Effects of GLP1RAs on pregnancy rate and menstrual cyclicity in women with polycystic ovary syndrome: a meta-analysis and systematic review.

PURPOSE: This study was aimed to assess the effectiveness of Glucagon-like peptide 1 receptor agonists on pregnancy rate, menses, anthropometric and hormonal parameters in PCOS patients. METHODS: We conducted searches of the published literature in PubMed, EMBASE, Cochrane Library, Web of Science up to September 2022. Data from randomized controlled trials were obtained to assess the effects of GLP1RAs in PCOS women. Weighted mean difference, standardized mean difference, and risks ratio were employed for effect size estimation using a random-effects model. RESULTS: A total of 840 patients with 469 individuals in GLP1RAs group and 371 individuals in control group from 11 RCTs were included. GLP1RAs usage was associated with an improvement in natural pregnancy rate (RR: 1.72, 95% CI 1.22 to 2.43, P = 0.002, I2 = 0%) and menstrual regularity (SMD: 1.72, 95% CI 0.60 to 2.85, P < 0.001, I2 = 95.6%). There were no statistically significant differences in total pregnancy rate, IVF pregnancy rate between two groups, but total PR elevated in a short time after GLP1RAs as shown in subgroup analysis. Randomization to GLP1RAs treatment was associated with great improvement in HOMA-IR, BMI, WC, SHBG and a slight reduction in TT compared to control group. A decrease in TBF was seen in European population. GLP1RAs monotherapy was not superior to metformin when it came to fT, DHEAS, FAI. CONCLUSIONS: Prescription of GLP1RAs improves natural pregnancy rate, menstrual cyclicity and insulin sensitivity, anthropometrics, hormonal indexes in PCOS women.

Case report: Fulminant type 1 diabetes following paucisymptomatic SARS-CoV-2 infection during late pregnancy.

Background: Dysregulation of glucose metabolism has been linked to SARS-CoV-2 infection. In addition, the occurrence of new onset diabetes mellitus, including fulminant type 1 diabetes, has been reported after SARS-CoV-2 infection or vaccination. Methods and results: A young Chinese woman in her last trimester of pregnancy presented with an abrupt progression of hyperglycemia and ketoacidosis, but with a near-normal glycohemoglobin level following paucisymptomatic SARS-CoV-2 infection. The low C peptide levels, both fasting and postprandial, reflected profound insulin deficiency in the setting of negative islet autoantibody testing, consistent with a diagnosis of fulminant type 1 diabetes. Ketoacidosis and hyperglycemia quickly improved following the introduction of insulin therapy, but not the ß cell function. The patient received treatment with insulin pump therapy after being discharged, and the first follow-up revealed a well-controlled glucose profile. Conclusions: New-onset FT1D can occur after SARS-CoV-2 infection. Our report raises awareness of this rare but serious situation, promoting early recognition and management of FT1D during the COVID-19 pandemic.

Identification of genes modified by N6-methyladenosine in patients with colorectal cancer recurrence.

Background: Recent studies demonstrate that N6-methyladenosine (m6A) methylation plays a crucial role in colorectal cancer (CRC). Therefore, we conducted a comprehensive analysis to assess the m6A modification patterns and identify m6A-modified genes in patients with CRC recurrence. Methods: The m6A modification patterns were comprehensively evaluated by the NMF algorithm based on the levels of 27 m6A regulators, and tumor microenvironment (TME) cell-infiltrating characteristics of these modification patterns were systematically assessed by ssGSEA and CIBERSORT algorithms. The principal component analysis algorithm based on the m6A scoring scheme was used to explore the m6A modification patterns of individual tumors with immune responses. The weighted correlation network analysis and univariable and multivariable Cox regression analyses were applied to identify m6A-modified gene signatures. The single-cell expression dataset of CRC samples was used to explore the tumor microenvironment affected by these signatures. Results: Three distinct m6A modification patterns with significant recurrence-free survival (RFS) were identified in 804 CRC patients. The TME characterization revealed that the m6A modification pattern with longer RFS exhibited robust immune responses. CRC patients were divided into high- and low-score subgroups according to the m6A score individually, which was obtained from the m6A-related signature genes. The patients with low m6A scores had both longer RFS and overall survival (OS) with altered immune cell infiltration. Notably, m6A-modified genes showed significant differences related to the prognosis of CRC patients in the meta-GEO cohort and TCGA cohort. Single-cell expression indicated that ALVRL1 was centrally distributed in endothelial tip cells and stromal cells. Conclusion: The m6A modification plays an indispensable role in the formation of TME diversity and complexity. Importantly, the signatures (TOP2A, LRRC58, HAUS6, SMC4, ACVRL1, and KPNB1) were identified as m6A-modified genes associated with CRC recurrence, thereby serving as a promising predictive biomarker or therapeutic target for patients with CRC recurrence.

Targeted profiling of polar metabolites in cancer metabolic reprogramming by hydrophilic interaction liquid chromatography-tandem mass spectrometry.

Metabolic reprogramming of cancer cells is a hallmark of cancer, in which the polar metabolites involving aerobic glycolysis, pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle, and glutaminolysis play a crucial role in the occurrence and development of cancer. Therefore, targeted analysis of the polar metabolites in these pathways is of great value for understanding cancers, finding diagnostic biomarkers, and identifying therapeutic targets. However, it is still challenging to directly determine polar metabolites in these pathways without derivatization due to their diverse chemical properties, isomers, and strong polarity. Herein, a highly selective and sensitive HILIC-MS/MS method was developed for direct determination of the polar metabolites in aerobic glycolysis, PPP, TCA cycle, and glutaminolysis pathways. Without derivatization, 19 polar metabolites and their isomers with carbonyl, carboxyl, or phosphoryl groups in human plasma and cell extracts of prostate cancer (PC) were determined with strong retention and high resolution. This method has been widely verified by measuring linearity, precision, sensitivity, repeatability, matrix effect, and accuracy. The analysis of plasma samples by HILIC-MS/MS revealed distinct PC-specific metabolic signatures compared to a healthy control. In addition, this method could also be used to screen the targets of metabolic inhibitors at the cellular level. We conclude that the developed HILIC-MS/MS method provides a valuable means to study the cancer metabolic reprogramming or energy metabolism in living organisms.

Identification of Genes Related to 5-Fluorouracil Based Chemotherapy for Colorectal Cancer.

Background: Colorectal cancer (CRC) is one of the most common malignancies and its incidence and mortality are increasing yearly. 5-Fluorouracil (5-FU) has long been used as a standard first-line treatment for CRC patients. Although 5-FU-based chemotherapy is effective for advanced CRC, the consequent resistance remains a key problem and causes the poor prognosis of CRC patients. Thus, there is an urgent need to identify new biomarkers to predict the response to 5-FU-based chemotherapy. Methods: CRC samples were retrieved from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). The immune-related genes were retrieved from the ImmPort database. Single-cell sequencing results from colorectal cancer were obtained by the ArrayExpress database. 5-FU resistance-related genes were filtered and validated by R packages. ESTIMATE algorithms were used to assess the tumor microenvironment (TME). KEGG and GO analysis were performed to explore the biological signaling pathway for resistant-response patients and sensitive-response patients in the tumor microenvironment. pRRophetic algorithms were used to predict 5-FU sensitivity. GSEA and GSVA analysis was performed to excavate the biological signaling pathway of the RBP7 gene. Results: Nine immune-related genes were identified to be associated with 5-FU resistance and poor disease-free survival (DFS) of CRC patients and the signature of these genes was developed in a DFS-prognostic model. Four immune-related genes were determined to be associated with 5-FU resistance and overall survival (OS) of CRC patients. The signature of these genes was developed an OS-prognostic model. ESTIMATE scores showed a significant difference between 5-FU resistant and 5-FU sensitive CRC patients. Resistant-response patients and sensitive-response patients to 5-FU based chemotherapy showed different GO and KEGG enrichment on the tumor microenvironment. RBP7, as a tumor immune microenvironment (TIME) related gene, was found to have the potential of predicting chemotherapy resistance and poor prognosis of CRC patients. GSEA analysis showed multiple signaling differences between the high and low expression of RBP7 in CRC patients. Hypoxia and TNFα signaling via NFκB gene sets were significantly different between chemotherapy resistant (RBP7High) and chemotherapy sensitive (RBP7Low) patients. Single-cell RNA-seq suggested RBP7 was centrally distributed in endothelial stalk cells, endothelial tip cells, and myeloid cells. Conclusions: Immune-related genes will hopefully be potential prognostic biomarkers to predict chemotherapy resistance for CRC. RBP7 may function as a tumor microenvironment regulator to induce 5-FU resistance, thereby affecting the prognosis of CRC patients.

Emerging Technologies for the Detection of Cancer Micrometastasis.

The most efficient way to treat tumors is through surgery. However, many cancer patients have a poor prognosis even when they undergo radical excision at an early stage. Micrometastasis is one of the most critical factors that induced this situation. Undetected micrometastasis can lead to the failure of initial treatment. Therefore, preoperative and intraoperative detection of micrometastasis could have a significant clinical influence on the prognosis and optimal therapy for cancer patients. Additionally, to achieve this goal, researchers have aimed to create more effective detection technologies. Herein, we classify the currently reported micrometastasis detection technologies, introduce some representative samples for each technology, including the limitations, and provide future directions to overcome the limitations.

A Novel Diagnostic and Therapeutic Strategy for Cancer Patients by Integrating Chinese Medicine Syndrome Differentiation and Precision Medicine.

Applying Chinese medicine (CM) is an important strategy for malignant tumor treatment in China. One of the significant characteristics of CM is to treat diseases based on syndrome differentiation. For Western medicine, it is of important clinical significance to formulate guidelines for the diagnosis and treatment of cancer patients based on the characteristics of disease differentiation. In Chinese clinical practice, the combination of disease differentiation and syndrome differentiation is an important feature for cancer treatment in the past. Currently, molecular profiling and genomic analysis-based precision medicine optimizes the anticancer drug design and holds the greatest success in treating cancer patients. Therefore, we want to know which populations of cancer patients can benefit more from CM treatment if the theory of precision medicine is applied to CM clinical practice. So, we developed a novel diagnostic and therapeutic strategy "disease-syndrome differentiation-genomic profiling-prescriptions" for cancer patients by CM syndrome differentiation and precision medicine. As a result, this strategy has greatly enhanced the anti-tumor efficacy of CM and improved clinical outcomes for cancer patients with some gene mutations. Our idea will hopefully establish a novel approach for the inheritance and innovation of CM.

Osa-miR535 targets SQUAMOSA promoter binding protein-like 4 to regulate blast disease resistance in rice.

Many rice microRNAs have been identified as fine-tuning factors in the regulation of agronomic traits and immunity. Among them, Osa-miR535 targets SQUAMOSA promoter binding protein-like 14 (OsSPL14) to positively regulate tillers but negatively regulate yield and immunity. Here, we uncovered that Osa-miR535 targets another SPL gene, OsSPL4, to suppress rice immunity against Magnaporthe oryzae. Overexpression of Osa-miR535 significantly decreased the accumulation of the fusion protein SPL4TBS -YFP that contains the target site of Osa-miR535 in OsSPL4. Consistently, Osa-miR535 mediated the cleavage of OsSPL4 mRNA between the 10th and 11th base pair of the predicted binding site at the 3' untranslated region. Transgenic rice lines overexpressing OsSPL4 (OXSPL4) displayed enhanced blast disease resistance accompanied by enhanced immune responses, including increased expression of defense-relative genes and up-accumulated H2 O2 . By contrast, the knockout mutant osspl4 exhibited susceptibility. Moreover, OsSPL4 binds to the promoter of GH3.2, an indole-3-acetic acid-amido synthetase, and promotes its expression. Together, these data indicate that Os-miR535 targets OsSPL4 and OsSPL4-GH3.2, which may parallel the OsSPL14-WRKY45 module in rice blast disease resistance.

Magnolol attenuates the locomotor impairment, cognitive deficit, and neuroinflammation in Alzheimer's disease mice with brain insulin resistance via up-regulating miR-200c.

In this study, we aimed to investigate the effect of Magnolol on Alzheimer's disease (AD). After the model of streptozotocin-induced AD mice with brain insulin resistance was established, the mice were treated with Magnolol or miR-200c antagomiR. The abilities of ambulations, rearings, discrimination, spatial learning, and memory were evaluated by open-field test (OFT), novel object recognition (NOR), and morris water maze (MWM) tests. The levels of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), and miR-200c in the mice hippocampus were evaluated by enzyme-linked immunosorbent assay, Western blot, or Quantitative real-time Polymerase Chain Reaction. In AD mice model, streptozotocin induced the locomotor impairment and cognitive deficit, up-regulated levels of MDA, TNF-α, IL-6, and CRP, while down-regulated levels of GSH, SOD, and miR-200c. Magnolol increased the rearings numbers and discrimination index of AD mice in OFT and NOR tests. Magnolol increased the number of entries in the target quadrant and time spent in the target quadrant and decreased the escape latency of AD mice in the MWM test. Magnolol also down-regulated the levels of MDA, TNF-α, IL-6, and CRP, and up-regulated the levels of GSH, SOD, and miR-200c in the hippocampus tissues of AD mice. However, miR-200c antagomiR did the opposite and further offset the effects of the Magnolol on AD mice. Magnolol attenuated the locomotor impairment, cognitive deficit, and neuroinflammatory in AD mice with brain insulin resistance via up-regulating miR-200c.

Blood Biomarkers Predict Cardiac Workload Using Machine Learning.

INTRODUCTION: Rate pressure product (the product of heart rate and systolic blood pressure) is a measure of cardiac workload. Resting rate pressure product (rRPP) varies from one individual to the next, but its biochemical/cellular phenotype remains unknown. This study determined the degree to which an individual's biochemical/cellular profile as characterized by a standard blood panel is predictive of rRPP, as well the importance of each blood biomarker in this prediction. METHODS: We included data from 55,730 participants in this study with complete rRPP measurements and concurrently collected blood panel information from the Health Management Centre at the Affiliated Hospital of Hangzhou Normal University. We used the XGBoost machine learning algorithm to train a tree-based model and then assessed its accuracy on an independent portion of the dataset and then compared its performance against a standard linear regression technique. We further determined the predictive importance of each feature in the blood panel. RESULTS: We found a fair positive correlation (Pearson r) of 0.377 (95% CI: 0.375-0.378) between observed rRPP and rRPP predicted from blood biomarkers. By comparison, the performance for standard linear regression was 0.352 (95% CI: 0.351-0.354). The top three predictors in this model were glucose concentration, total protein concentration, and neutrophil count. Discussion/. CONCLUSION: Blood biomarkers predict resting RPP when modeled in combination with one another; such models are valuable for studying the complex interrelations between resting cardiac workload and one's biochemical/cellular phenotype.

[Effects of salt stress on Nitraria roborowskii growth and physiological characteristics of stress resistance].

A pot experiment was conducted to study the influences of different NaCl concentrations (0, 50, 100, 200, 400 mmol x L(-1)) on the growth, leaf hydrogen peroxide (H2O2), malonaldehyde (MDA) content, superoxide dismutases (SOD), catalases (CAT), peroxidase (POD), ascorbate peroxidase (APX) enzymes activity, water potential, soluble sugar and proline contents of Nitraria roborowskii. The results showed that the growth of N. roborowskii was not affected at lower NaCl concentrations (< or = 50 mmol L(-1)), while the SOD, POD, CAT and APX activities in leaves of N. roborowskii were increased. However, higher NaCl concentrations (> 50 mmol x L(-1)) restrained the growth parameters of crown area, number of branches, dry mass of leaf, branch and lateral root, and remarkably reduced the SOD, POD and CAT activities, soluble sugar and proline contents in leaves of N. roborowskii. H2O2 and MDA contents in leaves were increased and water potential was reduced with increasing NaCl concentrations.

Effect of piglitazone and metformin on retinol-binding protein-4 and adiponectin in patients with type 2 diabetes mellitus complicated with non-alcohol fatty acid liver diseases.

OBJECTIVE: To compare the effects of piglitazone and metformin on retinol-binding protein-4 (RBP-4) and adiponcetin (APN) in patients with type 2 diabetes mellitus (T2DM) complicated with Non alcohol fatty acid liver disease (NAFLD). METHODS: Totally 60 T2DM patients complicated with NAFLD were equally and randomly divided into pioglitazone group and metform group. The levels of biochemical indicators including body mass index (BMI), glucose hemoglobin A1C (GHbA1C), insulin resistance (HOMA-IR), fasting blood glucose (FBG), fasting insulin (FIns), and serum triglycerides (TG) as well as serum RBP-4 and APN level were measured pre-treatment and 12 weeks after treatments. RESULTS: After 12 weeks of treaments, BMI, FBG, HOMA-IR, GHbA1C, FIns, and TG decreased (all P<0.05) in both piglitazone group and metform group. APN increased (all P<0.05) in both groups. RBP-4 decreased (P<0.05) in piglitazone group. Compare with the metform group, the levels of RBP-4, FIns ,and HOMA-IR decreased and BMI increased in piglitazone group (P<0.05). CONCLUSION: Piglitazone is superior to metoform in decreasing RBP-4 level and HOMA-IR in patients with T2DM complicated with NAFLD.

[A study on expression of Wnt signal pathway gene in familial aggregated hypertension].

OBJECTIVE: To determine the role of gene expression of Wnt signal pathway in the pathogenesis of familial aggregated hypertension. METHODS: The patients having directly related family members for more than three generations suffering from hypertension were enlisted in the hypertension group, and healthy individuals served as control group. The real-time polymerase chain reaction (PCR) gene array was used to detect the expression of functional classification genes of Wnt signal pathway in peripheral blood, with standard value deviated>2.0 from hypertension group/control group as differential genes. RESULTS: When hypertension group was compared with the control group, there were 6 differentially expressed genes, with 5 genes up-regulated, including Bcl-9, microphthalmia associated transcription factor (Mitf), secreted frizzled-related protein-1 (Sfrp-1), Wnt inhibiting factor-1 (Wif-1) and ribosomal protein-l13a (Rp-l13a). There was 1 gene down-regulated, i.e. dickkopf homolog-3 (Dkk-3). CONCLUSION: The result of this study suggested that the Wnt signal pathway may be related to the occurrence and development of the familial aggregated hypertension.

[Study on cardiovascular diseases marker gene expression profile of familial aggregation hypertension].

OBJECTIVE: To explore the cardiovascular diseases marker gene expression profile of the familial aggregation hypertension patients,and to screen differentially expressed genes. METHODS: The patients who had directly related family members for more than three generations suffering from hypertension were selected as experiment group, and healthy individuals as control group. Oligo GEArray gene chip technique was used to detect the expression of cardiovascular diseases marker gene in peripheral blood. The ratio of positive/negative standard value >2.0, or ≤0.5 and >0 was identified as differential gene. RESULTS: Compared with control group, there were 10 up-regulated differential genes in experiment group, composing genes involved in lipid metabolism, immune response-related molecules, cell adhesion molecules, extracellular molecules and coagulation, including apolipoprotein E (ApoE), epithelial V-like antigen-1 (EVA-1), interferon-γ (IFN-γ), interleukin-1ß (IL-1ß), IL-8, integrin-ß1 (ITGB-1), matrix metalloproteinase-9 (MMP-9), nuclear factor-ΚB (NF-ΚB), platelet endothelial cell adhesion molecule-1 (PECAM-1), selectin-P (SEL-P). There were 3 down-regulated genes, including coagulation factors-III (F-III), lectin-like oxidized low density lipoprotein receptor-1 (LOX-1), and serine protease inhibitor-1 (SERPINE-1). CONCLUSION: This study suggested that familial aggregation hypertension related to a variety of gene markers of cardiovascular disease, especially elements concerning coagulation and extracellular protease inhibitor-related genes.

[Association of endothelial nitric oxide synthase gene polymorphism with level of uric acid in serum for acute coronary syndrome].

OBJECTIVE: To evaluate the association of elevation in serum uric acid with the development of coronary artery disease, and to determine the relationship between uric acid and Glu(298) Asp polymorphism of the endothelial nitric oxide synthase (eNOS) gene in acute coronary syndrome (ACS) in the Chinese Han Nationality. METHODS: The Glu(298) Asp variant of the eNOS gene was detected by polymerase chain reaction/restriction fragment length polymorphism analysis in 58 patients with ACS and 43 healthy controls. The severity of ACS was expressed by the number of affected vessels and by the Duke scoring system. RESULTS: The frequencies of the eNOS Glu/Glu, Glu/Asp, and Asp/Asp genotypes in the ACS group were not significantly different from those of controls (43.1%, 36.2%, 20.7% vs. 48.8%, 34.9%, 16.3%, respectively; chi (2) = 0.446, P = 0.800). In comparison with subjects who had Glu(298) allele in the eNOS gene, the risk of ACS was not increased among Asp/Asp carriers (odds ratio 1.34, 95% confidence interval 0.479 to 3.755, P = 0.575). There was no significant association between the eNOS Glu(298) Asp variant and the Duke score [(46.73+/-19.90) score for Asp/Asp vs. (48.33+/-19.61) score and (38.19+/-15.12) score for Glu/Glu and Glu/Asp, respectively, P=0.248], but there was a significant association between the eNOS Glu(298) Asp variant and the serum uric acid level in ACS group [(298.92+/-87.27) micromol/L for Glu/Glu vs.(380.80+/-95.80) micromol/L and (346.16+/-93.71) micromol/L for Glu/Asp and Asp/Asp, respectively, P = 0.017]. CONCLUSION: Glu(298) Asp polymorphism of the eNOS gene appears to have no association with ACS in the Chinese Han Nationality, but a significant association between the eNOS Glu(298) Asp variant and the serum uric acid level is found in patients with ACS.

Kinetic study of nicotinic acetycholine rceptor / 中国临床药理学与治疗学

Aim The kinetics of nicotinic acetylcholine receptor (N-AChR) was stadied. MethodsThe saturation experiments of Torpedo electric organ N-AChR were taken with125I-?-BuTX. The results were calculated by Scatfit program. Experiments were thenperformed to study the kinetics of dissociation of ?-BuTX and nicotine from N-AChR,respectively. When their binding reached saturation, an excess of 1000 times ?-BuTX ornicotine was added. The saturation binding properties of the N-AChR extracted fromleg muscles of the 13th day chick embroys and optic lobes of the 20th day chick em-broys were studied. The results were calculated by Scatfit program. The othe experi-ments were taken to observe the competition between mcotine and 125I-?-BuTX forbinding with Torpedo, optic lobe and skeletal muscle of the chick N-AChRs. ResultsThe saturation experiments of Torpedo electric organ N-AChR resulted in a Scatchardplot of hyperbola which responded to the model of two kinds of receptor with on eli-gand.The difference of and B max between high affinity binding site and low affnitybineing site was significant. The dissaciation experiment showed that the fast dissocia-tion rate of tow ligands was 500 times more than that of the slow dissociation rate. Thisresult suggested that there may be two subtype N-AChRs.The saturation bindingproperties of N-AChR of leg muscles and optic lobe of the chick embroys revealed aScatchard plot of two kinds of N-AChR indicating a single type of site. The bindingaffinity of receptor of optic lobe was 100 times more than that of muscles. In competi-tion for Torpedo receptor by nicotine and 125I-?-BuTX, the values of IC50 were different:which suggested that two kinds of receptor sites were existent. In competition ofNicotine and 125I-?-BuTX for optic lobe and skeletal muscles of the chick N-AChR, thevalue IC50 of skeletal muscles N-AChR was 7. 7 times higher than that of optic lobe. Itindicated that two kinds of N-AChR subtype existed in the optic lobe and in theskeletal muscles of chick respectively. Conclusion N-AChR of Torpedo electric organcontains two kinds of subtype receptors. N-AChR of optic lobe of chick embroys is onesubtype receptor, and N-AChR of skeletal muscles of chick embroy is another subtypereceptor.