adults with type 2 diabetes mellitus (T2DM). Methods: Dietary survey, physical measurement, and blood biochemical examination were conducted on 316 patients with type 2 diabetes in Bengbu, China from May to July 2019. Possible confounding factors were identified by comparing between-group variability in the baseline table. To eliminate the effect of confounding factors, subgroup analysis was used to explore whether there were differences in the correlation between PRM intake status and the indicators in cardiovascular disease risk factors. A logistic regression model was used to analyze the association between PRM and the risk of abnormal levels of cardiovascular risk factors in T2DM patients. Restricted cubic spline plots were used to analyze the dose-response relationship between PRM intake and the indicators of cardiovascular disease risk factors. Results: A total of 316 subjects were included in the study, of whom 139 (44.0%) were male and 177 (56.0%) were female. In the multiplicative interaction, there was an effect modifier for smoking (Pinteraction = 0.033) on the association between PRM intake and the risk of substandard FPG level control; sex (Pinteraction = 0.035), smoking status (Pinteraction = 0.017), and alcohol consumption (Pinteraction = 0.046) had effect modifying effects on the association between PRM intake and risk of abnormal systolic blood pressure. Sex (Pinteraction = 0.045) had an effect modifier on the association of PRM intake status with the risk of diastolic blood pressure abnormality. In addition, age had an effect modifier on the association of PRM intake status with risk of abnormal triglyceride index (Pinteraction = 0.004) and risk of abnormal HDL index (Pinteraction = 0.018). After adjusting for potential confounding variables, logistic regression showed that the OR for substandard HbA1c control in patients in the highest PRM intake group, T3 (3.4 ~ 57.2 g/d), was 1.620-fold higher than in the lowest intake, i.e., the no-intake group, T1 (0.0 ~ 0.0 g/d; OR = 2.620; 95% CI 1.198 ~ 5.732; p = 0.016). Whereas the OR for abnormal control of systolic blood pressure levels was 1.025 times higher (OR = 2.025; 95% CI 1.033 ~ 3.968; p = 0.040) in patients in the PRM low intake group T2 (0.1 ~ 3.3 g/d) than in the non-intake group T1 (0.0 ~ 0.0 g/d), the OR for substandard control of systolic blood pressure in patients in the highest group T3 (3.4 ~ 57.2 g/d) was 1.166 times higher than in the no-intake group T1 (OR = 2.166; 95% CI 1.007 ~ 4.660; p = 0.048). The OR for abnormal TG levels in patients in the highest PRM intake group T3 (3.4 ~ 57.2 g/d) was 1.095 times higher than in the no-intake group T1 (OR = 2.095; 95% CI 1.076 ~ 4.078; p = 0.030). Restricted cubic spline plots presented a nonlinear dose-response relationship between PRM intake and risk of substandard HbA1c and SBP control (P nonlinear <0.05), and an atypical inverted U-shaped association between PRM intake and TC and LDL-C levels (P nonlinear <0.05). The strength of the associations between PRM intake and the control levels of FPG, DBP, HDL-C, and TG were not statistically significant (p > 0.05). Conclusion: PRM intake was generally low in patients with T2DM, but a nonlinear dose-response relationship between PRM intake and the risk of suboptimal control of HbA1c and SBP, with an atypical inverted U-shaped association with TC and LDL-C levels, was observed. Appropriate control of PRM intake may be important for tertiary prevention of T2DM and cardiovascular disease prevention. We need to better understand these relationships to promote improved cardiometabolism and global health.

The dual role of glucocorticoid regeneration in inflammation at parturition.

Introduction: Fetal membrane inflammation is an integral event of parturition. However, excessive pro-inflammatory cytokines can impose threats to the fetus. Coincidentally, the fetal membranes express abundant 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1), which generates biologically active cortisol to promote labor through induction of prostaglandin synthesis. Given the well-recognized anti-inflammatory actions of glucocorticoids, we hypothesized that cortisol regenerated in the fetal membranes might be engaged in restraining fetus-hazardous pro-inflammatory cytokine production for the safety of the fetus, while reserving pro-labor effect on prostaglandin synthesis to ensure safe delivery of the fetus. Methods: The hypothesis was examined in human amnion tissue and cultured primary human amnion fibroblasts as well as a mouse model. Results: 11ß-HSD1 was significantly increased in the human amnion in infection-induced preterm birth. Studies in human amnion fibroblasts showed that lipopolysaccharide (LPS) induced 11ß-HSD1 expression synergistically with cortisol. Cortisol completely blocked NF-κB-mediated pro-inflammatory cytokine expression by LPS, but STAT3-mediated cyclooxygenase 2 expression, a crucial prostaglandin synthetic enzyme, remained. Further studies in pregnant mice showed that corticosterone did not delay LPS-induced preterm birth, but alleviated LPS-induced fetal organ damages, along with increased 11ß-HSD1, cyclooxygenase 2, and decreased pro-inflammatory cytokine in the fetal membranes. Discussion: There is a feed-forward cortisol regeneration in the fetal membranes in infection, and cortisol regenerated restrains pro-inflammatory cytokine expression, while reserves pro-labor effect on prostaglandin synthesis. This dual role of cortisol regeneration can prevent excessive pro-inflammatory cytokine production, while ensure in-time delivery for the safety of the fetus.