Plastic footprint deteriorates dryland carbon footprint across soil-plant-atmosphere continuum.

Plastic fragments are widely found in the soil profile of terrestrial ecosystems, forming plastic footprint and posing increasing threat to soil functionality and carbon (C) footprint. It is unclear how plastic footprint affects C cycling, and in particularly permanent C sequestration. Integrated field observations (including 13C labelling) were made using polyethylene and polylactic acid plastic fragments (low-, medium- and high-concentrations as intensifying footprint) landfilling in soil, to track C flow along soil-plant-atmosphere continuum (SPAC). The result indicated that increased plastic fragments substantially reduced photosynthetic C assimilation (p < 0.05), regardless of fragment degradability. Besides reducing C sink strength, relative intensity of C emission increased significantly, displaying elevated C source. Moreover, root C fixation declined significantly from 21.95 to 19.2 mg m-2, and simultaneously root length density, root weight density, specific root length and root diameter and surface area were clearly reduced. Similar trends were observed in the two types of plastic fragments (p > 0.05). Particularly, soil aggregate stability was significantly lowered as affected by plastic fragments, which accelerated the decomposition rate of newly sequestered C (p < 0.05). More importantly, net C rhizodeposition declined averagely from 39.77 to 29.41 mg m-2, which directly led to significant decline of permanent C sequestration in soil. Therefore, increasing plastic footprint considerably worsened C footprint regardless of polythene and biodegradable fragments. The findings unveiled the serious effects of plastic residues on permanent C sequestration across SPAC, implying that current C assessment methods clearly overlook plastic footprint and their global impact effects.

Validation of mitochondrial biomarkers and immune dynamics in polycystic ovary syndrome.

PROBLEM: Polycystic ovary syndrome (PCOS), a prevalent endocrine-metabolic disorder, presents considerable therapeutic challenges due to its complex and elusive pathophysiology. METHOD OF STUDY: We employed three machine learning algorithms to identify potential biomarkers within a training dataset, comprising GSE138518, GSE155489, and GSE193123. The diagnostic accuracy of these biomarkers was rigorously evaluated using a validation dataset using area under the curve (AUC) metrics. Further validation in clinical samples was conducted using PCR and immunofluorescence techniques. Additionally, we investigate the complex interplay among immune cells in PCOS using CIBERSORT to uncover the relationships between the identified biomarkers and various immune cell types. RESULTS: Our analysis identified ACSS2, LPIN1, and NR4A1 as key mitochondria-related biomarkers associated with PCOS. A notable difference was observed in the immune microenvironment between PCOS patients and healthy controls. In particular, LPIN1 exhibited a positive correlation with resting mast cells, whereas NR4A1 demonstrated a negative correlation with monocytes in PCOS patients. CONCLUSION: ACSS2, LPIN1, and NR4A1 emerge as PCOS-related diagnostic biomarkers and potential intervention targets, opening new avenues for the diagnosis and management of PCOS.

Osthole Activates the Cholinergic Anti-Inflammatory Pathway via α7nAChR Upregulation to Alleviate Inflammatory Responses.

Osthole (also known as Osthol) is the main anti-inflammatory coumarin found in Cnidium monnieri and severs as the exclusive quality-controlled component according the Chinese Pharmacopoeia. However, its underlying anti-inflammatory mechanism remains unknown. In this study, we demonstrated that Osthole treatment significantly inhibited the generation of TNF-α, but not IL-6 in the classical LPS-stimulated RAW264.7 macrophage model. In addition, LPS induced the activation of both MAPK and NF-κB signalling pathways, of which the former was dose-dependently restrained by Osthole via suppressing the phosphorylation of JNK and P38 proteins, while the phosphorylation of IκB and P65 proteins remained unaffected. Interestingly, Osthole dose-dependently up-regulated the expression of the key cholinergic anti-inflammatory pathway regulator α7nAChR, and the TNF-α inhibition effect of Osthole was also significantly alleviated by the treatment of α7nAChR antagonist methylbetaine. These results demonstrate that Osthole may regulate TNF-α by promoting the expression of α7nAChR, thereby activate the vagus nerve-dependent cholinergic anti-inflammatory pathway.

Inulin Inhibits the Inflammatory Response through Modulating Enteric Glial Cell Function in Type 2 Diabetic Mellitus Mice by Reshaping Intestinal Flora.

Inulin, a commonly used dietary fiber supplement, is capable of modulating the gut microbiome. Chronic inflammation resulting from metabolic abnormalities and gut flora dysfunction plays a significant role in the development of type 2 diabetes mellitus (T2DM). Our research has demonstrated that inulin administration effectively reduced colonic inflammation in T2DM mice by inducing changes in the gut microbiota and increasing the concentration of butyric acid, which in turn modulated the function of enteric glial cells (EGCs). Experiments conducted on T2DM mice revealed that inulin administration led to an increase in the Bacteroidetes/Firmicutes ratio and the concentration of butyric acid in the colon. The anti-inflammatory effects of altered gastrointestinal flora and its metabolites were further confirmed through fecal microbiota transplantation. Butyric acid was found to inhibit the activation of the κB inhibitor kinase ß/nuclear factor κB pathway, regulate the expression levels of interleukin-6 and tumor necrosis factor-α, suppress the abnormal activation of EGCs, and prevent the release of inflammatory factors by EGCs. Similar results were observed in vitro experiments with butyric acid. Our findings demonstrate that inulin, by influencing the intestinal flora, modifies the activity of EGCs to effectively reduce colonic inflammation in T2DM mice.

Ecological risks of microplastics contamination with green solutions and future perspectives.

The rise of plasticulture as mulching material in farming systems has raised concerns about microplastics (MPs) in the agricultural landscape. MPs are emerging pollutants in croplands and water systems with significant ecological risks, particularly over the long term. In the soil systems, MPs polymer type, thinness, shape, and size induces numerous effects on soil aggregates, dissolved organic carbon (C), rapidly oxidized organic C, microbial biomass C, microbial biomass nitrogen (N), microbial immobilization, degradation of organic matter, N cycling, and production of greenhouse gas emissions (GHGs), thereby posing a significant risk of impairing soil physical and biochemical properties over time. Further, toxic chemicals released from polyethylene mulching (PMs) might indirectly harm plant growth by affecting soil wetting-drying cycles, releasing toxic substances that interact with soil matrix, and suppressing soil microbial activity. In the environment, accumulation of MPs poses a risk to human health by accelerating emissions of GHGs, e.g., methane and carbon dioxide, or directly releasing toxic substances such as phthalic acid esters (PAEs) into the soils. Also, larger sizes MPs can adhere to root surface and block stomata could significantly change the shape of root epidermal cells resulting in arrest plant growth and development by restricting water-nutrient uptake, and gene expression and altering the biodiversity of the soil pollutants. In this review, we systematically analyzed the potential risks of MPs to the soil-plant and human body, their occurrence, abundance, and migration in agroecosystems. Further, the impacts of MPs on soil microbial function, nutrient cycling, soil C, and GHGs are mechanistically reviewed, with emphasis on potential green solutions such as organic materials amendments along with future research directions for more eco-friendly and sustainable plastic management in agroecosystems.

Efficacy and safety of piperacillin-tazobactam compared with meropenem in treating complicated urinary tract infections including acute pyelonephritis due to extended-spectrum ß-lactamase-producing Enterobacteriaceae.

Introduction: Extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae pose a huge threat to human health, especially in the context of complicated urinary tract infections (cUTIs). Carbapenems and piperacillin-tazobactam (PTZ) are two antimicrobial agents commonly used to treat cUTIs. Methods: A monocentric retrospective cohort study focused on the treatment of cUTIs in adults was conducted from January 2019 to November 2021. Patients with a positive urine culture strain yielding ≥ 103 colony-forming units per milliliter (CFU/mL), and sensitive to PTZ and carbapenems, were included. The primary endpoint was clinical success after antibiotic therapy. The secondary endpoint included rehospitalization and 90-day recurrence of cUTIs caused by ESBL-producing Enterobacteriaceae. Results: Of the 195 patients included in this study, 110 were treated with PTZ while 85 were administered meropenem. The rate of clinical cure was similar between the PTZ and meropenem groups (80% vs. 78.8%, p = 0.84). However, the PTZ group had a lower duration of total antibiotic use (6 vs. 9; p < 0.01), lower duration of effective antibiotic therapy (6 vs. 8; p < 0.01), and lower duration of hospitalization (16 vs. 22; p < 0.01). Discussion: In terms of adverse events, the safety of PTZ was higher than that of meropenem in the treatment of cUTIs.

Thickness effects of polyethylene and biodegradable film residuals on soil properties and dryland maize productivity.

Plastic film residuals are increasingly remaining in cultivated lands. However, it is a critical issue how residual plastic type and thickness affect soil properties and crop yield. To address this issue, in situ landfill was conducted using thick polyethylene (PEt1), thin polyethylene (PEt2), thick biodegradable (BIOt1), thin biodegradable (BIOt2) residues, and CK (control) with no residues landfill in a semiarid maize field. The findings demonstrated that the impact of various treatments on soil characteristics and maize yield varied considerably. Soil water content decreased by 24.82% in PEt1 and 25.43% in PEt2, compared to BIOt1 and BIOt2, respectively. BIOt2 treatment increased soil bulk density by 1.31 g cm-3 and lowered soil porosity by 51.11%, respectively; it also elevated the silt/clay proportion by 49.42% relative to CK. In contrast, microaggregate composition in PEt2 was higher (43.02%). Moreover, BIOt2 lowered soil nitrate (NO3-) and ammonium (NH4+) content. Compared with other treatments, BIOt2 resulted in significantly higher soil total nitrogen (STN) and lower SOC/STN. Finally, BIOt2 exhibited the lowest water use efficiency (WUE) (20.57 kg ha-1 mm-1) and yield (6896 kg ha-1) among all the treatments. Therefore, BIO film residues exhibited detrimental impacts on soil quality and maize productivity compared to PE film ones. Considering film thickness, thin residual films more evidently influenced soil quality and maize productivity than thick film ones.

Involvement of enteric glial cells in colonic motility in a rat model of irritable bowel syndrome with predominant diarrhea.

The enteric nervous system (ENS) is one of the important systems that regulate gastrointestinal function. The ENS is made up of enteric glial cells (EGCs) and neurons. For a long time, it was believed that the function of EGCs was only to give structural support to neurons. However, recent evidence indicates EGCs are involved in most gut functions, including the development and plasticity of the ENS, epithelial barrier, and motility. However, it remains unclear whether EGCs have the potential to modify colonic motility following irritable bowel syndrome (IBS) with predominant diarrhea (IBS-D). This study aimed to investigate changes in EGCs during IBS-D and assessed the effects of manipulating EGCs. An IBS-D rat model was constructed using acetic acid and restraint stress, and DL-fluorocitric acid (FC), an inhibitor of EGCs, was administered. The changes in EGCs and colonic motility were studied by employing techniques comprising morphological, molecular biological and functional experiments. The results showed significant activation of EGCs in the myenteric plexus (MP) of the IBS-D-induced rat colon with accelerated colonic motility. FC significantly reduced the activation of EGCs and colonic motility caused by acetic acid and restraint stress. Hypercontraction of the colon caused by IBS-D may be associated with activation of EGCs in the MP of the colon and this was prevented by FC. Therefore, regulating colon hypercontraction through interference with the activation of EGCs has significant prospects for clinical application to alleviate diarrhea in patients with IBS-D.

Moss-dominated biocrust-based biodiversity enhances carbon sequestration via water interception and plant-soil-microbe interactions.

We investigated a nature-based solution (NbS) via incorporating biocrust into alfalfa-maize intercropping system to test carbon sequestration in seriously eroded agricultural soils. Field investigation showed that the NbS (moss-dominated biocrust + intercropping) massively lowered surface soil erosion by 94.5% and soil carbon (C) and nitrogen (N) loss by 94.7 and 96.8% respectively, while promoting rainwater interception by 82.2% relative to bare land (CK). There generally existed positive interactions between biocrust and cropping in the integrated standing biodiversity system. Enhanced plant biomass input into soils substantially promoted soil fungal community diversity and abundance under NbS (p < 0.05). This enabled NbS to evidently improve soil macroaggregate proportion and mean weight diameter. Critically, topsoil carbon storage was increased by 2.5 and 10.7%, compared with CK and pure intercropping (p < 0.05). Conclusively, the standing diversity under such NbS fostered soil C sequestration via water interception and plant-soil-microbe interactions in degraded agricultural soils.

Heavy metal(loid)s in agricultural soil from main grain production regions of China: Bioaccessibility and health risks to humans.

Unintentional ingestion of metal-contaminated soils may pose a great threat to human health. To accurately evaluate the health risks of heavy metal(loid)s in soils, their bioaccessibility has been widely determined by in vitro assays and increasingly employed to optimize the assessment parameters. Given that, using meta-analysis, we analyzed the literature on farmland heavy metal(loid)s (As, Cd, Cr, Cu, Hg, Pb, Ni, and Zn) in Chinese main grain production regions, and collected their total and bioaccessibility data to accurately assess their human health risks. Monte Carlo simulation was used to reduce the uncertainty in metal concentration, intake rate, toxicity coefficient, and body weight. We found that the mean concentration (0.47 mg/kg) and geological accumulation index (Igeo, 0-5.24) of Cd were the priority position of controlling metals. Moreover, children are more vulnerable to carcinogenic risks than adults. Soil mineralogy, physicochemical properties, Fe, and the types of in vitro assays are the influencing factors of bioaccessibility discrepancy. Furthermore, appropriate bioaccessibility determination methods can be adapted according to the differences in ecological receptors for the risk assessment, like developing a "personalized assessment" scheme for polluted farmland soil management. Collectively, bioaccessibility-based models may provide an accurate and effective approach to human health risk assessment.

[Plasma components of Danzhi Xiaoyao Formula and its mechanism of action in treating perimenopausal depression based on UPLC-Q-TOF-MS~E integrated with network pharmacology].

In this study, ultra-performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS~E) was used to analyze the plasma components of Danzhi Xiaoyao Formula after oral administration. Forty-nine plasma components were found in the serum of rats by comparing the compound extract, drug-containing serum, and blank serum. Components, such as 6-hydroxycoumarin, poricoic acid F, deoxoglabrolide, 30-norhederagenin, kanzonol R, 3',6'-di-O-galloylpaeoniflorin, 16α-hydroxytrametenolic acid, 16-deoxyporicoic acid B, 3-O-acetyl-16α-hydroxytrametenolic acid, and 16α,25-dihydroxydehydroeburiconic acid, were first found in rat serum. Behavioral tests, including the tail suspension test, novel object recognition test, and novelty-suppressed feeding test, were conducted for behavioral analysis. It was confirmed that this formula had therapeutic effects on perimenopausal depression. Furthermore, in combination with the network pharmacology method, 53 core targets including MAPK1, HRAS, AKT1, EGFR, and ESR1 were screened, and these targets participated in 165 signaling pathways, including PI3K-AKT, AMPK, VEGFA, MAPK, and HIF-1. In summary, the potential effects of Danzhi Xiaoyao Formula in treating perimenopausal depression are associated with mechanisms in accelerating inflammation repair, improving neuroplasticity, affecting neurotransmitters, regulating estrogen levels, and promoting new blood vessel formation.

Brain-gut-liver axis: Chronic psychological stress promotes liver injury and fibrosis via gut in rats.

Background: The effect of chronic psychological stress on hepatitis and liver fibrosis is concerned. However, its mechanism remains unclear. We investigated the effect and mechanism of chronic psychological stress in promoting liver injury and fibrosis through gut. Methods: Sixty male SD rats were randomly assigned to 6 groups. Rat models of chronic psychological stress (4 weeks) and liver fibrosis (8 weeks) were established. The diversity of gut microbiota in intestinal feces, permeability of intestinal mucosa, pathologies of intestinal and liver tissues, collagen fibers, protein expressions of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor kappa ß (NF-κß), tumor necrosis factor α (TNF-α) and interleukin 1 (IL-1) in liver tissue, liver function and coagulation function in blood and lipopolysaccharide (LPS) in portal vein blood were detected and analyzed. Results: The diversities and abundances of gut microbiota were significant differences in rats among each group. The pathological lesions of intestinal and liver tissues, decreased expression of occludin protein in intestinal mucosa, deposition of collagen fibers and increased protein expression of TLR4, MyD88, NF-κß, TNF-α and IL-1 in liver tissue, increased LPS level in portal vein blood, and abnormalities of liver function and coagulation function, were observed in rats exposed to chronic psychological stress or liver fibrosis. There were significant differences with normal rats. When the dual intervention factors of chronic psychological stress and liver fibrosis were superimposed, the above indicators were further aggravated. Conclusion: Chronic psychological stress promotes liver injury and fibrosis, depending on changes in the diversity of gut microbiota and increased intestinal permeability caused by psychological stress, LPS that enters liver and acts on TLR4, and active LPS-TLR4 pathway depend on MyD88. It demonstrates the possibility of existence of brain-gut-liver axis.

Correlation analysis between physicians' evaluations of doctor-patient relationship and their preferences for shared decision-making in China.

Shared decision-making (SDM) is a scientific and reasonable decision-making model. However, whether physicians choose SDM is usually influenced by many factors. It is not clear whether the strained doctor-patient relationship will affect physicians' willingness to choose SDM. Through a survey by questionnaire, 304 physicians' evaluations of doctor-patient relationship (DPR) were quantified by the difficult DPR questionnaire-8. Their preferences for SDM and the reasons were also evaluated. The correlation between physicians' evaluations of DPR and their preferences for SDM were analyzed. 84.5% physicians perceived DPR as poor or strained, 53.3% physicians preferred SDM, mainly because of the influences of medical ethics and social desirability bias. Their preferences for SDM were not significantly correlated with their evaluations of DPR (P > 0.05). Physicians with different evaluations of DPR (good, poor, and strained) all had similar preferences for SDM (42.6, 56.4, and 42.9%), with no significant difference (P > 0.05). There was no correlation between physicians' evaluations of DPR and their preferences for SDM. Physicians' evaluations of poor DPR did not affect their preferences for SDM. This may be influenced by the medical ethics and social desirability bias.

[Exercise regulates lipid metabolism via lipophagy and its molecular mechanisms].

Lipophagy is a kind of selective autophagy, which can selectively identify and degrade lipid droplets and plays an important role in regulating cellular lipid metabolism and maintaining intracellular lipid homeostasis. Exercise can induce lipophagy and it is also an effective means of reducing body fat. In this review, we summarized the relationship between exercise and lipophagy in the liver, pancreas, adipose tissue, and the possible molecular mechanisms to provide a new clue for the prevention and treatment of fatty liver, obesity and other related metabolic diseases by exercise.

Dermal bioaccessibility and cytotoxicity of heavy metals in urban soils from a typical plateau city: Implication for human health.

The dermal exposure of heavy metals in contaminated urban soils poses huge environmental health risks globally. However, their dermal bioaccessibility and adverse effects on human skin cells were not fully understood. In this study, we measured the total and dermal bioaccessibility of Cr, As, Cd, Pb, and Cu in four selected urban soil samples from Kunming, Yunnan, China, and evaluated the cellular responses of these bioaccessible extracts on human keratinocytes (HaCaT). Among all the metals, only As in Soil-3 (S3) exceeded Chinese risk screening and Yunnan background values at 38.2 mg/kg. The average concentrations of Cr, As, Cd, Pb, and Cu in all soil samples were 47.79, 15.50, 3.11, 104.27, and 180.29 mg/kg respectively. Although relatively high concentrations of heavy metals were detected in soil samples, the highest dermal bioaccessibility of Cd was 3.57% with others' being lower than 1%. The bioaccessible dermal-absorbed doses (DADs) of Cr, As, Cd, Pb, and Cu from soils reflected acceptable health risks since all DADs were below the corresponding derived dermal reference values. However, the toxic data showed the extracts of S3 and S4 presented certain cytotoxicity in HaCaT cells, indicating the existing models based on dermal bioaccessibility and DADs may be not accurate enough to assess their human health risk. Taken together, the human health risk assessment should be modified by taking their skin cytotoxicity into account.

An engineered third electrostatic constriction of aerolysin to manipulate heterogeneously charged peptide transport.

Reading the primary sequence directly using nanopores remains challenging due to the complex building blocks of 20 proteinogenic amino acids and the corresponding sophisticated structures. Compared to the uniformly negatively charged polynucleotides, biological nanopores hardly provide effective ionic current responses to all heterogeneously charged peptides under nearly physiological pH conditions. Herein, we precisely design a N226Q/S228K mutant aerolysin which creates a new electrostatic constriction named R3 in-between two natural sensing regions for controlling the capture and translocation of heterogeneously charged peptides. At nearly physiological pH, the decoration of positive charges at this constriction gives a large velocity of electroosmotic flow (EOF), leading to a maximum 8-fold increase in frequency for the heterogeneously charged peptides with the net charge from +1 to -3. Even the duration time of the negatively charged peptide Aß35-25D4 in N226Q/S228K AeL also rises from 0.07 ± 0.01 ms to 0.63 ± 0.01 ms after introducing the third electrostatic constriction. Therefore, the N226Q/S228K aerolysin nanopore with three electrostatic constrictions realizes the dual goals of both capturing and decelerating heterogeneously charged peptides without labelling, even for the folded peptides.

Validation of the Chinese version of the Malocclusion Impact Questionnaire (MIQ).

OBJECTIVE: To translate and cross-culturally adapt the Malocclusion Impact Questionnaire (MIQ) into Chinese and to assess the psychometric properties of the Chinese version of the MIQ (MIQ/C) for use among adolescents with malocclusion in China. MATERIALS AND METHOD: First, the MIQ/C was developed according to international guidelines. Then, the MIQ/C was filled out by 536 adolescents between 10 and 16 years of age. This study used exploratory factor analysis (EFA), confirmatory factor analysis (CFA), convergent validity, internal consistency, and test-retest reliability to evaluate the psychometric properties of the MIQ/C. RESULTS: Following EFA, three domains were extracted, accounting for 65.950% of the total variance. The CFA results showed that the fit indices of each factor in the three-factor model all reached the standard (chi-square/DF = 2.591, GFI = 0.919, TLI = 0.926, CFI = 0.928, RMSEA = 0.076). The scale evidenced a good relationship with the two global questions, indicating good convergent validity. The Cronbach alpha value and the intraclass correlation coefficients (ICC) value of the MIQ/C were 0.929 and 0.893, respectively. CONCLUSION: The MIQ/C demonstrated good reliability and validity and can be further studied and applied in Chinese adolescents with malocclusion. CLINICAL RELEVANCE: The MIQ/C can be applied to assess the psychosocial impact of malocclusion among Chinese adolescents.

Mechanisms of Cd and Cu induced toxicity in human gastric epithelial cells: Oxidative stress, cell cycle arrest and apoptosis.

Cadmium (Cd) and copper (Cu) are widely present in foods. However, their adverse effects on human gastric epithelium are not fully understood. Here, human gastric epithelial cells (SGC-7901) were employed to study the toxicity and associated mechanisms of Cd + Cu co-exposure. Their effects on cell viability, morphology, oxidative damage, cell cycle, apoptosis, and the mRNA levels of antioxidases and cell cycle regulatory genes were investigated. Co-exposure to Cd (5 µM)/Cu (10 µM) induced >40% cell viability loss, whereas little effect on cell viability at <10 µM Cd or 40 µM Cu. Compared to individual exposure, co-exposure induced greater oxidative damage by elevating ROS (3.5 folds), malondialdehyde (2.3 folds) and expression of SOD1 and HO-1 besides inhibiting CAT, GPX1 and Nrf2. A marked S cell-cycle arrest was observed in co-exposure, evidenced by more cells staying in the S phase (36%), up-regulation of cyclins-dependent kinase (CDK4) and CDKs inhibitor (p21) and down-regulation of CDK2, CDK6 and p27. Furthermore, higher apoptosis (22%) with floated and round cells occurred in co-exposure group. Our data implicate the cytotoxicity of Cd + Cu co-exposure was higher than individual exposure, and individual assessment would underestimate their potential health risk. Oxidative stress and cell cycle arrest possibly played a role in Cd + Cu induced toxicity and apoptosis in SGC-7901 cells. Our data suggest the importance to reduce Cd in foods to decrease its adverse impacts on human digestive system.

Sex Hormone-binding Globulin, Cardiometabolic Biomarkers, and Gestational Diabetes: A Longitudinal Study and Meta-analysis.

OBJECTIVE: This study investigated the prospective associations of circulating levels of sex hormone-binding globulin (SHBG) levels with cardiometabolic biomarkers and risk of gestational diabetes (GDM) during pregnancy. It also examines the longitudinal trajectory of SHBG in women with and without GDM. METHODS: We conducted a nested case-control study of 107 incident GDM cases and 214 matched controls within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singleton Cohort. The cohort enrolled non-obese and obese women aged 18-40 years with a singleton pregnancy between 8 and 13 weeks of gestation from 2009 to 2013. GDM was ascertained via medical records review. Blood samples were drawn four times at gestational weeks 10-14, 15-26, 23-31, and 33-39. The prospective associations between SHBG levels and cardiometabolic biomarkers were examined using the Spearman partial correlation among the controls. The longitudinal trajectories of SHBG levels were examined among the cases and the controls. Meta-analysis of prospective studies were performed to examine the association between SHBG levels and GDM risk. RESULTS: SHBG levels at gestational weeks 10-14 were significantly inversely associated with fasting insulin (r = -0.17, P = 0.01) and insulin resistance as measured by HOMA-IR (r = -0.17, P = 0.01) at gestational week 15-26. SHBG at gestational weeks 10-14 and 15-26 was lower in cases than controls (mean ± standard deviation: (204.0 ±â€Š97.6) vs. (220.9 ±â€Š102.5) nmol/L, P = 0.16 and (305.6 ±â€Š124.3) vs. (322.7 ±â€Š105.1) nmol/L, P = 0.14, respectively), yet the differences were not significant. In the meta-analysis, SHBG was 41.5 nmol/L (95% confidence interval: 23.9, 59.1, P < 0.01) significantly lower among women with GDM than without, and each 50 nmol/L increase in SHBG was significantly associated with an odds ratio of 0.85 (95% confidence interval: 0.76-0.95, P = 0.01) for GDM. CONCLUSION: Lower SHBG levels in early pregnancy were prospectively associated with higher high insulin levels and insulin resistance in mid-pregnancy and subsequent risk of GDM, independent of adiposity. SHBG may serve as a marker for the identification of high-risk pregnancies during early pregnancy.

Expression and functional characterization of transient receptor potential vanilloid 4 in the dorsal root ganglion and spinal cord of diabetic rats with mechanical allodynia.

Diabetic mechanical allodynia (DMA) is a common manifestation in patients with diabetes mellitus, and currently, no effective treatment is available. Transient receptor potential vanilloid 4 (TRPV4) is involved in mechanical hypersensitivity resulting from varying aetiologies in animal, but its expression pattern during DMA and whether it contributes to this condition are still unclear. We investigated the spatial and temporal expression patterns of TRPV4 in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) by qRT-PCR, Western blotting and immunofluorescence assays. The pathophysiological role of TRPV4 in DMA was also investigated by intrathecal application of the TRPV4 selective antagonist HC-067047 or the agonist GSK1016790A. The results showed that both the mRNA and protein levels of TRPV4 were strikingly upregulated on day 14 in the rats with DMA. The increase in TRPV4 was mainly observed in the soma and central processes of calcitonin gene-related peptide (CGRP)- or neurofilament 200 kDa (NF200)-containing DRG neurons. Both single and repetitive intrathecal applications of HC-067047 (400 ng/kg) significantly alleviated mechanical allodynia in the rats with DMA, whereas a single application of GSK1016790A (200 ng/kg) aggravated mechanical allodynia. The present data suggest that TRPV4 undergoes expression changes that are associated with mechanical hypersensitivity in diabetic rats. TRPV4 may be a new molecular target for developing a clinical strategy to treat this intractable neuropathic pain.