Dietary branched-chain amino acids intake and new-onset hypertension: a nationwide prospective cohort study in China.

OBJECTIVE: This study aimed to investigate the relationship between dietary branched-chain amino acids (BCAAs) and the risk of developing hypertension. METHODS: A cohort study of 14,883 Chinese adults without hypertension at baseline with were followed for an average of 8.9 years. Dietary intakes of BCAAs, including Ile, Leu, and Val, were collected using 3-day 24-h meal recall and household condiment weighing. Cox proportional hazards regression, restricted cubic splines, interaction analysis, and sensitivity analysis were used to assess the relationship between dietary BCAAs and risk of developing self-reported hypertension, adjusting for age, gender, region, body mass index (BMI), smoking and drinking status, physical activity, energy intake, salt intake. RESULTS: Among 14,883 study subjects, 6386(42.9%) subjects aged ≥ 45 years at baseline, 2692 (18.1%) had new-onset hypertension during the study period, with a median age of 56 years. High levels of dietary BCAAs were associated with an increased risk of new-onset hypertension. Compared with the 41st-60th percentile, multivariable adjusted hazard ratio (HR) for new-onset hypertension was 1.16 (95% CI 1.01-1.32) for dietary BCAAs 61st-80th percentiles, 1.30 (1.13-1.50) for 81st-95th, 1.60 (1.32-1.95) for 96th-100th. The cut-off value of new-onset hypertension risk, total BCAAs, Ile, Leu, and Val were 15.7 g/day, 4.1 g/day, 6.9 g/day, 4.6 g/day, respectively, and the proportion of the population above these intake values were 13.9%, 13.1%, 15.4%, and 14.4%, respectively. Age, BMI, and salt intake had an interactive effect on this relationship (P < 0.001). CONCLUSION: There was a significant positive association between total dietary BCAAs, Ile, Leu, Val intake and the risk of developing hypertension, after adjustment for confounders. This relationship was influenced by age, BMI, and salt intake. Further research is needed to clarify the mechanism and potential role of BCAAs in the pathogenesis of hypertension.

Analysis of microbiota reveals the underlying mechanism of PHF11 in the development of Enterococcus-regulated endometriotic cysts.

Endometriosis (EMS) is a prevalent disease and the etiologies has not uniform. Microbiota is associated with human diseases. To delve into the relationship between EMS and microbiota, Ectopic (EM) and eutopic (EU) endometrial tissues, pharyngeal swabs, and stools were collected from EMS patients. The microbiota composition of EM and EU partially overlapped, with similar taxon numbers and diversity, but the richness levels were significantly different. A comparison of intestinal microbes in healthy individuals (FN) and EMS patients (FE) revealed that the richness of Enterococcus, Pseudomonas, Haemophilus, and Neisseria was enhanced in FE. In addition, Enterococcus-induced mice (EFA) presented with a higher degree of lesion infiltration and a wider distribution of lesions. Proteomic analysis revealed the expression of plant homeodomain finger 11 (PHF11) was notably downregulated in EFA. And the downregulated expression of PHF11 was accompanied by the upregulated expression of interleukin 8 (IL-8). Our findings suggest a potential regulatory mechanism for PHF11 in EMS development.

Prediction and validation of common targets in atherosclerosis and non-small cell lung cancer influenced by atorvastatin.

BACKGROUND: Cardiovascular disease and cancer are the main causes of morbidity and mortality worldwide. Studies have shown that these two diseases may have some common risk factors. Atorvastatin is mainly used for the treatment of atherosclerosis in clinic. A large number of studies show that atorvastatin may produce anti-tumor activities. This study aimed to predict the common targets of atorvastatin against atherosclerosis and non-small cell lung cancer (NSCLC) based on network pharmacology. METHODS: The target genes of atherosclerosis and NSCLC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The disease-target-component model map and the core network were obtained using Cytoscape 3.7.1. The MTS and wound healing assay were used to detect the effect of atorvastatin on cell viability and migration of A549 cells. The expression of potential common target genes of atorvastatin against atherosclerosis and NSCLC were confirmed in A549 cells and lung cancer tissues of patients. RESULTS: We identified 15 identical pathogenic genes, and four of which (MMP9, MMP12, CD36, and FABP4) were considered as the key target genes of atorvastatin in anti-atherosclerosis and NSCLC. The MTS and wound healing assays revealed that atorvastatin decreased A549 cells migration significantly. Atorvastatin markedly decreased the expression of MMP9, MMP12, CD36, and FABP4 in A549 cells and patients were treated with atorvastatin. CONCLUSIONS: This study demonstrated 15 common pathogenic genes in both atherosclerosis and NSCLC. And verified that MMP 9, MMP 12, CD 36 and FABP 4 might be the common target genes of atorvastatin in anti-atherosclerosis and NSCLC.

The Roles and Targeting of Tumor-Associated Macrophages.

Tumor-associated macrophages (TAMs) are the most abundant infiltrating immune cells in the tumor microenvironment (TME) and play an important role in tumor progression. Clinically, the increase of TAMs infiltration is linked to poor prognosis of patients with various cancer types. Multiple studies have demonstrated that reducing or reprogramming TAMs can inhibit the occurrence or development of tumors. Therefore, TAMs have been identified as novel targets for the treatment of cancer therapy. In this review, the origin, polarization, roles, and targeting of TAMs in malignancies, are discussed.

The novel small molecule BH3 mimetic nobiletin synergizes with vorinostat to induce apoptosis and autophagy in small cell lung cancer.

Small cell lung cancer (SCLC) is a highly lethal subtype of lung cancer with few therapeutic options; therefore, the identification of new targets and drugs with potent combination therapy is desirable. We previously screened BH3 mimetics from a natural product library, and in this study, we validated nobiletin as a BH3 mimetic. Specifically, we observed its combination potential and mechanism with vorinostat in SCLC in vitro and in vivo. The results showed that combination treatment with nobiletin and vorinostat reduced the proliferation of SCLC H82 cells and increased the levels of apoptotic proteins such as cleaved caspase-9 and cleaved PARP. The combination treatment increased LC3-II expression and induced autophagic cell death. In addition, this treatment significantly inhibited H82 cell xenograft SCLC tumor growth in nude mice. The combination treatment with nobiletin and vorinostat efficiently increased autophagy by inhibiting the PI3K-AKT-mTOR pathway and promoting dissociation of the BCL-2 and Beclin 1 complex, increasing the level of isolated Beclin 1 to stimulate autophagy. Molecular docking and surface plasmon resonance analysis showed that nobiletin stably bound to the BCL-2, BCL-XL and MCL-1 proteins with high affinity in a concentration-dependent manner. These results suggest that nobiletin is a BH3-only protein mimetic. Furthermore, the combination of nobiletin with vorinostat increased histone H3K9 and H3K27 acetylation levels in SCLC mouse tumor tissue and enhanced the expression of the BH3-only proteins BIM and BID. We conclude that nobiletin is a novel natural BH3 mimetic that can cooperate with vorinostat to induce apoptosis and autophagy in SCLC.

Targeted nutritional intervention with enhanced recovery after surgery for carotid endarterectomy: A prospective clinical trial.

Ischemic stroke is the most common cerebrovascular disease, and vascular obstruction is an important cause of this disease. As the main method for the management of carotid artery stenosis, carotid endarterectomy (CEA) is an effective and preventive treatment measure in ischemic cerebrovascular disease. This study aims to propose the application of a new enhanced recovery after surgery (ERAS) nutritional support regimen in CEA, which can significantly improve the perioperative nutritional status of patients. A total of 74 patients who underwent CEA were included and randomly divided into two groups: 39 patients received nutritional therapy with the ERAS protocol (ERAS group) and 35 patients received routine perioperative nutritional support (control group). Our results showed that the levels of major clinical and biochemical parameters (albumin, hemoglobin, creatinine, calcium and magnesium levels, etc.) in the ERAS group were significantly higher than those in the control group after surgery (p < 0.05). Additionally, patients in the ERAS group had dramatically shorter postoperative length of stay and reflected higher mean satisfaction at discharge (p < 0.001). Moreover, no statistically significant differences were observed in postoperative complication rates and Mini-mental State Examination scores at discharge. The emergence of this neurosurgical ERAS nutritional support program can effectively intervene in perioperative nutritional status, and notably reduce postoperative hospital stays.

Effects of dietary chlorogenic acid on intestinal barrier function and the inflammatory response in broilers during lipopolysaccharide-induced immune stress.

Immune stress exerts detrimental effects on growth performance and intestinal barrier function during intensive animal production with ensuing serious economic consequences. Chlorogenic acid (CGA) is used widely as a feed additive to improve the growth performance and intestinal health of poultry. However, the effects of dietary CGA supplementation on amelioration of the intestinal barrier impairment caused by immune stress in broilers are unknown. This study investigated the effects of CGA on growth performance, intestinal barrier function, and the inflammatory response in lipopolysaccharide (LPS) mediated immune-stressed broilers. Three hundred and twelve 1-day-old male Arbor Acres broilers were divided randomly into 4 groups with 6 replicates of thirteen broilers. The treatments included: i) saline group: broilers injected with saline and fed with basal diet; ii) LPS group: broilers injected with LPS and fed with basal diet; iii) CGA group: broilers injected with saline and feed supplemented with CGA; and iv) LPS+CGA group: broilers injected with LPS and feed supplemented with CGA. Animals in the LPS and LPS+CGA groups were injected intraperitoneally with an LPS solution prepared with saline from 14 d of age for 7 consecutive days, whereas broilers in the other groups were injected only with saline. LPS induced a decrease in feed intake of broilers during the stress period, but CGA effectively alleviated this decrease. Moreover, CGA inhibited the reduction of villus height and improved the ratio of villus height to crypt depth in the duodenum of broilers 24 and 72 h after LPS injection. In addition, dietary CGA supplementation significantly restored the expression of cation-selective and channel-forming Claudin2 protein 2 h after LPS injection in the ileum. LPS enhanced the expression of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in the small intestine, but this enhancement was blocked by CGA supplementation. The expression of interleukin-10 (IL-10) increased with LPS injection and CGA promoted the production of IL-10. CGA addition downregulated the expression of intestinal interleukin-6 (IL-6) of broilers under normal rearing conditions. However, CGA supplementation upregulated the expression of IL-6 of broilers 72 h after LPS injection. The data demonstrate that dietary supplementation with CGA alleviates intestinal barrier damage and intestinal inflammation induced by LPS injection during immune stress thereby improving growth performance of broilers.

DNALI1 deficiency causes male infertility with severe asthenozoospermia in humans and mice by disrupting the assembly of the flagellar inner dynein arms and fibrous sheath.

The axonemal dynein arms (outer (ODA) and inner dynein arms (IDAs)) are multiprotein structures organized by light, intermediate, light intermediate (LIC), and heavy chain proteins. They hydrolyze ATP to promote ciliary and flagellar movement. Till now, a variety of dynein protein deficiencies have been linked with asthenospermia (ASZ), highlighting the significance of these structures in human sperm motility. Herein, we detected bi-allelic DNALI1 mutations [c.663_666del (p.Glu221fs)], in an ASZ patient, which resulted in the complete loss of the DNALI1 in the patient's sperm. We identified loss of sperm DNAH1 and DNAH7 rather than DNAH10 in both DNALI1663_666del patient and Dnali1-/- mice, demonstrating that mammalian DNALI1 is a LIC protein of a partial IDA subspecies. More importantly, we revealed that DNALI1 loss contributed to asymmetries in the most fibrous sheath (FS) of the sperm flagellum in both species. Immunoprecipitation revealed that DNALI1 might interact with the cytoplasmic dynein complex proteins in the testes. Furthermore, DNALI1 loss severely disrupted the transport and assembly of the FS proteins, especially AKAP3 and AKAP4, during flagellogenesis. Hence, DNALI1 may possess a non-classical molecular function, whereby it regulates the cytoplasmic dynein complex that assembles the flagella. We conclude that a DNALI deficiency-induced IDAs injury and an asymmetric FS-driven tail rigid structure alteration may simultaneously cause flagellum immotility. Finally, intracytoplasmic sperm injection (ICSI) can effectively resolve patient infertility. Collectively, we demonstrate that DNALI1 is a newly causative gene for AZS in both humans and mice, which possesses multiple crucial roles in modulating flagellar assembly and motility.

Critical Residues Involved in the Coassembly of L1 and L2 Capsid Proteins of Human Papillomavirus 16.

Human papillomaviruses (HPV) are small DNA viruses associated with cervical cancer, warts, and other epithelial tumors. Structural studies have shown that the HPV capsid consists of 360 copies of the major capsid protein, L1, arranged as 72 pentamers in a T=7 icosahedral lattice, coassembling with substoichiometric amounts of the minor capsid protein, L2. However, the residues involved in the coassembly of L1 and L2 remain undefined due to the lack of structure information. Here, we investigated the solvent accessibility surfaces (SASs) of the central cavity residues of the HPV16 L1 pentamer in the crystal structure because those internal exposed residues might mediate the association with L2. Twenty residues in L1 protein were selected to be analyzed, with four residues in the lumen of the L1 pentamer identified as important: F256, R315, Q317, and T340. Mutations to these four residues reduced the PsV (pseudovirus) infection capacity in 293FT cells, and mutations to R315, Q317, and T340 substantially perturb L2 from coassembling into L1 capsid. Compared with wild-type (WT) PsVs, these mutant PsVs also have a reduced ability to become internalized into host cells. Finally, we identified a stretch of negatively charged residues on L2 (amino acids [aa] 337 to 340 [EEIE]), mutations to which completely abrogate L2 assembly into L1 capsid and subsequently impair the endocytosis and infectivity of HPV16 PsVs. These findings shed light on the elusive coassembly between HPV L1 and L2. IMPORTANCE Over 200 types of HPV have been isolated, with several high-risk types correlated with the occurrence of cervical cancer. The HPV major capsid protein, L1, assembles into a T=7 icosahedral viral shell, and associates with the minor capsid protein, L2, which plays a critical role in the HPV life cycle. Despite the important role of the L2 protein, its structure and coassembly with L1 remain elusive. In this study, we analyzed the amino acid residues at the proposed interface between L1 and L2. Certain mutations at these sites decreased the amount of L2 protein assembled into the capsid, which, in turn, led to a decrease in viral infectivity. Knowledge about these residues and the coassembly of L1 and L2 could help to expand our understanding of HPV biology and aid in the development of countermeasures against a wide range of HPV types by targeting the L2 protein.

Associations between healthy lifestyle score and health-related quality of life among Chinese rural adults: variations in age, sex, education level, and income.

PURPOSE: This study aimed to investigate the associations between overall lifestyles and HRQoL, as well as the variations in age, sex, education level, and income. METHODS: A total of 23,402 participants from the Henan rural cohort were included. The healthy lifestyle score (HLS) consists of five lifestyle factors: smoking, alcohol drinking, physical activity, diet, and body mass index. HRQoL was assessed by the EQ-5D-5L questionnaire. The general linear model and Tobit regression model were utilized to assess the associations of HLS with visual analogue score (VAS) and utility index. RESULTS: Compared with participants with an HLS of 0-2, the corresponding regression coefficients (ß) and 95% confidence intervals (CI) of participants with an HLS of 3, 4, and 5 for VAS score were 1.09 (0.59, 1.59), 1.92 (1.38, 2.46), and 2.60 (1.83, 3.37); the corresponding ß and 95% CI for utility index were 0.02 (0.01, 0.03), 0.05 (0.03, 0.06), and 0.06 (0.04, 0.07). Notably, these positive associations were greater among the elderly, female, and those with lower education level and average monthly income (p for interaction < 0.05). For instance, the corresponding ß and 95% CI of individuals with an HLS of 5 for utility index in average monthly income < 500 RMB, 500-999 RMB, and ≥ 1000 RMB groups were 0.08 (0.05, 0.11), 0.06 (0.03, 0.09), and 0.02 (- 0.00, 0.05). CONCLUSION: Engaging in healthier lifestyle habits was associated with a higher level of HRQoL, especially in the elderly, females, and those with low education level and average monthly income.

The IL-2A receptor pathway and its role in lymphocyte differentiation and function.

Murine myeloid cells are developed from hemopoietic stem/progenitor cells. Different types of progenitor cells have variable differentiation potentials. Among the ten main types of cells differentiated from lymphoid progenitor cells, regulatory T cells (Tregs), an important cell subpopulation regulating immune and inflammatory responses, arise from the hematopoietic stem cells in the bone marrow. Tregs then differentiate into T lymphocytes and migrate to the thymus and finally generate Treg subsets, which are subsequently activated and regulated by inflammatory cytokines in the peripheral blood. Tregs also have different phenotypes and immunomodulatory functions. The cytokine interleukin-2/interleukin-2 receptor (IL-2/IL-2R) pathway is an important regulatory signaling pathway of Tregs. Besides, different types of CD4+ and CD8+ cells have different immune effects in the absence of IL-2. IL-2R consists of three subunits, α chain (CD25), ß chain (CD122), and γ chain (CD132). Different subunit combinations have different effects on the activation of immune cells. Multiple studies have shown that IL2RA deficiency has various effects on the immune function in mice. This article reviews the subunit composition and signaling pathway of IL-2R, the classification of Tregs in a murine myeloid cell line and the regulatory effect of IL-2/IL-2R on them, the regulatory impact and signaling mechanism of IL-2/IL-2R on CD4+/CD8+ lymphocyte differentiation, the primary manifestations and molecular mechanism of immune dysfunction in IL-2- and IL-2R-deficient mice, soluble IL-2Rα as a biomarker for diagnosis, prognosis and therapeutic efficacy of treatment in immune system disorders, and the development and clinical application of IL-2 mutants.

Stroke Risk Factors of Stroke Patients in China: A Nationwide Community-Based Cross-Sectional Study.

BACKGROUND: Stroke is the leading cause of death in China, and its burdens are rapidly increasing. The prevalence and control of stroke risk factors among stroke patients in China are unknown. OBJECTIVE: We investigated the stroke risk factors of stroke patients in China. DESIGN: We examined stroke risk factors in 6580 stroke patients aged 18 years or older in the China National Chronic Diseases and Nutrition Surveillance of Adults (2015-2017). With regard to the basic characteristics of the study participants, categorical variables were described as frequency (percent). The chi-square test was used to analyze the difference between men and women. The multivariate logistic regression model was used in the multivariate analysis. RESULTS: Among the 6580 stroke patients, hypertension was the most common stroke risk factor identified in most cases (78.51%), followed by overweight or obesity (61.58%), dyslipidemia (54.38%), smoking (24.04%), diabetes (21.75%), family history of stroke (17.43%), lack of exercise (16.35%), and atrial fibrillation (4.47%). Drinking stroke patients had a lower rate of hypertension, diabetes, and dyslipidemia. Patients with hyperuricemia had a higher rate of hypertension and dyslipidemia than no-hyperuricemia patients. The hypertension awareness, treatment, and control rates among hypertension stroke patients were 73.62%, 70.19%, and 17.79%, respectively. The diabetes awareness, treatment, and control rates among diabetes patients were 69.74%, 65.83%, and 34.59%, respectively. The dyslipidemia awareness, treatment, and control rates among dyslipidemia patients were 42.37%, 29.4%, and 20.07%, respectively. Among treated hypertension patients, the rates of taking medicine as medically advised, controlled diet, increased exercise, and blood pressure monitoring were 91.31%, 58.88%, 45.78%, and 73.99%, respectively. Among treated diabetes patients, the rates of oral antidiabetic medications, insulin injection, diet control, and blood glucose monitoring were 78.24%, 34.71%, 85.77%, and 78.24%, respectively. Among treated dyslipidemic patients, the rate of taking medicine as medical advice, controlled diet, increased exercise, and regular blood lipid monitoring was 80.61%, 77.57%, 56.46%, and 40.3%, respectively. CONCLUSIONS: The most common risk factors for community stroke patients in China are hypertension, dyslipidemia, and overweight or obesity. The stroke community patients' suboptimal awareness and treatment of hypertension, and suboptimal awareness, treatment, and control of diabetes, and dyslipidemia are significant problems in China.

Magnesium Nutritional Status, Risk Factors, and the Associations with Glucose Parameters of Childbearing Women in the China Adult Chronic Disease and Nutrition Surveillance (2015).

Magnesium is an essential element and participates in many metabolic pathways. Inadequate magnesium levels may lead to various health problems such as type 2 diabetes (T2DM), hypertension, and cancer. But the role of Mg in childbearing women of China is still a relatively narrow researched field. We aimed to assess the Mg nutritional status, explore the risk factors of Mg deficiency, and the associations between Mg and glucose parameters among childbearing women in a nationally representative sample. A total of 1895 18-44 years childbearing women were recruited from the China Adult Chronic Disease and Nutrition Surveillance (2015). Multivariate logistic regression was used to explore the risk factors for Mg deficiency and estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for the risk of hyperglycemia. The mean value of Mg was 0.87 mmol/L and the prevalence of deficiency was 4.69%. The risk factors of Mg deficiency (Mg < 0.75 mmol/L) was city-type of rural (p = 0.045), while calcium (p = 0.001), LDL-C (p = 0.024), age group of 26-35 years (p = 0.016), 36-44 years (p = 0.006), and CNNM2 rs3740393 genotypes of GC (p = 0.027) were protective factors. It was also found that magnesium deficiency induces an increase in plasma glucose (p = 0.001). Compared with the reference range, Mg < 0.75 mmol/L would have a 6.53 fold risk for T2DM, a 5.31 fold risk for glucose-hyperglycemia, and a 9.60 fold risk for HbA1c-hyperglycemia. Consistently, there was a negative association between plasma Mg and blood glucose parameters in the dose-response study. More attention should be paid to the nutritional status of magnesium and the impact of magnesium deficiency on human health.

Pontibacter pamirensis sp. nov., isolated from saline-alkaline soil.

A novel bacterium, designated TRT317T, was isolated from saline-alkaline soil collected from the Pamir plateau in northwest China. Cells of this strain were Gram-stain-negative, aerobic rods and red-pink-coloured. Phylogenetic analysis using 16S rRNA gene sequences indicated that strain TRT317T showed the highest sequence similarity to the type strains of Pontibacter diazotrophicus (96.3 %) and Pontibacter yuliensis (96.2 %). Growth was observed at 4-40 °C, pH 6.0-10.0 and in the presence of up to 7 % (w/v) NaCl. The major fatty acids were iso-C15 : 0 and summed feature 4 (iso-C17 : 1 I/anteiso-C17 : 1 B). The polar lipids included phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, one unidentified phospholipid, four unidentified glycolipids and five unidentified lipids. The whole-cell sugars of strain TRT317T were mannose, rhamnose, glucose, galactose, xylose, arabinose and four unidentified sugars. The sole respiratory quinone was MK-7. The genomic DNA G+C content of strain TRT317T was 47.7 mol%. The average nucleotide identity (ANI) value of strain TRT317T with P. diazotrophicus was 88.3 %, which is below the standard ANI threshold for species identification (95-96 %). Combined results of physiological, genotypic, phylogenetic and chemotaxonomic analyses demonstrated that strain TRT317T represents a novel species within the genus Pontibacter, for which the name Pontibacter pamirensis sp. nov. is proposed. The type strain is TRT317T (=CGMCC1.18690T=KCTC 82818T).

Dietary Pattern Associated with the Risk of Poor Glycemic Control in Chinese Diabetic Adults: Results from the China Nutrition and Health Surveillance 2015-2017 Survey.

The present study was conducted to investigate the nutrition status of dietary patterns and the association between dietary patterns and the risk of poor glycemic control in Chinese diabetics. The relevant data was collected from the China Nutrition and Health Surveillance 2015-2017 survey, which is a national cross-sectional surveillance program. A total of 2031 participants were included in the present statistical analysis. Food consumption was assessed through a validated and standard food frequency questionnaire. Dietary patterns were derived with reduced rank regression using hemoglobin A1c. Diabetes was diagnosed by medical institutions, glycemic control was defined as hemoglobin A1c less than 7%, poor glycemic control was defined as hemoglobin A1c greater than 7%. A multiple-variable-adjusted logistic regression, including age, living area, income level, educational attainment, body mass index, occupational physical activity, energy intake, current smoking status, current drinking status, diabetic medication use, insulin use, following diabetic diets, increased exercise, and glucose monitoring, was adjusted to explore the association between dietary patterns and the risk of poor glycemic control in diabetes. Two gender-specific dietary patterns have an increased risk of poor glycemic control and are characterized by a low intake of freshwater fish, poultry, and fruits. For male participants, the dietary pattern was characterized by a high intake of wheat and its products, a low intake of vegetables, corn and its products, shrimp and crab, and beans (Q4 vs. Q1, OR = 2.69, 95% CI: 1.76 to 4.10). For female participants, the dietary pattern was characterized by a low intake of snacks and nuts, and algae and mushroom (Q4 vs. Q1, OR = 2.18, 95% CI: 1.48 to 3.20).

Engineering for an HPV 9-valent vaccine candidate using genomic constitutive over-expression and low lipopolysaccharide levels in Escherichia coli cells.

BACKGROUND: The various advantages associated with the growth properties of Escherichia coli have justified their use in the production of genetically engineered vaccines. However, endotoxin contamination, plasmid vector instability, and the requirement for antibiotic supplementation are frequent bottlenecks in the successful production of recombinant proteins that are safe for industrial-scaled applications. To overcome these drawbacks, we focused on interrupting the expression of several key genes involved in the synthesis of lipopolysaccharide (LPS), an endotoxin frequently responsible for toxicity in recombinant proteins, to eliminate endotoxin contamination and produce better recombinant proteins with E. coli. RESULTS: Of 8 potential target genes associated with LPS synthesis, we successfully constructed 7 LPS biosynthesis-defective recombinant strains to reduce the production of LPS. The endotoxin residue in the protein products from these modified E. coli strains were about two orders of magnitude lower than that produced by the wild-type strain. Further, we found that 6 loci-lpxM, lpxP, lpxL, eptA, gutQ and kdsD-were suitable for chromosomal integrated expression of HPV L1 protein. We found that a single copy of the expression cassette conferred stable expression during long-term antibiotic-free cultivation as compared with the more variable protein production from plasmid-based expression. In large-scale fermentation, we found that recombinant strains bearing 3 to 5 copies of the expression cassette had 1.5- to 2-fold higher overall expression along with lower endotoxin levels as compared with the parental ER2566 strain. Finally, we engineered and constructed 9 recombinant E. coli strains for the later production of an HPV 9-valent capsid protein with desirable purity, VLP morphology, and antigenicity. CONCLUSIONS: Reengineering the LPS synthesis loci in the E. coli ER2566 strain through chromosomal integration of expression cassettes has potential uses for the production of a 9-valent HPV vaccine candidate, with markedly reduced residual endotoxin levels. Our results offer a new strategy for recombinant E. coli strain construction, engineering, and the development of suitable recombinant protein drugs.

Intravesical Mucoadhesive Hydrogel Induces Chemoresistant Bladder Cancer Ferroptosis through Delivering Iron Oxide Nanoparticles in a Three-Tier Strategy.

Bladder cancer (BCa) is the most costly solid tumor owing to its high recurrence. Relapsed cancer is known to acquire chemoresistant features after standard intravesical chemotherapy. This cancer state is vulnerable to ferroptosis, which occurs when lipid peroxides generated by iron metabolism accumulate to lethal levels. Increasing the labile iron pool (LIP) by iron oxide nanoparticles (IONPs) promises to inhibit chemoresistant BCa (CRBCa), but systemically administered IONPs do not sufficiently accumulate at the tumor site. Therefore, their efficacy is weakened. Here, we present a three-tier delivery strategy through a mucoadhesive hydrogel platform conveying hyaluronic acid-coated IONPs (IONP-HA). When instilled, the hydrogel platform first adhered to the interface of the tumor surface, sustainably releasing IONP-HA. Subsequently, the tumor stiffness and interstitial fluid pressure were reduced by photothermal therapy, promoting IONP-HA diffusion into the deep cancer tissue. As CRBCa expressed high levels of CD44, the last delivery tier was achieved through antibody-mediated endocytosis to increase the LIP, ultimately inducing ferroptosis. This three-tiered strategy delivered the IONPs stepwise from anatomical to cellular levels and increased the iron content by up to 50-fold from that of systematic administration, which presents a potential regimen for CRBCa.

Dysregulation of Principal Circulating miRNAs in Non-human Primates Following Ischemic Stroke.

Despite the recent interest in plasma microRNA (miRNA) biomarkers in acute ischemic stroke patients, there is limited knowledge about the miRNAs directly related to stroke itself due to the multiple complications in patients, which has hindered the research progress of biomarkers and therapeutic targets of ischemic stroke. Therefore, in this study, we compared the differentially expressed miRNA profiles in the plasma of three rhesus monkeys pre- and post-cerebral ischemia. After cerebral ischemia, Rfam sequence category revealed increased ribosomic RNA (rRNA) and decreased transfer RNAs (tRNAs) in plasma. Of the 2049 miRNAs detected after cerebral ischemia, 36 were upregulated, and 76 were downregulated (fold change ≥2.0, P < 0.05). For example, mml-miR-191-5p, miR-421, miR-409-5p, and let-7g-5p were found to be significantly overexpressed, whereas mml-miR-128a-5p_R - 2, miR-431_R - 1, and let-7g-3p_1ss22CT were significantly downregulated. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that these differentially expressed miRNAs were implicated in the regulation of ubiquitin-mediated proteolysis and signaling pathways in cancer, glioma, chronic myeloid leukemia, and chemokine signaling. miRNA clustering analysis showed that mml-let-7g-5p and let-7g-3p_1ss22CT, which share three target genes [RB1-inducible coiled-coil 1 (RB1CC1), G-protein subunit γ 5 (GNG5), and chemokine (C-X-C motif) receptor 4 (CXCR4)], belong to one cluster, were altered in opposite directions following ischemia. These data suggest that circulating mml-let-7g may serve as a therapeutic target for ischemic stroke.

Temozolomide chemotherapy combined with radiotherapy versus radiotherapy alone after surgery in patients with high-risk low-grade gliomas.

PURPOSE: The purpose of this study was to compare the clinical efficacy and safety of temozolomide (TMZ) combined with three-dimensional conformal radiotherapy (3D-CRT) and radiotherapy alone after surgery in patients with high-risk low-grade gliomas (LGGs). METHODS: Patients (N=110) with LGGs were enrolled. Patients receiving TMZ chemotherapy combined with radiotherapy were considered as combination group (n=55), while those treated with radiotherapy alone were regarded as control group (n=55). The patients were followed up, and the overall survival (OS) and progression-free survival (PFS) were recorded. Finally, factors possibly affecting prognosis were analyzed. RESULTS: The follow-up results exhibited median OS [(67.4±8.8) months vs. (63.9±8.6) months] and median PFS [(51.1±7.6) months vs. (46.8±6.9) months] as well as three-year OS rate and three-year PFS rate in combination group and control group. Log-rank test indicated that the difference in OS was not statistically significant between the two groups of patients, and PFS in combination group was significantly superior to that in control group. The results of univariate and multivariate analysis displayed that age <40 years old and complete tumor resection were independent factors affecting the three-year OS of patients with high-risk LGGs. Besides, age <40 years old, complete tumor resection and TMZ chemotherapy combined with radiotherapy after surgery were independent factors affecting the three-year PFS of patients with high-risk LGGs. CONCLUSION: TMZ chemotherapy combined with radiotherapy after surgery in patients with high-risk LGGs can prominently improve clinical efficacy, prolong PFS, and facilitate tolerance to adverse reactions, but not prolong the OS of patients. The OS is notably prolonged in patients aged <40 years old and receiving complete tumor resection.