Integrated metabolomics and network pharmacology study on the mechanism of herbal pair of danggui-kushen for treating ischemia heart disease.

DangGui-KuShen (DK) is a well-known classic traditional Chinese medicine recipe that improves blood circulation, eliminates moisture, and detoxifies, and is frequently used in the treatment of cardiovascular problems. Some protective effects of DK on cardiovascular disease have previously been identified, but its precise mechanism remains unknown. The goal of this study is to combine metabolomics and network pharmacology to investigate DK's protective mechanism in Ischemic Heart Disease(IHD) rat models. A combination of metabolomics and network pharmacology based on UPLC-Q-TOF/MS technology was used in this study to verify the effect of DK on IHD through enzyme-linked immunosorbent assay, HE staining, and electrocardiogram, and it was determined that DK improves the synergistic mechanism of IHD. In total, 22 serum differential metabolites and 26 urine differential metabolites were discovered, with the majority of them involved in phenylalanine, tyrosine, and tryptophan biosynthesis, glycine, serine, and threonine metabolism, arginine and proline metabolism, aminoacyl-tRNA biosynthesis, purine metabolism, and other metabolic pathways. Furthermore, using network pharmacology, a composite target pathway network of DangGui and KuShen for treating IHD was created, which is primarily associated to the tumor necrosis factor (TNF) signaling pathway, P53 signaling, and HIF-1 signaling pathways. The combined research indicated that the NF-B signaling pathway and the HIF-1 signaling pathway are critical in DK treatment of IHD. This study clearly confirms and expands on current knowledge of the synergistic effects of DG and KS in IHD.

Laponite Lights Calcium Flickers by Reprogramming Lysosomes to Steer DC Migration for An Effective Antiviral CD8+ T-Cell Response.

Immunotherapy using dendritic cell (DC)-based vaccination is an established approach for treating cancer and infectious diseases; however, its efficacy is limited. Therefore, targeting the restricted migratory capacity of the DCs may enhance their therapeutic efficacy. In this study, the effect of laponite (Lap) on DCs, which can be internalized into lysosomes and induce cytoskeletal reorganization via the lysosomal reprogramming-calcium flicker axis, is evaluated, and it is found that Lap dramatically improves the in vivo homing ability of these DCs to lymphoid tissues. In addition, Lap improves antigen cross-presentation by DCs and increases DC-T-cell synapse formation, resulting in enhanced antigen-specific CD8+ T-cell activation. Furthermore, a Lap-modified cocktail (Lap@cytokine cocktail [C-C]) is constructed based on the gold standard, C-C, as an adjuvant for DC vaccines. Lap@C-C-adjuvanted DCs initiated a robust cytotoxic T-cell immune response against hepatitis B infection, resulting in > 99.6% clearance of viral DNA and successful hepatitis B surface antigen seroconversion. These findings highlight the potential value of Lap as a DC vaccine adjuvant that can regulate DC homing, and provide a basis for the development of effective DC vaccines.

Mapping the regulatory effects of herbal organic compounds on gut bacteria.

Herbal organic compounds (HOCs) are bioactive natural products from medicinal plants and some traditional Chinese medicines (TCMs). Recently, ingestion of a few HOCs with low bioavailability has been associated with alterations in gut microbiota, but the extent of this phenomenon remains unclear. Here, we systematically screened 481 HOCs against 47 representative gut bacterial strains in vitro and found that almost one-third of the HOCs exhibited unique anticommensal activity. Quinones showed a potent anticommensal activity, while saturated fatty acids exhibited stronger inhibition of the Lactobacillus genus. Flavonoids, phenylpropanoids, terpenoids, triterpenoids, alkaloids and phenols displayed weaker anticommensal activity, but steroids, saccharides and glycosides had hardly any effect on strain growth. Notably, S-configuration HOCs demonstrated stronger anticommensal activity than R-configuration HOCs. The strict screening conditions ensured high accuracy (95%) through benchmarking validation. Additionally, the effects of HOCs on human fecal microbiota profiling were positively correlated with their anticommensal activity against bacterial strains. Molecular and chemical features such as AATS3i and XLogP3 were correlated with the anticommensal activity of the HOCs in the random forest classifier. Finally, we validated that curcumin, a polyhydric phenol with anticommensal activity, improved insulin resistance in HFD mice by modulating the composition and metabolic function of gut microbiota. Our results systematically mapped the profile of HOCs directly affecting human gut bacterial strains, offering a resource for future research on HOC-microbiota interaction, and broadening our understanding of natural product utilization through gut microbiota modulation.

Tongmai Yangxin pill alleviates myocardial no-reflow by activating GPER to regulate HIF-1α signaling and downstream potassium channels.

CONTEXT: The Tongmai Yangxin pill (TMYX) has potential clinical effects on no-reflow (NR); however, the effective substances and mechanisms remain unclear. OBJECTIVE: This study evaluates the cardioprotective effects and molecular mechanisms of TMYX against NR. MATERIALS AND METHODS: We used a myocardial NR rat model to confirm the effect and mechanism of action of TMYX in alleviating NR. Sprague-Dawley (SD) rats were divided into Control (Con), sham, NR, TMYX (4.0 g/kg), and sodium nitroprusside (SNP, 5.0 mg/kg), and received their treatments once a day for one week. In vitro studies in isolated coronary microvasculature of NR rats and in silico network pharmacology analyses were performed to reveal the underlying mechanisms of TMYX and determine the main components, targets, and pathways of TMYX, respectively. RESULTS: TMYX (4.0 g/kg) showed therapeutic effects on NR by improving the cardiac structure and function, reducing NR, ischemic areas, and cardiomyocyte injury, and decreasing the expression of cardiac troponin I (cTnI). Moreover, the mechanism of TMYX predicted by network pharmacology is related to the HIF-1, NF-κB, and TNF signaling pathways. In vivo, TMYX decreased the expression of MPO, NF-κB, and TNF-α and increased the expression of GPER, p-ERK, and HIF-1α. In vitro, TMYX enhanced the diastolic function of coronary microvascular cells; however, this effect was inhibited by G-15, H-89, L-NAME, ODQ and four K+ channel inhibitors. CONCLUSIONS: TMYX exerts its pharmacological effects in the treatment of NR via multiple targets. However, the contribution of each pathway was not detected, and the mechanisms should be further investigated.

Effects of baduanjin exercise on blood glucose, depression and anxiety among patients with type II diabetes and emotional disorders: A meta-analysis.

BACKGROUND: Diabetes mellitus (DM) is a group of metabolic disorders reflected by high blood glucose levels and lack of hormone insulin. Notably, T2DM patients are three times more likely to report depression than the general population. Conventional exercise training programs have been shown to be beneficial for T2DM, but less is known regarding the effects of Baduanjin exercise on hemoglobin A1c (HbA1c) and psychological measures among this unique group. Therefore, this systematic review and meta-analysis aimed to investigate the effects of Baduanjin exercise on HbA1c, depression, and anxiety among type 2 diabetes mellitus (T2DM) patients with emotional disorders. METHODS: The potential literature was searched from six electronic databases (PubMed, MEDLINE, CINAHL, Scopus, Wanfang, and CNKI) from their inception to July 2022. The randomized controlled studies that investigated the effects of Baduanjin on HbA1c, depression , and anxiety in T2DM with emotional disorders were included. The effect sizes were calculated using the random-effect models with a 95% confidence interval (CI). The Physiotherapy Evidence Database (PEDro) scale was employed to assess the study quality. RESULTS: Eleven studies involving 755 T2DM participants with emotional disorders were analyzed in this study. The pooled results showed that Baduanjin had significant improvements in HbA1c (SMD = 0.75, 95% CI 0.46 to 1.04, p < 0.001), depression (SMD = 0.69, 95% CI 0.30 to 1.08, p < 0.01) and anxiety (SMD = 0.98, 95% CI 0.44 to 1.53, p < 0.01) compared to the control group. CONCLUSION: Findings suggest that Baduanjin exercise may effectively alleviate HbA1c, depression, and anxiety among T2DM patients with emotional disorders. However, more well-designed studies are required to further substantiate the promising findings.

The responses of marine anammox bacteria-based microbiome to multi-antibiotic stress in mariculture wastewater treatment.

Saline mariculture wastewater containing multi-antibiotics poses a challenge to anaerobic ammonia oxidation (anammox) process. Herein, the halophilic marine anammox bacteria (MAB)-based microbiome was used for treating mariculture wastewater (35‰ salinity) under multi-antibiotics (enrofloxacin + oxytetracycline + sulfamethoxazole, EOS) stress. And the main focus of this study lies in the response of MAB-based microbiome against multi-antibiotics stress. It is found that MAB-based microbiome shows stable community structure and contributes high nitrogen removal efficiency (>90%) even under high stress of EOS (up to 4 mg·L-1). The relative abundance of main functional genus Candidatus Scalindua, responsible for anammox, had little change while controlling the influent EOS concentration within 4 mg·L-1, whereas, significantly decreased to 2.23% at EOS concentration of as high as 24 mg·L-1. As an alternative, antibiotic resistance bacteria (ARB) species Rheinheimera dominated the microbial community of MAB-based biological reactor under extremely high EOS stress (e.g. 24 mg·L-1 in influent). The response mechanism of MAB-based microbiome consists of extracellular and intracellular defenses with dependence of EOS concentration. For example, while EOS within 4 mg·L-1 in this study, most of the antibiotics were retained by extracellular polymeric substances (EPS) via adsorption; If increasing the EOS concentration to 8 and even 24 mg·L-1, part of antibiotics could intrude into the cells and cause the intracellular accumulation of antibiotic resistance genes (ARGs) (total abundance up to 2.44 × 10-1 copies/16S rRNA) for EOS response. These new understandings will facilitate the practical implementation of MAB-based bioprocess for saline nitrogen- and antibiotics-laden wastewater treatment.

Effects of traditional Chinese exercises on mental health in individuals with drug rehabilitee: A systematic review and meta-analysis.

Purpose: The intent of this systematic review and meta-analysis was to examine the effects of Traditional Chinese Exercise (TCE) on mental health and drug cravings in drug rehabilitees. Methods: Six electronic databases (PubMed, Web of Science, MEDLINE, CINAHL, PsycArticles, and CNKI) were searched to identify the potential literature from inception to March 2022. The controlled studies with a pro-posttest design that investigated the effects of TCE on mental health (depression, anxiety, drug craving, and sleep quality) were included. The effect sizes were calculated using the random-effect models with a 95% confidence interval. The Physiotherapy Evidence Database (PEDro) scale was employed to evaluate study quality. Results: A total of 10 studies (740 participants, mean age 35 years old) were included in this study. The pooled results showed that TCE produced significant improvements in depression (SMD = 0.65, 95% CI 0.29 to 1.02, p < 0.01), anxiety (SMD = 0.98, 95% CI 0.44 to 1.53, p < 0.01), and drug craving (SMD = 0.87, 95% CI 0.54 to 1.21, p < 0.01) compared to the control group. The subgroup analysis results showed that TCE resulted in significant improvements in depression compared to active intervention (SMD = 0.33, 95% CI 0.07 to 0.60) or passive intervention (SMD = 1.07, 95% CI 0.40 to 1.74). A significant improvement in depression was observed in both male and female drug rehabilitee (p < 0.05). Moreover, Tai Chi (SMD = 0.69, 95% CI 0.19 to 1.18) or Qigong (SMD = 0.49, 95% CI 0.24 to 0.74) exercise, 3-4 times per week (SMD = 1.06, 95% CI 0.39 to 1.74) or ≥5 times (SMD = 0.39, 95% CI 0.12 to 0.66), >45 min (SMD = 0.62, 95% CI 0.09 to 1.15) or ≤ 45 min (SMD = 0.68, 95% CI 0.10 to 1.27), and for a duration of 12 weeks (SMD = 0.84, 95% CI 0.15 to 1.54) produced significant improvement in depression. Conclusion: This current study suggests that TCE (Tai Chi, Qigong) may have benefits in alleviating depression, anxiety, and drug cravings in drug rehabilitees. Further studies are required to verify our results through the implementation of well-designed experimental protocols.

Dietary sodium butyrate and/or vitamin D3 supplementation alters growth performance, meat quality, chemical composition, and oxidative stability in broilers.

The present study was conducted to elucidate the effects of sodium butyrate (SB) and vitamin D3 (VD3) supplementation on meat quality, oxidative stability, and nutritional value of the broiler chicken. The results indicated that dietary SB decreased lightness (L*), cooking and drip loss, free fatty acids (FFA), C14:0, C16:0, saturated fatty acids (SFA), C20:4n6, and n-6: n3 polyunsaturated fatty acids (PUFA) and increased DPPH and ABTS in chicken meat. The PUFAs content in the chicken meat increased only when SB was added along with higher VD3 levels. However, the amino acid content was reduced with an increase in the VD3 levels. In conclusion, dietary SB supplementation improved chicken meat quality by enhancing the antioxidant capacity and physical properties. Moreover, adding SB or combined with higher VD3 levels optimized the fatty acid composition. However, higher VD3 levels reduced the amino acid content of the chicken meat.

The water extract of Radix scutellariae, its total flavonoids and baicalin inhibited CYP7A1 expression, improved bile acid, and glycolipid metabolism in T2DM mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix scutellariae (the root of Scutellaria baicalensis Georgi), is a traditional Chinese medicine (TCM) used to treat type 2 diabetes mellitus (T2DM). Abundant flavonoids are the antidiabetic components of Radix scutellariae, of which baicalin (Baicalein 7-O-glucuronide, BG) is the major bioactive component. Our previous studies found that the water extract of Radix scutellariae (WESB) could exert hypoglycemic and hypolipidemic efficacies by adjusting the ileum FXR-medicated interaction between gut microbiota and bile acid (BA) metabolism. However, it remains unclear whether WESB and its biologically active ingredients exert an antidiabetic effect through bile acid signaling mediated by FXR-CYP7A1. AIMS OF THE STUDY: To explore the mechanism of WESB and its total flavonoids (TF) further and BG on BA signals and glycolipid metabolism in T2DM mice. MATERIALS AND METHODS: The antidiabetic effects of WESB, TF and BG were evaluated by indexing the body weight, fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) in HFD/STZ-induced (high-fat diet and streptozocin) diabetic mice, and comparing them with the positive control (metformin). The lipids in the mouse liver and the total bile acids (TBA) in the mouse liver and bile were detected by commercial kits. The concentration of BAs in the mouse feces was determined by liquid chromatography-tandem mass spectrometry. The protein expression levels of cholesterol 7α-hydroxylase (CYP7A1), farnesol X receptor (FXR), etc., in the liver and/or ileum, play a key role in the BAs metabolism of T2DM mice were evaluated by immunoblot analysis. RESULTS: The hyperglycemia and impaired glucose tolerance of T2DM mice were improved after WESB, TF and BG treatment. Especially after BG administration, the levels of low-density lipoprotein-cholesterol (LDL-c) and total glyceride (TG) in the T2DM mouse liver were significantly decreased (p < 0.05). While the level of high-density lipoprotein cholesterol (HDL-c) was significant increased (p < 0.001). Meanwhile, the levels of TBA in both the liver and bile of T2DM mice were significantly decreased by BG (p < 0.05). Moreover, the high expression of CYP7A1 in the liver of T2DM mice was significantly inhibited by WESB, TF and BG (p < 0.05), and the high expression of FXR in the ileum of T2DM mice was significantly inhibited by TF (p < 0.05). CONCLUSION: These results indicated that the hypoglycemic effects of WESB, TF and BG might be exerted by inhibiting the expression of CYP7A1 in T2DM mice, and TF inhibited expression of intestinal FXR by inducing changes in fecal BA profile. BG significantly improved hepatic lipid metabolism. Moreover, BG reduced lipid accumulation in the liver and bile by inhibiting the expression of CYP7A1 in T2DM mice. These findings provide useful explanations for the antidiabetic mechanism of Radix scutellariae.

The pharmacokinetic profiles of mogrosides in T2DM rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Luohanguo (LHG) extract major contenting mogrosides, as a nonnutritive sweetener, has been reported to exert a hypoglycemic effect on diabetic patients and animals. As the pharmacokinetics and pharmacodynamics of drugs were changed with diabetes, it may lead to the different pharmacological of mogrosides between diabetic and normal subjects. AIMS OF THE STUDY: To characterise the pharmacokinetic profiles of mogrosides in T2DM rats. STUDY DESIGN AND METHODS: High-fat diet and streptozocin induced type 2 diabetic mellitus rats were used to investigate the pharmacokinetic behavior of mogroside V and mogrosides IIIA1, IIA1, and IA1 after T2DM rats orally administrated with mogroside V and 1-3 glucose residues' mogrosides, respectively. The validated convenient UPLC-QTOF/MS and UPLC-MS/MS methods were established to use in the pharmacokinetic studies of mogrosides in normal and T2DM rats. Additionally, the expression of the intestinal tight junction protein zonula occludens-1 (ZO-1) was also detected by immunohistochemical analysis, which assessed the function of passive intestinal permeability in T2DM rats. RESULTS: The results showed that for rats treated with mogroside V, its metabolite mogroside IIIA1 has a significant increase (p < 0.05) in maximum plasma concentration (Cmax, 163.80 ± 25.56 ng/mL) and area under the plasma concentration (AUC0-t, 2327.44 ± 474.63 h·ng/mL) in T2DM rats compared with in normal rats. The mean residence time (MRT0-t, 12.04 ± 0.97 h) of mogroside V showed a significant decrease (p < 0.05) in T2DM rats. However, the mogrosides IIIA1, IIA1and IA1 showed no statistical differences in the normal and T2DM rats after administered with 1-3 glucose residues' mogrosides. Furthermore, the expression level of ZO-1 in the duodenum and colon of T2DM rats were downregulated. CONCLUSION: The pharmacokinetic profiles of mogroside V and its metabolite mogroside IIIA1 in T2DM rats and normal rats showed some difference, it might be affected by the metabolic changes in the pathological state of T2DM.

Regulating the gut microbiota and SCFAs in the faeces of T2DM rats should be one of antidiabetic mechanisms of mogrosides in the fruits of Siraitia grosvenorii.

ETHNOPHARMACOLOGICAL RELEVANCE: The Siraitia grosvenorii fruits extract (SG, in which mogrosides are the main components), considered as a non-nutritional sweetener, has an antidiabetic effect. Our previous studies have confirmed that an extract of mogrosides being rich in triterpene glycosides with 1-3 glucosyl residues, designated as low-polar S. grosvenorii glycosides (L-SGgly), had a significant antidiabetic effect. However, whether the mechanism through impacting on gut microbiota to exert the antidiabetic effect of mogrosides remains unclear. AIMS OF THE STUDY: To explore the potential mechanism of mogrosides (SG and L-SGgly) on gut microbiota and faecal metabolites in the treatment of diabetes. STUDY DESIGN AND METHODS: In this study, the effects of SG and L-SGgly on gut microbiota and faecal endogenous metabolites were explored by sequencing the 16S rRNA V3-V4 region of gut microbiota, and detecting with gas chromatography-mass spectrometry (GC-MS) and liquid chromatography quadrupole time-of-flight MS (LC-Q-TOF/MS), respectively. In particular, correlation analyses revealed how these influences affect the anti-hyperglycaemic effect, to give the underlying antidiabetic mechanisms of the mogrosides in S. grosvenorii fruits. RESULTS: After a 14-day treatment with SG and L-SGgly for type 2 diabetes mellitus (T2DM) rats induced by a high-fat diet (HFD) and streptozotocin (STZ), the disordered gut microbiota in the faeces of T2DM rats were recovered. At the same time, the short-chain fatty acids (SCFAs) concentration significantly increased and the deoxycholic acid and 1ß-hydroxycholic acid content decreased in the faeces of T2DM rats. Moreover, correlation analyses provided the evidences that gut microbiota and its metabolites could be the target for exerting the anti-hyperglycaemic effects of SG and L-SGgly. Especially, Elusimicrobium, Lachnospiraceae_UCG-004, acetate, butyrate, and 1ß-hydroxycholic acid would be the potential dominant bacteria and biomarkers for SG and L-SGgly in reducing the blood glucose and insulin resistance of T2DM rats. CONCLUSION: It is the first time that a mechanism of targeting on gut microbiota for the antidiabetic effect of mogrosides in S. grosvenorii fruits has been proposed.

Amelioration of hyperglycaemia and hyperlipidaemia by adjusting the interplay between gut microbiota and bile acid metabolism: Radix Scutellariae as a case.

BACKGROUND: Our previous clinical research showed that the interaction between gut microbiota and bile acids (BAs) in patients with type 2 diabetes mellitus (T2DM) changed significantly. We hypothesized that T2DM could be improved by adjusting this interaction mediated by farnesoid X receptor (FXR). T2DM belongs to the category of "xiaoke" in traditional Chinese medicine. Radix scutellariae has the effects of clearing away heat and eliminating dampness, curing jaundice and quenching thirst and is widely used alone or in combination with other medicines for the treatment of T2DM in China and throughout Asia. Additionally, the interaction between Radix scutellariae and gut microbiota may influence its efficacy in the treatment of T2DM. PURPOSE: This study chose Radix scutellariae to validate that T2DM could improve by adjusting the interaction between gut microbiota and bile acid metabolism. STUDY DESIGN AND METHODS: Radix scutellariae water extract (WESB) was administered to a T2DM rat model established by a high-fat diet combined with streptozotocin. The body weight and blood glucose and insulin levels were measured. The levels of serum lipids, creatinine, uric acid, albumin and total bile acid were also detected. Changes in the pathology and histology of the pancreas, liver and kidney were observed by haematoxylin-eosin staining. The 16S rRNAs of gut microbiota were sequenced, and the faecal and serum BAs were determined by liquid chromatography tandem mass spectrometry. The expression levels of BA metabolism-associated proteins in the liver and intestine were evaluated by immunoblot analysis. RESULTS: The results showed that WESB improved hyperglycaemia, hyperlipaemia, and liver and kidney damage in T2DM rats. In addition, the abundances of key gut microbiota and the concentrations of certain secondary BAs in faeces and serum were restored. Moreover, there was a significant correlation between the restored gut microbiota and BAs, which might be related to the activation of liver cholesterol 7α-hydroxylase (CYP7A1) and the inhibition of FXR expression in the intestine rather than the liver. CONCLUSIONS: This study provided new ideas for the prevention or treatment of clinical diabetes and its complications by adjusting the interaction between gut microbiota and bile acid metabolism.

Immunostimulatory Potential of MoS2 Nanosheets: Enhancing Dendritic Cell Maturation, Migration and T Cell Elicitation.

BACKGROUND: Due to their extraordinary physical and chemical properties, MoS2 nanosheets (MSNs) are becoming more widely used in nanomedicine. However, their influence on immune systems remains unclear. MATERIALS AND METHODS: Two few-layered MSNs at sizes of 100-250 nm (S-MSNs) and 400-500 nm (L-MSNs) were used in this study. Bone marrow-derived dendritic cells (DCs) were exposed to both MSNs at different doses (0, 8, 16, 32, 64, 128 µg/mL) for 48 h and subjected to analyses of surface marker expression, cytokine secretion, lymphoid homing and in vivo T cell priming. RESULTS: Different-sized MSNs of all doses did not affect the viability of DCs. The expression of CD40, CD80, CD86 and CCR7 was significantly higher on both S-MSN- and L-MSN-treated DCs at a dose of 128 µg/mL. As the dose of MSN increased, the secretion of IL-12p70 remained unchanged, the secretion of IL-1ß decreased, and the production of TNF-α increased. A significant increase in IL-6 was observed in the 128 µg/mL L-MSN-treated DCs. In particular, MSN treatment dramatically improved the ex vivo movement and in vivo homing ability of both the local resident and blood circulating DCs. Furthermore, the cytoskeleton rearrangement regulated by ROS elevation was responsible for the enhanced homing ability of the MSNs. More robust CD4+ and CD8+ T cell proliferation and activation (characterized by high expression of CD107a, CD69 and ICOS) was observed in mice vaccinated with MSN-treated DCs. Importantly, exposure to MSNs did not interrupt LPS-induced DC activation, homing and T cell priming. CONCLUSION: Few-layered MSNs ranging from 100 to 500 nm in size could play an immunostimulatory role in enhancing DC maturation, migration and T cell elicitation, making them a good candidate for vaccine adjuvants. Investigation of this study will not only expand the applications of MSNs and other new transition metal dichalcogenides (TMDCs) but also shed light on the in vivo immune-risk evaluation of MSN-based nanomaterials.

Refractory overactive bladder patients who chose sacral neuromodulation therapy after failed OnabotulinumtoxinA treatment: A systematic review and meta-analysis.

OBJECTIVE: To systematically review outcomes in patients with refractory overactive bladder (OAB) patients who underwent sacral neuromodulation therapy (SNM) therapy after unsuccessful onabotulinumtoxinA (BTX) therapy, and to compare outcomes with those who SNM as initial therapy. METHODS: A systematic search of Cochrane Library, Pubmed and Embase databases from July 2002 to November 2019, to analyze randomized controlled trials and retrospective studies of SNM therapy after failed initial BTX therapy. Two reviewers independently screened the studies and extracted data. A quality assessment of the included literature was conducted using Newcastle-Ottawa Scale (NOS), and Stata 12.0 software was used to conduct a meta-analysis of the collected data. RESULTS: A total of seven studies involving 319 patients were finally included. The success rate in refractory OAB patients who used SNM therapy after failed BTX therapy was 58.5%, 95% CI (0.47-0.70). There was no significant difference between refractory OAB patients who chose SNM as replacement therapy after failed BTX therapy and those who used SNM therapy as first choice [RR = 0.96, 95%CI (0.72-1.26), P = 0.735]. CONCLUSION: OAB patients for whom an initial choice of BTX therapy ends in failure or dissatisfaction may consider switching to SNM therapy. There is no difference in outcomes between these patients and those whose first choice was SNM therapy.

Decreased Insulin Resistance by Myo-Inositol Is Associated with Suppressed Interleukin 6/Phospho-STAT3 Signaling in a Rat Polycystic Ovary Syndrome Model.

Myo-inositol supplementation may reduce insulin resistance (IR) with few serious side effects in patients with polycystic ovary syndrome (PCOS). To explore the mechanism of this action in an animal model, a PCOS-IR rat model was generated. Enzyme-linked immunosorbent assay was used to assess changes in ovulation function during treatment with a myo-inositol supplement, and Western blotting, real-time polymerase chain reaction, and immunohistochemistry were performed to investigate the underlying molecular mechanisms. The results showed that the myo-inositol supplement decreased the homeostatic model assessment of insulin resistance (HOMA-IR) index and significantly decreased the serum levels of luteinizing hormone (LH), LH/follicle-stimulating hormone ratio, and testosterone, while increasing the serum level of estradiol. Upregulation of interleukin 6 (IL-6), phospho-STAT3 (p-STAT3), Mir-21, and Mir-155 and significant downregulation of PPAR-γ and GLUT4 were detected in the untreated PCOS-IR rat model. However, downregulation of IL-6, p-STAT3, miR-21, and miR-155 and significant upregulation of PPAR-γ and GLUT4 were detected with myo-inositol supplementation. Thus, myo-inositol supplementation may reduce Mir-21 and Mir-155 levels by downregulating IL-6 and p-STAT3 and, subsequently, reverse the expression of PPAR-γ and GLUT4, leading to a decreased HOMA-IR index. In conclusion, the identification of an IL-6/p-STAT3/Mir-155/Mir-21/PPAR-γ/GLUT4 system in the PCOS-IR rat model provides insight into the pathogenesis of PCOS and may indicate a possible therapeutic strategy. Amelioration of the basal serum glucose levels and of the HOMA/HOMA-IR index may be achieved by the reversal of the expression of PPAR-γ and GLUT4 through the downregulation of IL-6, p-STAT3, miR-21, and miR-155 with myo-inositol supplementation.

Anti-hyperglycemic and anti-hyperlipidemic effects of a special fraction of Luohanguo extract on obese T2DM rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Luohanguo (LHG), a traditional Chinese medicine, could clear heat, moisten the lung, soothe the throat, restore the voice, and lubricate intestine and open the bowels. LHG has been utilized for the treatment of sore throats and hyperglycemia in folk medicine as a homology of medicine and food. The hypoglycemic pharmacology of LHG has attracted considerable attention, and mogrosides have been considered to be active ingredients against diabetes mellitus. We have found that these mogrosides could be metabolized into their secondary glycosides containing 1-3 glucose residues in type 2 diabetes mellitus (T2DM) rats in previous studies. These metabolites may be the antidiabetic components of LHG in vivo. Thus far, no reports have been found on reducing blood glucose of mogrosides containing 1-3 glucose residues. AIMS OF THE STUDY: The aim of this study was to confirm that mogrosides containing 1-3 glucose residues were the active components of LHG for antidiabetic effects and to understand their potential mechanisms of action. MATERIALS AND METHODS: First, the special fraction of mogrosides containing 1-3 glucose residues was separated from a 50% ethanol extract of LHG, and the chemical components were identified by ultra-performance liquid chromatography (UPLC) and named low-polar Siraitia grosvenorii glycosides (L-SGgly). Second, the antidiabetic effects of L-SGgly were evaluated by HFD/STZ-induced (high-fat diet and streptozocin) obese T2DM rats by indexing fasting blood glucose (FBG), fasting insulin (FINS), and insulin resistance, and then compared with other fractions in the separation process. The changes in serum lipid levels were also detected. Finally, possible mechanisms of antidiabetic activity of L-SGgly were identified as increasing GLP-1 levels and activating liver AMPK in T2DM rats. RESULTS: The chemical analysis of L-SGgly showed that they contain 11-oxomogroside V, mogroside V, mogroside III, mogroside IIE, mogroside IIIA1, mogroside IIA1, and mogroside IA1, respectively. The total content of the mogrosides in L-SGgly was 54.4%, including 15.7% mogroside IIA1 and 12.6% mogroside IA1. L-SGgly showed excellent effects on obese T2DM rats compared with the other fractions of LHG extract, including significantly reducing the levels of FBG (p < 0.001) and modifying insulin resistance (p < 0.05). Meanwhile, they could significantly decrease the content of triglyceride (p < 0.01), total cholesterol (p < 0.01), low-density lipoprotein cholesterol (p < 0.01) and free fatty acid (p < 0.001) and increase the content of high-density lipoprotein cholesterol (p < 0.001) in serum of T2DM rats. Moreover, L-SGgly can significantly increase (p < 0.01) GLP-1 levels and decrease (p < 0.01) IL-6 levels in T2DM rat serum. AMPK-activating activity in T2DM rats was also upregulated by L-SGgly, but no statistical significance was shown. CONCLUSION: L-SGgly, fractions separated from LHG extract, were verified to have obvious anti-hyperglycemic and anti-hyperlipidemic effects on T2DM rats. Furthermore, L-SGgly regulated insulin secretion in T2DM rats by increasing GLP-1 levels. These findings provide an explanation for the antidiabetic role of LHG.

Can Melatonin Improve the Osteopenia of Perimenopausal and Postmenopausal Women? A Meta-Analysis.

OBJECTIVE: To assess the effectiveness and safety of melatonin for perimenopausal and postmenopausal women with osteopenia. METHODS: In this meta-analysis, data from randomized controlled trials were obtained to assess the effects of melatonin versus placebo or western medicine in perimenopausal and postmenopausal women with osteopenia. The study's registration number is CRD42018086238. The primary outcomes included bone mineral density (BMD) and T-score. RESULT: From 551 articles retrieved, three trials involving 121 patients were included. Due to the high-to-substantial heterogeneity (BMD: I2=96.9%, P=0.000; T-score: I2=74.9%, and P=0.019), the statistical analysis of BMD and T-score was abandoned. A systematic review was undergone for the two outcomes. Compared with the control group, melatonin may increase osteocalcin (WMD 4.97; 95% CI 3.14, 6.79; P < 0.00001). CONCLUSION: Based on current evidence, melatonin might be used as a safe nutritional supplement to improve bone density in perimenopausal and postmenopausal women, but its efficacy needs to be further affirmed.

A Comparison of Characterization and Its Actions on Immunocompetent Cells of Polysaccharides from Sijunzi Decoction.

Sijunzi decoction (SJZD) is a classic recipe in Traditional Chinese Medicine (TCM) with strong immune-enhancement activity. To further understand the characterization and immunomodulatory effect of polysaccharides from SJZD, the monosaccharide compositions of crude polysaccharide (SJZDP), polysaccharide fraction (S-3), and homogeneous polysaccharide (S-3-AG) from SJZD were compared by GC analysis, as well as their immunomodulatory effects on Peyer's patch cells, splenocytes, and macrophages which are related to intestinal immunity, specific immunity, and nonspecific immunity. The results showed that S-3-AG mainly contained Ara with a proportion of 38.9%, while Glc accounted for the largest proportion in S-3 (55.6%) and SJZDP (87.6%). The SJZDP, S-3, and S-3-AG all showed strong capability to stimulate Peyer's patch cells to proliferate and produce IgA and promoted the proliferation and IFN-γ production of splenocytes and increased the NO production and TNF-α production of macrophages. However, S-3 and S-3-AG were able to stimulate splenocytes to secret IL-4, SJZDP had no effect on IL-4 production of splenocytes in the tested concentrations. In addition, S-3 could stimulate the phagocytic activity of macrophages, and S-3-AG restrained the proliferation of macrophages at the concentration of 50-200 µg/mL. These results suggested that SJZDP, S-3, and S-3-AG might have different immunomodulatory effects on intestinal immunity, specific immunity, and nonspecific immunity due to their different monosaccharide compositions. It will provide references for the material basis and mechanism of SJZD immunomodulation activity.

The Effects of the Honey-Roasting Process on the Pharmacokinetics of the Six Active Compounds of Licorice.

A convenient UPLC-MS/MS method was established to determine the contents of six bioactive compounds, namely, liquiritin apioside, liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, and glycyrrhetinic acid, in rat plasma and their pharmacokinetics. By comparing the pharmacokinetic parameters of these compounds in rats by orally administering raw and honey-roasting licorice, the Cmax of isoliquiritin showed a significant decrease, while the AUC0-24h showed no significant differences. The Cmax and AUC0-24h of isoliquiritigenin were increased by 49.3% and 42.7% over those of the raw licorice group, respectively. These results indicate that the absorption of isoliquiritin in rats was reduced while the absorption of isoliquiritigenin was promoted in the honey-roasting process. These results may provide one explanation as to why licorice is more able to relieve cough, while honey-roasting licorice is better at invigorating qi and restoring pulse. Furthermore, the Cmax of glycyrrhetinic acid was increased, suggesting that it may enhance the tonic effect of licorice. Additionally, the amount of honey added in the honey-roasting process influenced the pharmacokinetic parameters of the six compounds whose absorption decreased when the 50% honey-roasting licorice water decoction was administered. These results provide an experimental basis for studying the influence of licorice processing on bioactive compound pharmacokinetics.

Global-scale patterns of nutrient density and partitioning in forests in relation to climate.

Knowledge of nutrient storage and partitioning in forests is imperative for ecosystem models and ecological theory. Whether the nutrients (N, P, K, Ca, and Mg) stored in forest biomass and their partitioning patterns vary systematically across climatic gradients remains unknown. Here, we explored the global-scale patterns of nutrient density and partitioning using a newly compiled dataset including 372 forest stands. We found that temperature and precipitation were key factors driving the nutrients stored in living biomass of forests at global scale. The N, K, and Mg stored in living biomass tended to be greater in increasingly warm climates. The mean biomass N density was 577.0, 530.4, 513.2, and 336.7 kg/ha for tropical, subtropical, temperate, and boreal forests, respectively. Around 76% of the variation in biomass N density could be accounted by the empirical model combining biomass density, phylogeny (i.e., angiosperm, gymnosperm), and the interaction of mean annual temperature and precipitation. Climate, stand age, and biomass density significantly affected nutrients partitioning at forest community level. The fractional distribution of nutrients to roots decreased significantly with temperature, suggesting that forests in cold climates allocate greater nutrients to roots. Gymnosperm forests tended to allocate more nutrients to leaves as compared with angiosperm forests, whereas the angiosperm forests distributed more nutrients in stems. The nutrient-based Root:Shoot ratios (R:S), averaged 0.30 for R:SN , 0.36 for R:SP , 0.32 for R:SK , 0.27 for R:SCa , and 0.35 for R:SMg , respectively. The scaling exponents of the relationships describing root nutrients as a function of shoot nutrients were more than 1.0, suggesting that as nutrient allocated to shoot increases, nutrient allocated to roots increases faster than linearly with nutrient in shoot. Soil type significantly affected the total N, P, K, Ca, and Mg stored in living biomass of forests, and the Acrisols group displayed the lowest P, K, Ca, and Mg.