Supplementation with high-GABA-producing Lactobacillus plantarum L5 ameliorates essential tremor triggered by decreased gut bacteria-derived GABA.

BACKGROUND: The γ-aminobutyric acid (GABA) hypothesis posits a role of GABA deficiency in the central nervous system in the pathogenesis and progression of essential tremor (ET). However, the specific causative factor for GABA deficiency is not clear. The gut microbiota in mammals has recently been considered as a significant source of GABA. Furthermore, the GABA-based signals originating from the intestine can be transmitted to the brain through the "enteric nervous system-vagus nerve-brain" axis. However, the plausible contribution of gut microbiota to ET seems inspiring but remains obscure. METHODS: Fecal samples from patients with ET and healthy controls were examined by metagenomic sequencing to compare the composition of gut microbiota and the expression of genes involved in GABA biosynthesis. The impact of gut microbiota on ET was explored through transplantation of fecal microbiota from patients with ET into the murine ET model. Lactic acid bacteria producing high amounts of GABA were identified through whole-genome sequencing and ultra-performance liquid chromatography-tandem mass spectrometry. Subsequently, mice were treated with the high-GABA-producing strain Lactobacillus plantarum L5. Tremor severity, behavioral tests, pro-inflammatory cytokines, GABA concentration, and gut microbiota composition were examined in these mice. RESULTS: The gut microbiota of patients with ET demonstrated an impaired GABA-producing capacity and a reduced fecal GABA concentration. Transplantation of the gut microbiota from patients with ET induced an extension of tremor duration and impaired mobility in the murine model of ET. L5 exhibited an augmented GABA-producing capacity, with the De Man-Rogosa-Sharpe culture broth containing 262 mg/l of GABA. In addition, administration of L5 significantly decreased the tremor severity and enhanced the movement capability and grasping ability of ET mice. In vivo mechanistic experiments indicated that L5 reshaped the gut microbial composition, supplemented the mucosa-associated microbiota with GABA-producing capacity, increased the GABA concentrations in the cerebellum, and diminished inflammation in the central nervous system. CONCLUSIONS: These findings highlight that deficiency of GABA-producing gut microbes plays an essential role in the pathogenesis of ET and that L5 is a promising candidate for treating ET.

Nutritional geometry framework of sucrose taste in Drosophila.

Dietary protein (P) and carbohydrate (C) have a major impact on the sweet taste sensation. However, it remains unclear whether the balance of P and C influences the sweet taste sensitivity. Here, we use the nutritional geometry framework (NGF) to address the interaction of protein and carbohydrates on sweet taste using Drosophila as a model. Our results reveal that high-protein, low-carbohydrate (HPLC) diets sensitize to sweet taste and low-protein, high-carbohydrate (LPHC) diets desensitize sweet taste in both male and female flies. We further investigate the underlying mechanisms of the effects of two diets on sweet taste using RNA sequencing. When compared to the LPHC diet, the mRNA expression of genes involved in the metabolism of glycine, serine, and threonine is significantly upregulated in the HPLC diet group, suggesting these amino acids may mediate sweet taste perception. We further find that sweet sensitization occurs in flies fed with the LPHC diet supplemented with serine and threonine. Our study demonstrates that sucrose taste sensitivity is affected by the balance of dietary protein and carbohydrates possibly through changes in serine and threonine.

[Synchronous evaluation of continuous dynamic dissolution and absorption of Compound Danshen Dropping Pills based on cellular bioelectrical effect].

The real-time cell-based assay(RTCA) was used to establish the bioelectrical sensing model of Compound Danshen Dripping Pills with rat cardiomyocytes(H9 c2). The time/dose-dependent cell response profiles(TCRPs) of in vitro dissolution and absorption of the pills were determined to establish the continuous dynamic dissolution and absorption kinetic models. Thereby, the cell index(CI)-based dissolution and absorption kinetic curves and kinetic models of Compound Danshen Dripping Pills were obtained. The optimal dissolution kinetic model was Weibull model. The similarity factors f_2 of dissolution curves were greater than 50 and the correlation coefficients of absorption curves were larger than 0.95. With the experiment about the efficacy on mice, percentages of the bleeding time of mice administrated with Compound Danshen Dripping Pills were calculated, and there was a correlation among dissolution, absorption, and efficacy curves(r > 0.9). RTCA is applicable to the study of the dissolution and absorption kinetics of solid compound Chinese medicine preparations. Thus, it is an innovative and feasible method to evaluate the quality and batch consistency of compound Chinese medicine preparations.

The Association of Folic Acid, Iron Nutrition during Pregnancy and Congenital Heart Disease in Northwestern China: A Matched Case-Control Study.

Background: The purpose of this study was to investigate the relationship between folic acid and iron nutrition during pregnancy and congenital heart disease (CHD) in the offspring. Methods: Conditional logistic regression models and nonlinear mixed-effects models were used to analyze the effects of folic acid and iron nutrition during pregnancy on CHD in offspring. Results: After adjusting for confounders, folic acid or iron supplementation during pregnancy reduced the risk for fetal CHD (OR = 0.60 (0.45, 0.82) or 0.36 (0.27, 0.48)). Similarly, dietary iron intake during pregnancy (≥29 mg/d) was associated with a reduced risk of fetal CHD (OR = 0.64 (0.46, 0.88)). Additionally, compared with women who only supplemented folic acid (OR = 0.59 (0.41, 0.84)) or iron (OR = 0.32 (0.16, 0.60)), women who supplemented both folic acid and iron had lower risk for newborns with CHD (OR = 0.22 (0.15, 0.34)). Similarly, compared with women who only supplemented folic acid (OR = 0.59 (0.41, 0.84)) or higher dietary iron intake (≥29 mg/d) (OR = 0.60 (0.33, 1.09)), women who supplemented both folic acid and higher dietary iron intake (≥29 mg/d) had lower risk for the newborn with CHD (OR = 0.41 (0.28, 0.62)). The combined effects were significant in the multiplication model (OR = 0.35 (0.26, 0.48) or 0.66 (0.50, 0.85)) but not in the additive model. Conclusions: Our study found that folic acid and iron nutrition during pregnancy were associated with a reduced risk of CHD in the offspring and confirmed a statistically significant multiplicative interaction between folic acid and iron nutrition on the reduced risk of CHD in offspring.

Icariin exhibits protective effects on cisplatin-induced cardiotoxicity via ROS-mediated oxidative stress injury in vivo and in vitro.

BACKGROUND: Cisplatin-induced cardiotoxicity severely limits its clinical application as an antitumor drug and increases the risk of cardiovascular disease. Icariin (ICA), the main flavonoid isolated from Epimedii Folium, has been demonstrated to have various beneficial effects on cardiovascular disease. However, the protective effect of ICA against cisplatin-induced cardiotoxicity remains unclear. PURPOSE: In present study, we explored the protective action of ICA against cisplatin-induced cardiotoxicity and its possible molecular mechanisms in vitro and in vivo. METHODS: Mice were intraperitoneally injected with cisplatin 4 mg/kg every other day for 7 times to establish myocardial injury model. ICA (15, 30 mg/kg) was administered to mice by gavage for 21 days. H9c2 cells were treated with ICA (3, 6, 12 µM) in the presence or absence of cisplatin (40 µM), and then cell viability, oxidative stress, apoptosis, and mitochondrial function were evaluated. RESULTS: Biochemical index detection and histopathological staining analysis showed that ICA had a good protective effect on cisplatin-induced cardiotoxicity. Cellular experiments showed that ICA inhibited cisplatin-induced oxidative stress in a dose-dependent manner by regulating the levels of glutathione peroxidase (GSH-Px), catalase (CAT), superoxide dismutase (SOD) and malondialdehyde (MDA). ICA could inhibit the expression of NF-κB and the secretion of inflammatory factors, thereby alleviating the inflammatory injury caused by cisplatin. In addition, ICA could alleviate cisplatin-induced myocardial injury by activating SIRT1 and PI3K/Akt signaling pathways and inhibiting MAPKs signaling pathway. CONCLUSION: These results suggest that ICA could attenuate cisplatin-induced cardiac injury by inhibiting oxidative stress, inflammation and apoptosis, laying a foundation for ICA to reduce chemotherapy-induced cardiotoxicity in clinical practice.

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.

Multifunctional nanocarrier with self-catalytic production of nitric oxide for photothermal and gas-combined therapy of tumor.

Single treatment often faces the problem that it cannot completely eradicate tumor and inhibit the tumor metastasis. In order to overcome this shortcoming, multi-modal tumor treatment has attracted widespread attention. In the present article, based on ascorbyl palmitate (PA) and l-arginine (l-Arg), a multifunctional nanocarrier is designed for synergetic treatment of tumor with photothermal and nitric oxide (NO) gas therapy. Firstly, PA and l-Arg were self-assembled to form novel functional micelles, PL, with high biosafety using electrostatic interaction and hydrogen bonding. The functional micelles could self-catalyze to produce NO at the tumor site. Then, Ag2S quantum dots having fluorescence imaging and photothermal properties were encapsulated to obtain the nanocarrier, A@PL. The results show that A@PL had a hydrated size of around 78 nm and presented good stability within 30 d. Moreover, in vitro studies indicate that it was efficient with regards to NO self-generating capacity, whereas the photothermal conversion efficiency was as high as 34% under near-infrared light irradiation. The cytotoxicity results show that, when the concentration of A@PL was as high as 2 mM, the survival rate of 3 T3 cells was still 78.23%, proving that the probe has good safety characteristics. Fluorescence imaging results show that its maximum enrichment can be achieved at the tumor site after tail vein injection for 3 h, and out of the body after 24 h, indicating good internal circulation. The in vivo studies show that the rate of inhibition of tumor using the nanocarrier was as high as 98%, and almost overcame the problem of tumor recurrence caused by single treatment, thus presenting a significant tumor treatment effect. This new multifunctional nanocarrier with self-catalytic production of NO provides a new idea for the efficient treatment of tumors.

Ethnobotanical survey of antifertility medicinal plants in Dali District, Yunnan Province, China.

In recent years, contraceptive medication has been widely used for birth control. It is worth noting that contraceptive medication from botanical source has great potential for clinical use. Yunnan is the province with the most species of plants in China and is known as the "plant kingdom". This study aims to archive herbal remedies traditionally used as antifertility remedies in Dali District, Yunnan Province, P. R. China. The survey was conducted from February 2011 to September 2016 in the population distributed in Dali and the surrounding counties. The data were collected from three groups of practitioners within the study area: therapists using traditional medicines (n = 104), aboriginal families (n = 37), and herbalists in commercial stalls (n = 12), and a total number of 117 plant species were recorded. Among the 117 plant species, 104 of which have been authenticated by a plant taxonomist from the Dali Herbarium. These plants were classified into 98 genera and 54 families, including Leguminosae (12 species), Liliaceae (7 species), Cucurbitaceae, Rosaceae and Rutaceae (5 species, respectively), Malvaceae, Compositae and Euphorbiaceae (4 species, respectively). Our data provides an in-depth delineation of the contraceptive plants used in Dali, which serve as valuable information for the practitioners of traditional Chinese medicine in contraceptive use. In addition, these data also hint that plants from different genus contain contraceptive components, which should be avoided by pregnant women. Future studies are required to identify the active contraceptive components, assess the toxicology, and elucidate the pharmacological mechanism of action.

Anti-inflammatory and analgesic monoterpenoid indole alkaloids of Kopsia officinalis.

ETHNOPHARMACOLOGICAL RELEVANCE: "Ya gai", an important part of Dai medical theory, is traditionally recognized as an antidote. Kopsia officinalis Tsiang et P. T. Li is a "Ya gai" related medicine and has been widely used by Dai people for the treatment of pain and inflammation. Previous literature on title species suggested that monoterpenoid indole alkaloids (MIAs) could be its main bioactive components. However, the specific bioactive ingredients for inflammation-related treatment are still unrevealed, which inspired us to conduct a phytochemical and pharmacological investigation related to its traditional use. AIM OF THE STUDY: To support the traditional use of K. officinalis by assessing the anti-inflammatory and analgesic effects of its purified MIAs. MATERIAL AND METHODS: Compounds were isolated and purified from the barks and leaves of K. officinalis using diverse chromatographic methods. The structures were established by means of extensive spectroscopic analyses and quantum computational technique. The anti-inflammatory activities of the purified MIAs were evaluated in vitro based on the suppression of lipopolysaccharide-activated inflammatory mediators (COX-2, IL-1ß, and TNF-α) in RAW 264.7 macrophage cells. Anti-inflammatory and analgesic activities in vivo were assessed with carrageenan-induced paw edema and acetic acid-stimulated writhing in mice models. RESULTS: 23 MIAs including four new compounds were obtained and structurally established. Most of isolates showed significant anti-inflammatory effects in vitro by inhibiting inflammatory mediators (COX-2, IL-1ß, and TNF-α). Further pharmacological evaluation in vivo revealed that 12-hydroxy-19(R)-hydroxy-ibophyllidine (1) and 11,12-methylenedioxykopsinaline N4-oxide (5) remarkably decreased the number of writhing, while kopsinic acid (8), (-)-kopsinilam (12), and normavacurine-21-one (20) significantly relieved paw edema, respectively, even better than the positive control aspirin. CONCLUSIONS: The in vitro and in vivo findings supported the traditional use of K. officinalis with respect to its anti-inflammatory and analgesic effect, as well as provided potent bioactive MIAs for further chemical modification and pharmacological investigation.

Diosmetin has therapeutic efficacy in colitis regulating gut microbiota, inflammation, and oxidative stress via the circ-Sirt1/Sirt1 axis.

Diosmetin (3',5,7 -trihydroxy-4'-methoxy flavone) is a natural flavonoid compound in the citrus species, it exhibits a variety of pharmacological activities, but little is known of its effects on colitis. In this study we evaluated the therapeutic effects of diosmetin on mouse models of chronic and acute colitis. Chronic colitis was induced in mice by drinking water containing 3% dextran sulfate sodium (DSS) from D0 to D8, followed by administration of diosmetin (25, 50 mg · kg-1 · d-1) for another 8 days. Acute colitis was induced by drinking water containing 5% DSS from D0 to D7, the mice concomitantly received diosmetin (25, 50 mg · kg-1 · d-1) from D1 to D7. During the experiments, body weight and disease activity index (DAI) were assessed daily. After the mice were sacrificed, colon tissue and feces samples were collected, and colon length was measured. We showed that in both models, diosmetin administration significantly decreased DAI score and ameliorated microscopic colon tissue damage; increased the expression of tight junction proteins (occludin, claudin-1, and zonula occludens-1), and reduced the secretion of proinflammatory cytokines IL-1ß, IL-6, TNF-α, and Cox-2 in colon tissue. We found that diosmetin administration remarkably inhibited colon oxidative damage by adjusting the levels of intracellular and mitochondrial reactive oxygen species, GSH-Px, SOD, MDA and GSH in colon tissue. The protection of diosmetin against intestinal epithelial barrier damage and oxidative stress were also observed in LPS-treated Caco-2 and IEC-6 cells in vitro. Furthermore, we demonstrated that diosmetin markedly increased the expression of Nrf2 and HO-1 and reduced the ratio of acetylated NF-κB and NF-κB by activating the circ-Sirt1/Sirt1 axis, which inhibited oxidative stress and inflammation in vivo and in vitro. Diosmetin reversed the effects of si-circSirt1 and si-Sirt1 in LPS-treated Caco-2 and IEC-6 cells. When the gut microbiota was analyzed in the mouse model of colitis, we found that diosmetin administration modulated the abundance of Bacteroidetes, Actinobacteria, Cyanobacteria and Firmicutes, which were crucial for inflammatory bowel disease. Our results have linked colitis to the circ-Sirt1/Sirt1 signaling pathway, which is activated by diosmetin. The results imply that diosmetin may be a novel candidate to alleviate DSS-induced colitis and can be a lead compound for future optimization and modification.

The Role of TGF-ß Signaling Pathways in Cancer and Its Potential as a Therapeutic Target.

The transforming growth factor-ß (TGF-ß) signaling pathway mediates various biological functions, and its dysregulation is closely related to the occurrence of malignant tumors. However, the role of TGF-ß signaling in tumorigenesis and development is complex and contradictory. On the one hand, TGF-ß signaling can exert antitumor effects by inhibiting proliferation or inducing apoptosis of cancer cells. On the other hand, TGF-ß signaling may mediate oncogene effects by promoting metastasis, angiogenesis, and immune escape. This review summarizes the recent findings on molecular mechanisms of TGF-ß signaling. Specifically, this review evaluates TGF-ß's therapeutic potential as a target by the following perspectives: ligands, receptors, and downstream signaling. We hope this review can trigger new ideas to improve the current clinical strategies to treat tumors related to the TGF-ß signaling pathway.

Dual mitigation of immunosuppression combined with photothermal inhibition for highly effective primary tumor and metastases therapy.

T-cell based immune response can attack cancer cells formidably when certain immune checkpoint (e.g., PD-1/PD-L1) is blocked. Unfortunately, PD-1/PD-L1 blockade only provoke limited immune response because the differentiation of tumor-reactive T lymphocytes is often suppressed by TGF-ß pathway. Namely, the combating cancer weapon is weakened. In this study, other than employing photothermal therapy (PTT) to eliminate the primary tumor, we also aimed to expose in situ tumor-associated antigens and exert immune response for metastases inhibition. This enhanced immunotherapeutic strategy is achieved by IR780/SB-505124 based nanoliposomes (Nano-IR-SB@Lip). Upon administration, TGF-ß pathway is inhibited by SB to drive effector T cells into a responsive state and reduce the infiltration of Treg cells, eventually greatly enhancing the weapon against cancer. In the meantime, the immunosuppressive "protection" of tumor cells is also neutralized by blocking PD-1/PD-L1 immune checkpoint. By virtue of inherent characteristics of IR780, Nano-IR-SB@Lip can selectively accumulate, penetrate deeply in tumor tissues, and preferentially retain in mitochondria. The above features are of critical importance to tumor therapy. Thus, highly effective cancer immunotherapy is implemented via selective accumulation/deep penetration of Nano-IR-SB@Lip in tumor, achieving PTT induced immunogenic cell death and dual mitigation of immunosuppression strategy (TGF-ß inhibition/PD-1/PD-L1 blockade), which is a promising therapeutic modality for cancer.

Maternal B-vitamin intake and B-vitamin supplementation during pregnancy in relation to neonatal congenital heart defects: a case-control study with propensity score matching.

BACKGROUND/OBJECTIVES: The effect of dietary folate intake or folic acid (FA) supplementation during pregnancy on neonatal congenital heart defects (CHDs) remains inconclusive. There are limited data about non-folate-B-vitamin intake and the risk of CHDs. Furthermore, few studies have investigated dietary B-vitamin intake and B-vitamin supplement use simultaneously in relation to the risk of CHDs. This study aimed to explore the associations between maternal folate, vitamin B6, and vitamin B12 intake (dietary intake, total intake from diet and supplements); B-vitamin supplement use during pregnancy; and the risk of CHDs using the propensity score matching (PSM) method. METHODS: We conducted a case-control study and included 760 cases and 1600 controls in Shaanxi Province, China. Diet, supplement use and other information were collected through a questionnaire interview. By using the 1:2 ratio PSM method, 396 cases were matched with 792 controls. Conditional logistic regression was used to investigate the associations between maternal B-vitamin intake and supplement use during pregnancy and CHDs. RESULTS: Higher maternal dietary and total intake of folate and vitamin B12 were associated with reduced risk of CHDs, and the tests for linear trend were significant. Compared with non-users, maternal FA + VB6 + VB12 containing supplement use during pregnancy (OR 0.61, 95%CI 0.40-0.94), FA supplement use during pregnancy (OR 0.70, 95%CI 0.50-0.98) and in the first trimester (OR 0.62, 95%CI 0.46-0.85) were associated with a lower risk of CHDs. CONCLUSIONS: The findings of this study suggest that a higher intake of folate and vitamin B12 during pregnancy reduces the risk of CHDs.

Uncovering the mechanism of Jueyin granules in the treatment of psoriasis using network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Our clinical practice demonstrated that Jueyin granules (JYG) benefit patients with mild to moderate psoriasis vulgaris without apparent adverse effects. JYG have been shown to inhibit epidermal proliferation in an imiquimod (IMQ)-induced psoriasis-like mouse model, as well as keratinocyte proliferation. Moreover, JYG causes no acute or chronic toxicity in animal models. However, its related molecular mechanism has still not been elucidated. AIM OF THE STUDY: To assess the mechanism of JYG against psoriasis. MATERIALS AND METHODS: This study combined network pharmacology analysis with experiments to investigate the mechanism of JYG against psoriasis. First, the molecular docking technology was used to construct the network of medicinal materials-core active plant ingredients-core targets and identify possible drug targets. Next, high-performance liquid chromatography (HPLC) was used for quality control of JYG. Finally, a mice model of psoriasis was used to further verify the effects of JYG. RESULTS: (1) Molecular docking analysis of network pharmacology revealed that the therapeutic effects of JYG on psoriasis might be achieved through Vitamin D Receptor (VDR) effects. (2) The concentrations of chlorogenic acid and paeoniflorin were determined using HPLC to establish quality control of JYG. (3) JYG ameliorated pathological characteristics that included in vivo reductions in erythema, scale, and infiltration scores of back and ear lesions in IMQ-induced psoriasis-like mice. Moreover, a reduced number of PCNA-positive and Ki67-positive cells were observed in the epidermis of JYG-treated lesions. JYG also reduced inflammation (interleukin (IL)-17, IL-23) in the peripheral blood of IMQ-induced psoriasis-like mice. As expected, JYG was found to upregulate VDR expression and downregulate p-STAT3 expression in the IMQ group, which may contribute to its mechanism against psoriasis. CONCLUSION: Overall, this study clarifies the mechanism of JYG against psoriasis and provides evidence to support its clinical use.

Efficacy and safety of YinQiSanHuang-antiviral decoction in chronic hepatitis B: study protocol for a randomized, placebo-controlled, double-blinded trial.

INTRODUCTION: Chronic hepatitis B (CHB) is a global public health problem. Antiviral therapy is the primary treatment. Studies have shown that a combined therapy of traditional Chinese medicine (TCM) and conventional antiviral drugs has better efficacy than conventional antiviral for treatment of CHB. YinQiSanHuang-antiviral decoction (YQSH) is a TCM compound preparation that has shown an effect on anti-hepatitis B virus and on slowing progression of hepatitis B-related liver diseases. To evaluate the efficacy and safety of YQSH combined with entecavir and its preventive effect on hepatitis B cirrhosis, we designed this randomized, double-blind and placebo-controlled trial. The objective is that the combination of YinQiSanHuang-antiviral decoction with entecavir will reduce the annual incidence of liver fibrosis/cirrhosis to 1%. METHODS: This is a multicenter, randomized, placebo-controlled, double-blinded trial involving five hospitals. A total of 802 patients are randomly allocated to two groups: the YQSH group (n = 401) or the placebo group (n = 401). The YQSH group receives YQSH with entecavir; the placebo group receives granules of placebo with entecavir. Patients receive treatment for 52 weeks and then are followed up for 52 ± 2 weeks. The primary outcome measure is the annual incidence of cirrhosis. The secondary outcome measures are hepatitis B virus DNA negative rate, hepatitis B surface antigen negative rate, hepatitis B e antigen seroconversion rate, liver function (alanine aminotransferase, aspartate aminotransferase , gamma-glutamyl transferase , alkaline phosphatase , serum albumin, and total bilirubin), spleen thickness, evaluation scores of patients' clinical symptoms, and safety assessment. Outcomes will be assessed at baseline and after treatment. DISCUSSION: Combination therapy could become a trend for treatment of CHB, and this trial expects to provide credible clinical evidence for the future combination of TCM and conventional antiviral drugs for the treatment of CHB. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR1900021521. Registered on 25 February 2019.

Iron intake and iron status during pregnancy and risk of congenital heart defects: A case-control study.

BACKGROUND: The relationships between iron nutritional status and congenital heart defects (CHDs) among humans are still unclear. This study aimed to explore the associations of maternal iron intake during pregnancy and maternal and neonatal iron status with CHDs. METHODS: This hospital-based case-control study analyzed 474 cases and 948 controls in Shaanxi China. Eligible women waiting for delivery in the hospital were interviewed to report their diets and characteristics during pregnancy. We conveniently collected maternal blood before delivery and neonatal cord blood to get a subgroup of 50 cases and 100 controls. Mixed logistic regression models were used to estimate ORs (95%CIs) for CHDs associated with iron intake. Mixed linear regression models were used to assess the relationships between CHDs and iron status. RESULTS: Mothers whose fetuses have CHDs were less likely to have higher intakes of total iron and heme iron during pregnancy, and the tests for linear trend were significant (all P < 0.05). Mothers whose fetuses have CHDs were less likely to take iron supplements during pregnancy (OR = 0.28, 95%CI: 0.21, 0.36) and during the first trimester (OR = 0.32, 95%CI: 0.12, 0.84). Maternal SF and Hb concentrations before delivery were lower and maternal sTfR/SF before delivery was higher among the cases than the controls. CONCLUSIONS: Mothers whose fetuses have CHDs are less likely to have higher intakes of total iron and heme iron and take iron supplements during pregnancy compared to their counterparts. Maternal iron status before delivery is low among mothers whose fetuses have CHDs.

Polydopamine-Based Multifunctional Antitumor Nanoagent for Phototherapy and Photodiagnosis by Regulating Redox Balance.

The development of multifunctional nanoagents for the simultaneous achievement of high diagnostic and therapeutic performances is significant for precise cancer treatment. Herein, we report on a polydopamine (PDA)-based multifunctional nanoagent, PML, in which the methylene blue (MB) photosensitizer (PS) and l-arginine (l-Arg) tumor-targeting species are equipped. After selectively accumulating in tumor sites, glutathione (GSH)-responsive PML degradation can controllably release loaded MB to produce singlet oxygen (1O2) under near-infrared (NIR) photoirradiation. This GSH-depleted PS release process can not only weaken the body's antioxidant defence ability but also synergistically increase the 1O2 concentration. Therefore, GSH depletion-enhanced photodynamic therapy (PDT) efficiency is logically achieved by regulating the intracellular redox balance. In addition, our nanoagent can guide photoacoustic/NIR thermal dual-modal imaging and convert light into heat for cooperative cancer phototherapy because of the inherent photothermal conversion nature of PDA. As a result, excellent in vivo antitumor phototherapy (PDT + PTT) is achieved under the precise guidance of dual-modal imaging. This work not only realizes the integration of cancer diagnosis and treatment through PDA-based nanocarriers but also delivers dimensions in designing the next generation of multifunctional antitumor nanoagents for enhanced phototherapy and photodiagnosis by regulating the redox balance.

The association of maternal dietary folate intake and folic acid supplementation with small-for-gestational-age births: a cross-sectional study in Northwest China.

The effect of maternal folate intake on small-for-gestational-age (SGA) births remains inconclusive. The present study aimed to investigate the associations of maternal folate intake from diet and supplements with the risk of SGA births using data from a cross-sectional study in Shaanxi Province of Northwest China. A total of 7307 women who were within 12 months (median 3; 10th-90th percentile 0-7) after delivery were included. Two-level models were adopted to examine the associations of folate (dietary folate, supplemental folic acid and total folate) intake with the risk of SGA births and birth weight Z score, controlling for a minimum set of confounders that were identified in a directed acyclic graph. Results showed that a higher supplemental folic acid intake during the first trimester was negatively associated with the risk of SGA births (≤60 d v. non-use: OR 0·80; 95 % CI 0·66, 0·96; >60 d v. non-use: OR 0·78; 95 % CI 0·65, 0·94; Ptrend = 0·010; per 10-d increase: OR 0·97; 95 % CI 0·95, 0·99). A higher total folate intake during pregnancy was associated with a reduced risk of SGA births (highest tertile v. lowest tertile: OR 0·77; 95 % CI 0·64, 0·94; Ptrend = 0·010; per one-unit increase in the log-transformed value: OR 0·81; 95 % CI 0·69, 0·95). A similar pattern was observed for the birth weight Z score. Our study suggested that folic acid supplementation during the first trimester and a higher total folate intake during pregnancy were associated with a reduced risk of SGA births.

Maternal adherence to micronutrient supplementation before and during pregnancy in Northwest China: a large-scale population-based cross-sectional survey.

OBJECTIVES: To report the situation of maternal micronutrient supplementation before and during pregnancy in Northwest China and to examine the rates of and factors related to the adherence to micronutrient supplementation among pregnant women in this region, where dietary micronutrient intake is commonly insufficient. DESIGN: A large-scale population-based cross-sectional survey. SETTING: Twenty counties and ten districts of Shaanxi Province. PARTICIPANTS: A sample of 30 027 women were selected using a stratified multistage random sampling method. A total of 28 678 women were chosen for the final analysis after excluding those who did not provide clear information about nutritional supplementation before and during pregnancy. MAIN OUTCOME MEASURES: Maternal adherence to micronutrient supplementation (high and low) were the outcomes. They were determined by the start time and duration of use according to Chinese guidelines (for folic acid (FA) supplements) and WHO recommendations (for iron, calcium and multiple-micronutrient (MMN) supplements). RESULTS: In total, 83.9% of women took at least one kind of micronutrient supplement before or during pregnancy. FA (67.6%) and calcium (57.5%) were the primarily used micronutrient supplements; few participants used MMN (14.0%) or iron (5.4%). Adherence to supplementation of all micronutrients was low (7.4% for FA, 0.6% for iron, 11.7% for calcium and 2.7% for MMN). Higher educational levels, higher income levels, urban residence and better antenatal care (including pregnancy consultation and a higher frequency of antenatal visits) were associated with high adherence to micronutrient supplementation. CONCLUSION: Maternal micronutrient supplementation before and during pregnancy in Northwest China was way below standards recommended by the Chinese guidelines or WHO. Targeted health education and future nutritional guidelines are suggested to improve this situation, especially in pregnant women with disadvantaged sociodemographic conditions.

Isoliquiritigenin, an Orally Available Natural FLT3 Inhibitor from Licorice, Exhibits Selective Anti-Acute Myeloid Leukemia Efficacy In Vitro and In Vivo.

Licorice is a medicinal herb widely used to treat inflammation-related diseases in China. Isoliquiritigenin (ISL) is an important constituent of licorice and possesses multiple bioactivities. In this study, we examined the selective anti-AML (acute myeloid leukemia) property of ISL via targeting FMS-like tyrosine kinase-3 (FLT3), a certified valid target for treating AML. In vitro, ISL potently inhibited FLT3 kinase, with an IC50 value of 115.1 ± 4.2 nM, and selectively inhibited the proliferation of FLT3-internal tandem duplication (FLT3-ITD) or FLT3-ITD/F691L mutant AML cells. Moreover, it showed very weak activity toward other tested cell lines or kinases. Western blot immunoassay revealed that ISL significantly inhibited the activation of FLT3/Erk1/2/signal transducer and activator of transcription 5 (STAT5) signal in AML cells. Meanwhile, a molecular docking study indicated that ISL could stably form aromatic interactions and hydrogen bonds within the kinase domain of FLT3. In vivo, oral administration of ISL significantly inhibited the MV4-11 flank tumor growth and prolonged survival in the bone marrow transplant model via decreasing the expression of Ki67 and inducing apoptosis. Taken together, the present study identified a novel function of ISL as a selective FLT3 inhibitor. ISL could also be a potential natural bioactive compound for treating AML with FLT3-ITD or FLT3-ITD/F691L mutations. Thus, ISL and licorice might possess potential therapeutic effects for treating AML, providing a new strategy for anti-AML.