5-Aminolevulinic Acid-Hyaluronic Acid Complexes Enhance Skin Retention of 5-Aminolevulinic Acid and Therapeutic Efficacy in the Treatment of Hypertrophic Scar.

Hypertrophic scar is a serious skin disorder, which reduces the patient's quality of life. 5-aminolevulinic acid (5-ALA)-mediated photodynamic therapy has been used to treat patients with hypertrophic scar. However, the poor skin retention of 5-ALA limited the therapeutic effect. In this study, we constructed the 5-ALA-hyaluronic acid (HA) complex to potentially prolong the skin retention of 5-ALA for improving the therapeutic efficacy. HA is a polysaccharide with viscoelasticity and the carboxyl groups could conjugate with amino groups of 5-ALA via electrostatic interaction. The protoporphyrin IX (PpIX) assay revealed that 5-ALA-HA complexes markedly enhanced the skin retention, resulting in increased generation and accumulation of endogenous photosensitizer PpIX. Furthermore, 5-ALA-HA complexes allowed PpIX to be maintained at a high level for 12 h, much longer than the 3 h of 5-ALA alone. And then, the accumulative PpIX induced by 5-ALA-HA in human hypertrophic scar fibroblasts (HSF) was triggered by laser irradiation to produce sufficient reactive oxygen species, leading to efficient necrosis and apoptosis of HSF. In vivo therapeutic efficacy study indicated that 5-ALA-HA effectively reduced the appearance and scar thickness, and the scar elevation index with 5-ALA-HA treatment was significantly lower than other groups, suggesting that the 5-ALA-HA-treated scar became flattened and was closely matched to the unwounded tissues. Moreover, 5-ALA-HA treatment markedly downregulated the gene expression levels of α-SMA and TGF-ß1, demonstrating attenuated the scar formation and growth. Therefore, the 5-ALA-HA complex enhancing skin retention and PpIX accumulation at the lesion site provide a promising therapeutic strategy for hypertrophic scar.

PREVIOUS DELIVERY OF MACROSOMIA IS ASSOCIATED WITH MATERNAL ADIPOSITY IN LATER LIFE IN CHINESE PAROUS WOMEN WITH NORMAL WEIGHT BEFORE AND/OR AFTER PREGNANCY.

Objective: Obesity has become a major worldwide health challenge. Macrosomic infants are more likely to experience type 2 diabetes mellitus, obesity and hypertension in adulthood. However, whether macrosomia increases the risk of maternal adiposity later in life is still unknown. Methods: One thousand nine hundred eighty-six unrelated parous women of Chinese Han ancestry aged from 40 to 76 years were enrolled. Self-reported information about reproductive status, including age at menarche, number of children, previous delivery of macrosomic infants, and body weight before and after pregnancy were obtained from personal interview by trained interviewers using a standard questionnaire. Macrosomia was defined as birth weight greater than 4,000 g. Adiposity indexes were measured or calculated. Results: Prior delivery of macrosomia was associated with an increased risk of having obesity in parous women with normal weight before pregnancy (odds ratio [OR] = 1.840; 95% confidence interval [CI] 1.028, 3.294; P = .040), as well as a higher risk of overweight/obesity in parous women with normal weight after pregnancy (OR = 1.777; 95% CI 1.131, 2.794; P = .013). In addition, previous delivery of macrosomia was related with 1.919 (95% CI 1.207, 3.050; P = .006) times higher risk of overweight/obesity in parous women with normal weight before and after pregnancy. Conclusion: The present study suggests that prior delivery of macrosomia may be an independent risk factor for adiposity later in life in parous women with normal weight before and/or after pregnancy. Abbreviations: BMI = body mass index; CI = confidence interval; OR = odds ratio; WC = waist circumference; WHR = waist-to-hip ratio; WHtR = waist-to-height ratio.

A Glutamine-Rich Carrier Efficiently Delivers Anti-CD47 siRNA Driven by a "Glutamine Trap" To Inhibit Lung Cancer Cell Growth.

It is not efficient enough using the current approaches for tumor-selective drug delivery based on the EPR effect and ligand-receptor interactions, and they have largely failed to translate into the clinic. Therefore, it is urgent to explore an enhanced strategy for effective delivery of anticancer agents. Clinically, many cancers require large amounts of glutamine for their continued growth and survival, resulting in circulating glutamine extraction by the tumor being much greater than that for any organs, behaving as a "glutamine trap". In the present study, we sought to elucidate whether the glutamine-trap effect could be exploited to deliver therapeutic agents to selectively kill cancer cells. Here, a macromolecular glutamine analogue, glutamine-functionalized branched polyethylenimine (GPI), was constructed as the carrier to deliver anti-CD47 siRNA for the blockage of CD47 "don't eat me" signals on cancer cells. The GPI/siRNA glutamine-rich polyplexes exhibited remarkably high levels of cellular uptake by glutamine-dependent lung cancer cells, wild-type A549 cells (A549WT), and its cisplatin-resistant cells (A549DDP), specifically under glutamine-depleted conditions. It was noted that the glutamine transporter ASCT2 was highly expressed both on A549WT and A549DDP but with almost no expression in normal human lung fibroblasts cells. Inhibition of ASCT2 significantly prevented the internalization of GPI polyplexes. These findings raised the intriguing possibility that the glutamine-rich GPI polyplexes utilize the ASCT2 pathway to selectively facilitate their cellular uptake by cancer cells. GPI further delivered anti-CD47 siRNA efficiently both in vitro and in vivo to downregulate the intratumoral mRNA and protein expression levels of CD47. CD47 functions as a "don't eat me" signal and binds to the immunoreceptor SIRPα inducing evasion of phagocytic clearance. GPI/anti-CD47 siRNA polyplexes achieved significant antitumor activities both on A549WT and A549DDP tumor-bearing nude mice. Notably, it had no adverse effect on CD47-expressing red blood cells and platelets, likely because of selective delivery. Therefore, the glutamine-rich carrier GPI driven by the glutamine-trap effect provides a promising new strategy for designing anticancer drug delivery systems.

Effects of acupuncture on vascular dementia (VD) animal models: a systematic review and meta-analysis.

BACKGROUND: Vascular dementia is the second most common type of dementia that causes cognitive dysfunction. Acupuncture, an ancient therapy, has been mentioned for the treatment of vascular dementia in previous studies. This study aimed to evaluate the effects of acupuncture in animal models of vascular dementia. METHODS: Experimental animal studies of treating vascular dementia with acupuncture were gathered from Embase, PubMed and Ovid Medline (R) from the dates of the databases' creation to December 2016. We adopted the CAMARADES 10-item checklist to evaluate the quality of the included studies. The Morris water maze test was considered as an outcome measure. The software Stata12.0 was used for the meta-analysis. Heterogeneity was examined using I2 statistics, and we conducted subgroup analyses to determine the causes of heterogeneity for escape latency and duration in original platform. RESULTS: Sixteen studies involving 363 animals met the inclusion criteria. The included studies scored between 4 and 8 points, and the mean was 5.44. The results of the meta-analysis indicated remarkable differences with acupuncture on increasing the duration in the former platform quadrant both in EO models (SMD = 1.56, 95% CI: 1.02 ~ 2.11; p < 0.00001) and 2-VO models (SMD 4.29, 95% CI 3.23 ~ 5.35; p < 0.00001) compared with the control groups. CONCLUSIONS: Acupuncture may be effective in improving cognitive function in vascular dementia animal models. The mechanisms of acupuncture for vascular dementia are multiple such as anti-apoptosis, antioxidative stress reaction, and metabolism enhancing of glucose and oxygen.

Desferrioxamine Enhances 5-Aminolaevulinic Acid- Induced Protoporphyrin IX Accumulation and Therapeutic Efficacy for Hypertrophic Scar.

Hypertrophic scar is a common problem after skin burns or trauma which brings physical, psychological, and cosmetic problems to patients. Photodynamic therapy with 5-aminolevulinic acid (5-ALA) is a promising therapy for hypertrophic scar. However, clinical applications of 5-ALA are limited because of the low permeability of 5-ALA in the skin stratum corneum and the rapid binding of protoporphyrin IX (PpIX) with iron ions, which lead to insufficient PpIX production in target tissues. Herein, a mixture of 5-ALA and DFO (deferoxamine, a special iron chelator) was applied for the treatment of hypertrophic scar. 5-ALA/DFO could efficiently block the biotransformation of PpIX to heme, thus realizing a significant accumulation of photosensitizer. In addition, injection locally into the lesion was applied, which combined with enhanced photodynamic therapy to destroy hypertrophic scar fibroblasts. In vitro experiments showed that 5-ALA/DFO could increase more ROS generation by increasing the accumulation of PpIX, resulting in the apoptosis of hypertrophic scar fibroblasts. Furthermore, 5-ALA/DFO inhibited the proliferation and migration of hypertrophic scar fibroblasts. In vivo study showed that 5-ALA/DFO could effectively inhibit the formation of proliferative scar. Therefore, 5-ALA/DFO has the potential to enhance the photodynamic therapy of 5-ALA and provides a new treatment strategy for hypertrophic scar.

Identification of a newly isolated erythritol-producing yeast and cloning of its erythrose [corrected] reductase genes.

A new erythritol-producing yeast (strain BH010) was isolated in this study. Analysis of the D1/D2 domain of the 26S rDNA sequence, the ITS/5.8S rDNA sequence [corrected] and the 18S rDNA sequence allowed the taxonomic position of strain BH010 to be discussed, [corrected] and it was identified and named Moniliella sp. BH010. Physiological characteristics were described. Scanning electron micrography clearly indicated that the cells were cylindrical to elliptical with an average size of 5 × 10 µm when growing in liquid medium [corrected] and that pseudohyphae and blastoconidia were observed when cultivated in agar plates. The erythrose [corrected] reductase genes were cloned, sequenced, and analyzed. BLAST analysis and multiple sequence alignment demonstrated that erythrose [corrected] reductase genes of Moniliella sp. BH010 shared very high homology with that of Trichosporonoides megachiliensis SNG-42 except for the presence of introns. The deduced amino acid sequences showed high homology to the aldo-keto reductase superfamily.

The Inverse Association of Leg Fat Mass and Osteoporosis in Individuals with Type 2 Diabetes Independent of Lean Mass.

Purpose: Recent studies revealed that high levels of thigh fat were independently associated with better glucose and lipid metabolism, as well as lower risk of hypertension and cardiometabolic disease. Therefore, the purpose of this study was to evaluate the association between leg fat mass (FM) and osteoporosis (OP) in individuals with type 2 diabetes (T2DM). Patients and Methods: In this cross-sectional study, a total of 1,259 individuals aged 50 years or older with T2DM (female 536, male 723) were included. A bioelectrical impedance analyser was used to assess the segment body composition containing FM and lean mass (LM) of arms, legs, and trunk. Bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry. Results: Leg FM was positively correlated with BMD of all sites in females and BMD of femoral neck and total hip in males after adjusting age, diabetes duration, glucose and lipid metabolism indexes, and lifestyle (all P<0.05). LM was positively associated with BMD at almost sites (P<0.001), while leg FM/LM ratio had no relationship with BMD at any skeleton sites (P>0.05). Compared with the bottom tertile group of leg FM, the risk of OP was significantly lower in the top tertile group both in females (T3 vs T1: OR=0.206, 95% CI=0.098-0.433, P<0.001) and males (T3 vs T1: OR=0.385, 95% CI=0.182-0.815, P<0.05), even after adjusting for LM. Conclusion: In the present study, higher leg FM was correlated with the lower risk of OP in both men and postmenopausal women with T2DM independently of total LM.

Prognostic Nutritional Index and Major Cardiovascular Events in Patients Undergoing Invasive Coronary Angiography: A Clinical Retrospective Study.

We aimed to examine whether prognostic nutritional index (PNI) could serve as an auxiliary predictor for major cardiovascular events (MCEs) in patients undergoing invasive coronary angiography (ICA). A total of 485 participants were enrolled, divided into low-PNI (≥47.40) and high-PNI (<47.40) groups. ICA determined the stenotic vessels of coronary artery disease. The primary outcome was incidental MCEs, a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or rehospitalization of in-stent restenosis. There were 47 (9.69%) MCEs during the 3.78-years follow-up. The cumulative incidence of MCEs was significantly higher in the low-PNI patients compared with the high-PNI patients (17.07% vs. 7.18%, p = 0.001). Malnutrition risk (low PNI) was significantly and independently associated with a higher risk of MCEs (hazard ratios: 2.593, 95% confidence intervals [CI]: 1.418−4.742). Combined use of the number of stenotic vessels with malnutrition risk showed a higher capacity to predict the MCEs than the presence of stenotic vessels alone (areas under the receiver operator characteristic curve: 0.696 [95% CI, 0.618−0.775] vs. 0.550 [95% CI, 0.466−0.633], p = 0.013). In conclusion, lower PNI levels may predict a higher risk of cardiovascular events in patients undergoing ICA, which supports the necessity of the risk assessment of nutrition status and guide the clinical treatment on strengthening nutritional support before ICA is performed, as well as nutritional intervention after ICA.

Predictive value of the prognostic nutritional index for the severity of coronavirus disease 2019.

OBJECTIVES: Malnutrition plays a critical role in the onset and progress of the coronavirus disease 2019 (COVID-19). The aim of the present study was to explore the association of the prognostic nutritional index (PNI) score with the severity of COVID-19 and its predictive value of the severe form of COVID-19. METHODS: Clinical data were collected from 122 patients infected with COVID-19 and hospitalized at the Sixth People's Hospital of Wenzhou, China, a specialized infectious hospital affiliated with the Wenzhou Central Hospital. PNI score was calculated as serum albumin (g/L) + 5 × total lymphocyte count (/nL). RESULTS: The study population consisted of 105 patients (86.1%) with a common form and 17 patients (13.9%) with a severe form of COVID-19. PNI score significantly decreased from patients with common to severe forms of COVID-19 (P = .029) regardless of sex, age range, and body mass index (BMI). After adjustment for sex, age, indexes of liver and renal function, C-reactive protein, and current smoking status, PNI scores remained independently and inversely associated with the severity of COVID-19 (odd ratio: 0.797; P = .030). A receiver operating characteristic analysis showed that PNI scores had a similar accuracy to predict severe forms of COVID-19 compared with its combination with sex, age, and BMI (P = .402). PNI < 49 was defined as the cutoff value to predict the severe form of COVID-19. CONCLUSIONS: Poorer nutritional status predisposed patients infected with COVID-19 to its severe form. Independently associated with the severity of COVID-19, PNI score could serve as a simple, fast, and effective predictor among patients with different sex, age, and BMI.

Duration of reproductive years and time since menopause were associated with metabolic syndrome in postmenopausal parous women of Chinese ancestry.

OBJECTIVE: Although duration of reproductive years and time since menopause were previously implicated in the metabolic syndrome, the evidence is more limited. Few of the previous studies were able to take into account related reproductive variables simultaneously. The aim of the present study was to explore the influence of these two reproductive factors on the prevalence of metabolic syndrome in postmenopausal parous women from Southeast China. METHODS: In all, 1,536 postmenopausal parous women were recruited. Self-reported information about reproductive status, including age at menarche, age at menopause, number of children, prepregnancy body weight, and oral contraceptive use, was collected, and duration of reproductive years and time since menopause were calculated. Clinical parameters related with metabolic syndrome were also measured. RESULTS: Longer duration of reproductive years was significantly related with increased presence of the metabolic syndrome (odds ratio [OR] 1.570, 95% confidence interval [CI] 1.091, 2.259 for tertile 2 group; OR 1.850, 95% CI 1.163, 2.944 for tertile 3 group; P for trend = 0.010). Women with more than 20 years since menopause were more likely to experience metabolic syndrome (OR 2.422, 95% CI 1.109, 5.286, P = 0.026) and elevated blood pressure (OR 3.239, 95% CI 1.406, 7.458, P = 0.006) when compared with those with less than 10 years since menopause. CONCLUSIONS: Longer duration of reproductive years and time since menopause were associated with higher prevalence of metabolic syndrome in postmenopausal parous women from Southeast China.

Ordered Coimmobilization of a Multienzyme Cascade System with a Metal Organic Framework in a Membrane: Reduction of CO2 to Methanol.

Enzymatic reduction of CO2 is of great significant, which involves an efficient multienzyme cascade system (MECS). In this work, formate dehydrogenase (FDH), glutamate dehydrogenase (GDH), and reduced pyridine nucleotide (NADH) (FDH&GDH&NADH), formaldehyde dehydrogenase (FalDH), GDH, and NADH (FalDH&GDH&NADH), and alcohol dehydrogenase (ADH), GDH, and NADH (ADH&GDH&NADH) were embedded in ZIF-8 (one kind of metal organic framework) to prepare three kinds of enzymes and coenzymes/ZIF-8 nanocomposites. Then by dead-end filtration these nanocomposites were sequentially located in a microporous membrane, which was combined with a pervaporation membrane to timely achieve the separation of product methanol. Incorporation of the pervaporation membrane was helpful to control reaction direction, and the methanol amount increased from 5.8 ± 0.5 to 6.7 ± 0.8 µmol. The reaction efficiency of an immobilized enzymes-ordered distribution in a membrane was higher than that disordered distribution in the membrane, and the methanol amount increased from 6.7 ± 0.8 to 12.6 ± 0.6 µmol. Moreover, it appeared that introduction of NADH into ZIF-8 enhanced the transformation of CO2 to methanol from 12.6 ± 0.6 to 13.4 ± 0.9 µmol. Over 50% of their original productivity was retained after 12 h of use. This method has wide applicability and can be used in other kinds of multienzyme systems.

Robust Photodynamic Therapy Using 5-ALA-Incorporated Nanocomplexes Cures Metastatic Melanoma through Priming of CD4+CD8+ Double Positive T Cells.

Advanced melanoma can rarely be cured. Photodynamic therapy (PDT) readily eradicates the primary melanoma but has limited ability to destroy the spreading tumor cells unless supported by other combinative interventions to augment systemic antitumor immunity. Based on the previously synthesized penetration-enhancing biomaterials, a topically administered nanoformulation is developed, which profoundly assists 5-aminolevulinic acid (5-ALA) in circumventing skin barrier to be selectively delivered to tumor cells. After endocytosis, accumulated 5-ALA is efficiently metabolized to a photosensitizer protoporphyrin IX (PpIX) which stimulates a large production of cytotoxic reactive oxygen species (ROS) under illumination. Accompanied by the robust inflammatory responses followed by primary tumor destruction, CD4+CD8+ double positive T cells are highly boosted to harness host immunity to purge metastases in lymphoid organs. Compared with dacarbazine and programmed death 1 (PD-1) antibody, this treatment in advanced melanoma murine models, achieves a striking curable rate of 90% without melanoma prognostic markers LDH and S-100B detection, followed by a relapse-free survival rate of 83.33% in 300 days. Moreover, the cured mice's immune system function recovers to an extent similar to healthy mice without prolonged or exaggerated inflammation. This study using the synergistic biomaterials approach may thus render 5-ALA-mediated PDT a potentially curative therapy for advanced melanoma in clinic.

Association of serum copper, zinc and selenium levels with risk of metabolic syndrome: A nested case-control study of middle-aged and older Chinese adults.

Trace elements, such as copper, zinc and selenium, have been linked to the development of metabolic syndrome. However, previous studies concerning these trace elements in association with metabolic syndrome have presented conflicting results in different countries. The aim of this study was to analyse the association between serum copper, zinc and selenium concentrations and the risk of metabolic syndrome among middle-aged and older Chinese adults. We performed a nested case-control study that included 349 individuals who developed metabolic syndrome (125 males and 224 females) during a 3-year follow-up and 349 controls matched by baseline age (±1 years), sex and area. Serum trace element concentrations were measured using atomic absorption spectrometry. The median serum selenium levels in males and females in the metabolic syndrome group were 82.2 (13.4) µg/L and 82.6 (11.1) µg/L, respectively, which were significantly higher than the serum selenium levels in the control group (p = 0.001 and p < 0.001). After adjusting for potential confounders, the odds ratios of risk for metabolic syndrome in the highest tertile of serum selenium levels were 2.72 [95% confidence interval (CI) 1.43-5.20; p for trend 0.002] for males and 5.30 (95% CI 3.31-8.74; p for trend <0.001) for females, respectively, compared with the lowest tertile. In addition, serum selenium levels were positively correlated with postprandial plasma glucose in both genders (for males: odds ratio 2.42; 95% CI 1.27-4.61; for females: odds ratio 2.11; 95% CI 1.32-3.37) and negatively associated with high-density lipoprotein in only females (odds ratio 3.21; 95% CI 1.75-5.91). These results suggest that higher levels of serum selenium might be an independent risk factor for metabolic syndrome, especially in relation to elevated postprandial plasma glucose and reduced high-density lipoprotein levels. However, we failed to demonstrate an association between copper or zinc status and metabolic syndrome or its components.

Peripheral Arterial Disease in Type 2 Diabetes Is Associated with an Increase in Fibrinogen Levels.

BACKGROUND: The present study is undertaken to investigate the fibrinogen levels in type 2 diabetes mellitus (T2DM) and its relation to peripheral artery disease (PAD) based on a more accurate and applied noninvasive measurements of duplex ultrasonography. METHODS: We performed a cross-sectional study including 1096 T2DM patients (474 males and 622 females). The odds ratios (ORs) and 95% confidence intervals (CIs) were presented to show the association between PAD and fibrinogen in the subjects divided by fibrinogen levels quarterly. Furthermore, the univariate and multiple logistic analyses were performed to explore the correlation between PAD and fibrinogen levels, individual components in the cross-sectional study. RESULTS: Finally, 887 (80.9%) T2DM patients meet the diagnostic criteria of PAD and these patients had considerably higher serum fibrinogen concentration than non-PAD group (P < 0.001). Multiple logistic analyses revealed that higher fibrinogen quartiles were positively related with the development of PAD in the adjusted model. After adjusting for known confounding parameters, the ORs for PAD were 1.993 (95% CI: 1.322-3.005, P < 0.001), 2.469 (95% CI: 1.591-3.831, P < 0.001), and 2.942 (95% CI, 1.838-4.711, P < 0.001) for Q2, Q3, and Q4, respectively (all P values <0.05). CONCLUSIONS: Our results suggest that serum fibrinogen concentration can be considered as an independent risk factor for PAD in T2DM patients.

Glutamine addiction activates polyglutamine-based nanocarriers delivering therapeutic siRNAs to orthotopic lung tumor mediated by glutamine transporter SLC1A5.

Many human cancer cells exhibit an oncogenetic-driven addiction to glutamine (Gln) as rapidly proliferating cancer cells consume Gln at a dramatically increased rate compared to normal cells. Tumor cells, therefore, compete with host cells for Gln, which causes Gln to flux from normal tissues to the tumor. We have developed and characterized a Gln macromolecular analog polyglutamine (PGS) for the delivery of gene regulators, such as siRNAs, in our previous works. Here, we hypothesize that PGS can utilize the Gln transporter SLC1A5 to specifically deliver therapeutic compounds to Gln-addicted cancer cells. Compared to human lung fibroblast HLF cells, cisplatin-resistant human lung adenocarcinoma A549/DDP cells significantly overexpress SLC1A5, which has a high binding affinity to PGS, as confirmed through molecular docking analysis. Due to the differences in Gln metabolism between malignant and normal cells, PGS/siRNA complexes were remarkably increased in cancer cells, especially when cells were deprived of Gln, which mirrors the conditions that are commonly found in a tumor microenvironment. Furthermore, we identified that chemical and genetic inhibition of Gln transporter SLC1A5 reduced the cellular internalization of PGS/siRNA complexes, suggesting a critical role for SLC1A5 in PGS uptake in cells. In turn, PGS upregulated SLC1A5 expression. Increased uptake of PGS complexes profoundly decreased intracellular Gln levels. Decreased Gln caused a moderate reduction in cell growth. To restore drug sensitivity and further enhance anti-tumor effects, the hybrid siRNAs anti-Survivin and anti-MDR1 (siSM), as model therapeutics, were administered through the PGS delivery system, which resulted in knockdown of Survivin and MDR1 and further sensitized cancer cells to the drug cisplatin (DDP). Since PGS complexes administered i.v. mostly accumulated in the lung parenchyma, a lung orthotopic tumor model was established to evaluate their inhibitory effects on tumors in the lungs. PGS/siSM comparably decreased the rate of tumor growth, while concurrent administration of PGS/siSM and DDP enhanced this effect and insignificantly improved life span. Consistent with our hypothesis, this study demonstrated that PGS mimicked Gln in the SLC1A5 pathway and selectively ferried therapeutics to Gln-addicted cancer cells. Our findings identified a new lung cancer targeting strategy based on Gln metabolism and can be used as a drug/gene delivery system.

Involvement of BDNF/TrkB and ERK/CREB axes in nitroglycerin-induced rat migraine and effects of estrogen on these signals in the migraine.

Migraine is a highly prevalent headache disorder, especially in women. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinases (TrkB), as well as extracellular signal-regulated kinase (ERK) and its downstream target c-AMP-responsive element binding protein (CREB) are strongly associated with the transmission of nociceptive information. However, the involvement of these substances in migraine has rarely been examined. In the present study, intraperitoneal injection of nitroglycerin (NTC) successfully induced rat migraine attack, as evidenced by behavioral testing. The location and abundance of these substances in the migraine model were determined by immunohistochemistry, real-time polymerase chain reaction (RT-PCR), western blot and enzyme-linked immunosorbant assays (ELISA). Results showed that BDNF, TrkB, phosphor(p)-ERK and p-CREB were up-regulated in the brain neurons of both male and female rats with NTG-induced migraine compared to non-migraine control, whereas their expression levels were decreased in headache-free intervals of the migraine compared to migraine attacks. Estrogen is an important contributor to migraine. Female ovariectomized rats showed significant reduction in the expression of BDNF, TrkB, p-CREB and p-ERK in both attacks and intervals of NTG-induced migraine, relative to rats that have their ovaries. But, intraperitoneal administration of exogenous estrogen recovered their expression in ovariectomized rats. Collectively, this study unveiled a positive correlation of BDNF/TrkB and ERK/CREB axes in NTG-induced migraine and promoting effects of estrogen on their signals in the migraine. These findings contribute to further understanding the pathogenesis of migraine in the molecular basis.

Gibberellin Is Involved in Inhibition of Cucumber Growth and Nitrogen Uptake at Suboptimal Root-Zone Temperatures.

Suboptimal temperature stress often causes heavy yield losses of vegetables by suppressing plant growth during winter and early spring. Gibberellin acid (GA) has been reported to be involved in plant growth and acquisition of mineral nutrients. However, no studies have evaluated the role of GA in the regulation of growth and nutrient acquisition by vegetables under conditions of suboptimal temperatures in greenhouse. Here, we investigated the roles of GA in the regulation of growth and nitrate acquisition of cucumber (Cucumis sativus L.) plants under conditions of short-term suboptimal root-zone temperatures (Tr). Exposure of cucumber seedlings to a Tr of 16°C led to a significant reduction in root growth, and this inhibitory effect was reversed by exogenous application of GA. Expression patterns of several genes encoding key enzymes in GA metabolism were altered by suboptimal Tr treatment, and endogenous GA concentrations in cucumber roots were significantly reduced by exposure of cucumber plants to 16°C Tr, suggesting that inhibition of root growth by suboptimal Tr may result from disruption of endogenous GA homeostasis. To further explore the mechanism underlying the GA-dependent cucumber growth under suboptimal Tr, we studied the effect of suboptimal Tr and GA on nitrate uptake, and found that exposure of cucumber seedlings to 16°C Tr led to a significant reduction in nitrate uptake rate, and exogenous application GA can alleviate the down-regulation by up regulating the expression of genes associated with nitrate uptake. Finally, we demonstrated that N accumulation in cucumber seedlings under suboptimal Tr conditions was improved by exogenous application of GA due probably to both enhanced root growth and nitrate absorption activity. These results indicate that a reduction in endogenous GA concentrations in roots due to down-regulation of GA biosynthesis at transcriptional level may be a key event to underpin the suboptimal Tr-induced inhibition of root growth and nitrate uptake. These findings may have important practical implications in effective mitigation of suboptimal temperature-induced vegetable loss under greenhouse conditions.

Association of Serum Magnesium Level with Odds of Prediabetes and Diabetes in a Southern Chinese Population: a Prospective Nested Case-Control Study.

Although emerging clinical evidence supports that magnesium deficiency is a risk factor for the development of type 2 diabetes, there are sparse studies concerning the dynamic change of serum magnesium with the risk of diabetes and its early stages. In this nested case-control study, we performed a 75-g oral glucose tolerance test or a standardized steamed bread meal test in 178 subjects with incident glucose metabolism impairment (33 with type 2 diabetes and 145 with prediabetes) and 178 matched controls at baseline and at 3-year follow-up and determined the associations between baseline serum magnesium levels as well as changes in serum magnesium levels at follow-up and odds of prediabetes and diabetes. After adjusting for potential confounders, the odds ratios of risk for prediabetes and type 2 diabetes in the highest quartile of serum magnesium levels were 0.22 (95 % confidence intervals [CI] 0.10-0.49; p for trend <0.001) and 0.02 (95 % CI 0.00-0.29; p for trend = 0.009), respectively, as compared with the lowest quartile. In addition, a significant decline in the serum magnesium level was detected in type 2 diabetes cases (p = 0.015) at 3 years as compared with at baseline. These results suggest that a low magnesium level is an independent risk factor for prediabetes and type 2 diabetes, and that the reduction of serum magnesium is associated with type 2 diabetes in a southern Chinese population.

Waist-to-height ratio is an appropriate index for identifying cardiometabolic risk in Chinese individuals with normal body mass index and waist circumference.

BACKGROUND: The waist-to-height ratio (WHtR), a novel index that has been reported to correlate more strongly than body mass index (BMI) and waist circumference (WC) with cardiometabolic risk factors, has not been studied in Chinese individuals with normal body mass index and waist circumference. The present study compared the predictive power of WHtR with those of BMI and WC for such factors in non-obese Chinese, and to define optimal cutoffs of WHtR in this population. METHODS: A total of 2137 subjects aged 40-75 years were recruited. Three anthropometric indices (WHtR, BMI, and WC) were compared and the optimal cutoffs of WHtR were identified by receiver operating characteristic curve (ROC) analysis. WHtR was divided into four quartiles (WHtR-Q), and multiple linear regression analyses were used to calculate the relationship between WHtR-Q and clinical biochemical index. RESULTS: Waist-to-height ratio was more efficient than WC to identify cardiometabolic risk factors in both genders, but was only superior to BMI in females. WHtR-Q was positively correlated with fasting plasma glucose, 2-h postprandial blood glucose, and systolic blood pressure, and negatively connected with high density lipoprotein cholesterol in both genders after controlling for age, current smoking and drinking, moderate-intensity physical activity, daily sedentary time, daily screen time and menopause (only for females). The optimal cutoffs of WHtR for detecting cardiometabolic risk factors were 0.47 in males and 0.51 in females. CONCLUSION: Waist-to-height ratio might be an effective index to identify cardiometabolic risk factors in Chinese with normal BMI and WC, particularly in females.