Aloe-emodin alleviates cerebral ischemia-reperfusion injury by regulating microglial polarization and pyroptosis through inhibition of NLRP3 inflammasome activation.

BACKGROUND: Microglial activation plays a crucial role in injury and repair after cerebral ischemia, and microglial pyroptosis exacerbates ischemic injury. NOD-like receptor protein 3 (NLRP3) inflammasome activation has an important role in microglial polarization and pyroptosis. Aloe-emodin (AE) is a natural anthraquinone compound originated from rhubarb and aloe. It exerts antioxidative and anti-apoptotic effects during cerebral ischemia/reperfusion (I/R) injury. However, whether AE affects microglial polarization, pyroptosis, and NLRP3 inflammasome activation remains unknown. PURPOSE: This study aimed to explore the effects of AE on microglial polarization, pyroptosis, and NLRP3 inflammasome activation in the cerebral infarction area after I/R. METHODS: The transient middle cerebral artery occlusion (tMCAO) and oxygen-glucose deprivation/re-oxygenation (OGD/R) methods were used to create cerebral I/R models in vivo and in vitro, respectively. Neurological scores and triphenyl tetrazolium chloride and Nissl staining were used to assess the neuroprotective effects of AE. Immunofluorescence staining, quantitative polymerase chain reaction and western blot were applied to detect NLRP3 inflammasome activation and microglial polarization and pyroptosis levels after tMCAO or OGD/R. Cell viability and levels of interleukin (IL)-18 and IL-1ß were measured. Finally, MCC950 (an NLRP3-specific inhibitor) was used to evaluate whether AE affected microglial polarization and pyroptosis by regulating the activation of the NLRP3 inflammasome. RESULTS: AE improved neurological function scores and reduced the infarct area, brain edema rate, and Nissl-positive cell rate following I/R injury. It also showed a protective effect on BV-2 cells after OGD/R. AE inhibited microglial pyroptosis and induced M1 to M2 phenotype transformation and suppressed microglial NLRP3 inflammasome activation after tMCAO or OGD/R. The combined administration of AE and MCC950 had a synergistic effect on the inhibition of tMCAO- or OGD/R-induced NLRP3 inflammasome activation, which subsequently suppressed microglial pyroptosis and induced microglial phenotype transformation. CONCLUSION: AE exerts neuroprotective effects by regulating microglial polarization and pyroptosis through the inhibition of NLRP3 inflammasome activation after tMCAO or OGD/R. These findings provide new evidence of the molecular mechanisms underlying the neuroprotective effects of AE and may support the exploration of novel therapeutic strategies for cerebral ischemia.

Association and mediation analyses among multiple metal exposure, mineralocorticoid levels, and serum ion balance in residents of northwest China.

Toxic metals are vital risk factors affecting serum ion balance; however, the effect of their co-exposure on serum ions and the underlying mechanism remain unclear. We assessed the correlations of single metal and mixed metals with serum ion levels, and the mediating effects of mineralocorticoids by investigating toxic metal concentrations in the blood, as well as the levels of representative mineralocorticoids, such as deoxycorticosterone (DOC), and serum ions in 471 participants from the Dongdagou-Xinglong cohort. In the single-exposure model, sodium and chloride levels were positively correlated with arsenic, selenium, cadmium, and lead levels and negatively correlated with zinc levels, whereas potassium and iron levels and the anion gap were positively correlated with zinc levels and negatively correlated with selenium, cadmium and lead levels (all P < 0.05). Similar results were obtained in the mixed exposure models considering all metals, and the major contributions of cadmium, lead, arsenic, and selenium were highlighted. Significant dose-response relationships were detected between levels of serum DOC and toxic metals and serum ions. Mediation analysis showed that serum DOC partially mediated the relationship of metals (especially mixed metals) with serum iron and anion gap by 8.3% and 8.6%, respectively. These findings suggest that single and mixed metal exposure interferes with the homeostasis of serum mineralocorticoids, which is also related to altered serum ion levels. Furthermore, serum DOC may remarkably affect toxic metal-related serum ion disturbances, providing clues for further study of health risks associated with these toxic metals.

Highly elastic, fatigue-resistant, antibacterial, conductive, and nanocellulose-enhanced hydrogels with selenium nanoparticles loading as strain sensors.

The fabrication of highly elastic, fatigue-resistant and conductive hydrogels with antibacterial properties is highly desirable in the field of wearable devices. However, it remains challenging to simultaneously realize the above properties within one hydrogel without compromising excellent sensing ability. Herein, we fabricated a highly elastic, fatigue-resistant, conductive, antibacterial and cellulose nanocrystal (CNC) enhanced hydrogel as a sensitive strain sensor by the synergistic effect of biosynthesized selenium nanoparticles (BioSeNPs), MXene and nanocellulose. The structure and potential mechanism to generate biologically synthesized SeNPs (BioSeNPs) were systematically investigated, and the role of protease A (PrA) in enhancing the adsorption between proteins and SeNPs was demonstrated. Additionally, owing to the incorporation of BioSeNPs, CNC and MXene, the synthesized hydrogels showed high elasticity, excellent fatigue resistance and antibacterial properties. More importantly, the sensitivity of hydrogels determined by the gauge factor was as high as 6.24 when a high strain was applied (400-700 %). This study provides a new horizon to synthesize high-performance antibacterial and conductive hydrogels for soft electronics applications.

Non-pharmacological and pharmacological treatments for bone health after stroke: Systematic review with meta-analysis.

BACKGROUND: Hemi-osteoporosis is a common secondary complication of stroke. No systematic reviews of pharmacological and non-pharmacological agents for post-stroke bone health have estimated the magnitude and precision of effect sizes to guide better clinical practice. OBJECTIVES: To examine the benefits and harms of pharmacological and non-pharmacological agents on bone health in post-stroke individuals. METHODS: Eight databases were searched (PubMed, Cochrane library, Scopus, CINAHL Complete, Embase, PEDro, Clinicaltrils.gov and ICTRP) up to June 2023. Any controlled studies that applied physical exercise, supplements, or medications and measured bone-related outcomes in people with stroke were included. PEDro and the GRADE approach were used to examine the methodological quality of included articles and quality of evidence for outcomes. Effect sizes were calculated as standardized mean differences (SMD) and risk ratio (RR). Review Manager 5.4 was used for data synthetization. RESULTS: Twenty-four articles from 21 trials involving 22,500 participants (3,827 in 11 non-pharmacological and 18,673 in 10 pharmacological trials) were included. Eight trials were included in the meta-analysis. The methodological quality of half of the included non-pharmacological studies was either poor or fair, whereas it was good to excellent in 8 of 10 pharmacological studies. Meta-analysis revealed a beneficial effect of exercise on the bone mineral density (BMD) of the paretic hip (SMD: 0.50, 95 % CI: 0.16; 0.85; low-quality evidence). The effects of anti-resorptive medications on the BMD of the paretic hip were mixed and thus inconclusive (low-quality evidence). High-quality evidence showed that the administration of antidepressants increased the risk of fracture (RR: 2.36, 95 % CI 1.64-3.39). CONCLUSION: Exercise under supervision may be beneficial for hip bone health in post-stroke individuals. The effect of anti-resorptive medications on hip BMD is uncertain. The adverse effects of antidepressants on fracture risk among post-stroke individuals warrant further attention. Further high-quality studies are required to better understand this issue. REGISTRATION: PROSPERO CRD42022359186.

Superoxide Dismutase Catalyzed Size-Adjustable Selenium Nanoparticles in Saccharomyces boulardii.

Selenium nanoparticles (SeNPs) are important and safe food and feed additives that can be used for dietary supplementation. In this study, a mutagenic strain of Saccharomyces boulardii was employed to obtain biologically synthesized SeNPs (BioSeNPs) with the desired particle size by controlling the dosage and duration of sodium selenite addition, and the average particle size achieved was 55.8 nm with protease A encapsulation. Transcriptomic analysis revealed that increased expression of superoxide dismutase 1 (SOD1) in the mutant strain effectively promoted the synthesis of BioSeNPs and the formation of smaller nanoparticles. Under sodium selenite stress, the mutant strain exhibited significantly increased expression of glutathione peroxidase 2 (GPx2), which was significantly greater in the mutant strain than in the wild type, facilitating the synthesis of glutathione selenol and providing abundant substrates for the production of BioSeNPs. Furthermore, based on the experimental results and transcriptomic analysis of relevant genes such as sod1, gpx2, the thioredoxin reductase 1 gene (trr1) and the thioredoxin reductase 2 gene (trr2), a yeast model for the size-controlled synthesis of BioSeNPs was constructed. This study provides an important theoretical and practical foundation for the green synthesis of controllable-sized BioSeNPs or other metal nanoparticles with potential applications in the fields of food, feed, and biomedicine.

The association between trace metals in both cancerous and non-cancerous tissues with the risk of liver and gastric cancer progression in northwest China.

Liver cancer and gastric cancer have extremely high morbidity and mortality rates worldwide. It is well known that an increase or decrease in trace metals may be associated with the formation and development of a variety of diseases, including cancer. Therefore, this study aimed to evaluate the contents of aluminium (Al), arsenic (As), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), nickel (Ni), lead (Pb), selenium (Se), and zinc (Zn) in cancerous liver and gastric tissues, compared to adjacent healthy tissues, and to investigate the relationship between trace metals and cancer progression. During surgery, multiple samples were taken from the cancerous and adjacent healthy tissues of patients with liver and gastric cancer, and trace metal levels within these samples were analysed using inductively coupled plasma mass spectrometry (ICP-MS). We found that concentrations of As, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Se, and Zn in tissues from patients with liver cancer were significantly lower than those in healthy controls (P < 0.05). Similarly, patients with gastric cancer also showed lower levels of Cd, Co, Cr, Mn, Ni, and Zn-but higher levels of Cu and Se-compared to the controls (P < 0.05). In addition, patients with liver and gastric cancers who had poorly differentiated tumours and positive lymph node metastases showed lower levels of trace metals (P < 0.05), although no significant changes in their concentrations were observed to correlate with sex, age, or body mass index (BMI). Logistic regression, principal component analysis (PCA), Bayesian kernel regression (BKMR), weighted quantile sum (WQS) regression, and quantile-based g computing (qgcomp) models were used to analyse the relationships between trace metal concentrations in liver and gastric cancer tissues and the progression of these cancers. We found that single or mixed trace metal levels were negatively associated with poor differentiation and lymph node metastasis in both liver and gastric cancer, and the posterior inclusion probability (PIP) of each metal showed that Cd contributed the most to poor differentiation and lymph node metastasis in both liver and gastric cancer (all PIP = 1.000). These data help to clarify the relationship between changes in trace metal levels in cancerous liver and gastric tissues and the progression of these cancers. Further research is warranted, however, to fully elucidate the mechanisms and causations underlying these findings.

A paleoecological investigation of recent cyanobacterial blooms and their drivers in two contrasting lakes.

Cyanobacterial blooms are one of the most significant threats to global water security and freshwater biodiversity. Interactions among multiple stressors, including habitat degradation, species invasions, increased nutrient runoff, and climate change, are key drivers. However, assessing the role of anthropogenic activity on the onset of cyanobacterial blooms and exploring response variation amongst lakes of varying size and depth is usually limited by lack of historical records. In the present study we applied molecular, paleolimnological (trace metal, Itrax-µ-XRF and hyperspectral scanning, chronology), paleobotanical (pollen) and historical data to reconstruct cyanobacterial abundance and community composition and anthropogenic impacts in two dune lakes over a period of up to 1200 years. Metabarcoding and droplet digital PCR results showed very low levels of picocyanobacteria present in the lakes prior to about CE 1854 (1839-1870 CE) in the smaller shallow Lake Alice and CE 1970 (1963-1875 CE) in the larger deeper Lake Wiritoa. Hereafter bloom-forming cyanobacteria were detected and increased notably in abundance post CE 1984 (1982-1985 CE) in Lake Alice and CE 1997 (1990-2007 CE) in Lake Wiritoa. Currently, the magnitude of blooms is more pronounced in Lake Wiritoa, potentially attributable to hypoxia-induced release of phosphorus from sediment, introducing an additional source of nutrients. Generalized linear modelling was used to investigate the contribution of nutrients (proxy = bacterial functions), temperature, redox conditions (Mn:Fe), and erosion (Ti:Inc) in driving the abundance of cyanobacteria (ddPCR). In Lake Alice nutrients and erosion had a statistically significant effect, while in Lake Wiritoa nutrients and redox conditions were significant.

From biomaterials to biotherapy: cuttlefish ink with protoporphyrin IX nanoconjugates for synergistic sonodynamic-photothermal therapy.

Biologically produced nanomaterials capable of therapeutic purposes have received increasing interest in tumor therapy because of their intrinsic biocompatibility. In this study, we made cuttlefish ink (extracted from cuttlefish) and protoporphyrin IX (PpIX) nanoconjugates (CIPs) where PpIX was an endogenous organic compound. In the case of CIPs, PpIX could be triggered by ultrasound (US) for sonodynamic therapy (SDT), and the cuttlefish ink could be excited by a near-infrared laser for photothermal therapy (PTT). Thereafter, tumor growth was greatly inhibited through synergistic SDT-PTT in comparison to single SDT or PTT. In addition, in vivo administration of CIPs showed no noticeable side effects for mouse blood and chief organs, providing an effective strategy for developing biologically produced biomaterials and using them for biotherapy.

Green and highly effective extraction of bioactive flavonoids from Fructus aurantii employing deep eutectic solvents-based ultrasonic-assisted extraction protocol.

In China, Jiang Fructus aurantii (JFA) has attracted increasing interest as a famous traditional herbal medicine and valuable economic food for its valuable medicinal and industrial properties. In the current work, contrasted with conventional extraction techniques, natural flavonoids from JFA (naringin and neohesperidin) were extracted with remarkable effectiveness utilizing a sustainable deep eutectic solvents combined ultrasonic-assisted extraction (DESs-UAE) protocol. The optimal extraction capacity can be achieved by mixing 30 % water with a molar ratio of 1:3 for choline chloride and ethylene glycol, as opposed to the classical extraction solvents of 95 % ethanol, methanol, and water. Moreover, the DESs-UAE extraction programs were also systematically optimized employing Box-Behnken design (BBD) trials, and the eventual findings suggested that the best parameters were a 27 % water content in DES, a 16 mL/g liquid-solid ratio, a 72 min extraction time, and a 62 °C extraction temperature, along with the corresponding greatest contents of NAR (48.18 mg/g) and NEO (34.50 mg/g), respectively. Notably, by comparison with the pre-optimization data, the optimized DES extraction efficiency of flavonoids is markedly higher. Thereafter, the characterization of the solvents before and after extraction, as well as the differences between the four extraction solvent extracts, were compared using the FT-IR analyses. Furthermore, SEM results suggested that the penetration and erosion abilities of the plant cell wall of DES-1 were stronger than those of the other three traditional solvents, thus allowing more release of flavonoid compounds. In conclusion, the present research develops a straightforward, sustainable, and exceedingly efficient approach for the extraction of bioactive flavonoids from JFA, which has the potential to facilitate the efficient acquisition of active ingredients from TCM.

[Clinical comprehensive evaluation of Xiangju Capsules in treatment of rhinosinusitis].

The articles involving Xiangju Capsules were retrieved, and qualitative research and quantitative research methods were combined to evaluate the evidence of the safety, effectiveness, economy, innovation, suitability, accessibility, and characteristics of traditional Chinese medicine( "6+1" dimensions) of this drug. Multi-criteria decision analysis(MCDA) model and CSC v2.0 software were used to comprehensively evaluate the clinical value of Xiangju Capsules in the treatment of rhinosinusitis and clarify the precise clinical positioning. The dimensions are graded A, B, C, or D. Multi-source safety evidence showed that the main adverse reactions were gastrointestinal reactions, rash, itching, dizziness, and headache. Based on the available studies, the risk is controllable and the safety is grade A. Meta-analysis showed that Xiangju Capsules + conventional western medicine could recover the Lund-Kennedy score, Lund-Mackay score, and CT score, relieve headache, nasal congestion, olfactory disturbance, and facial pain, with the effectiveness is grade B. The incremental cost-effectiveness ratio of Xiangju Capsules + conventional western medicine compared with conventional western medicine alone in the treatment of chronic rhinosinusitis was 263.71 yuan, about 0.82% of the per capita disposable income. The results of sensitivity analysis showed that the research results were relatively robust. Based on the assumption that the per capita disposable income in 2020 will be the threshold of patients' willingness to pay, it is more economical to use Xiangju Capsules + conventional western medicine. The drug belongs to grade A of the national medical insurance, with an average daily cost of 3.06 yuan, and the economy is grade B. This formula is modified from classic formulas and characteristic empirical formulas, be capable of improving immunity and preventing repeated attacks. It can be used for acute and chronic rhinitis-rhinosinusitis. It had a wide range of applicability, especially for the patients with head and face tenderness. Service innovation was reflected in the measures to guarantee supply, capacity, scalability, and coverage of grass-roots sales channels. The industrial innovation was improved through the management of medicinal resources, pharmaceutical industry, production technology, quality control, scientific research and development, and this formula won three national invention patents. Comprehensively, the innovation of Xiangju Capsules is grade B. According to the survey of 188 medical practitioners and 196 patients in 20 provinces, municipalities, and autonomous regions of China, the drug was characterized by easy preparation and administration, individualized medication, simple technology and management, convenient use, storage, and transport, and controllable adverse reactions, with the suitability is grade B. Xiangju Capsules showed the cost of 45.9 and 275.4 yuan for treatment of acute and chronic rhinitis-rhinosinusitis, respectively, being well affordable. It was sold in 35 000 medical institutions in China. The dosage form was suitable for transportation, storage, and grass-root application. With rich, sustainable, and available medicinal resources, the accessibility of Xiangju Capsules is grade A. This drug can be used for both acute and chronic rhinitis-rhinosinusitis, clearing heat and expelling pus, and strengthening the exterior to prevent relapse. After this drug was available on the market, over 4 000 cases were studied, with rich experience in human use accumulated, and characteristics of traditional Chinese medicine is grade B. Overall, the clinical value of Xiangju Capsules is class B. It is suggested that Xiangju Capsules should be used in accordance with the relevant policies of basic clinical drug administration to play its role.

Dual-targeted delivery of paclitaxel and indocyanine green with aptamer-modified ferritin for synergetic chemo-phototherapy.

The combination of phototherapy and chemotherapy has become attractive and effective cancer treatment. However, the accurate delivery of both chemo-phototherapy drugs to the target site as well as the development of high-efficient phototherapy and chemotherapy drugs remain major challenges. In this study, indocyanine green (ICG) and paclitaxel (PTX)-loaded aptamer ferritin (HAS1411-PTX-ICG) was developed as a biocompatible nanoplatform for combined chemo/photothermal/photodynamic (PTT/PDT) therapy that was safe and highly effective against tumors. HAS1411 was prepared by coupling aptamer AS1411 to the surface of human H chain ferritin (HFtn) by the carbon diimide method to further enhance the targeting of HFtn. Both ICG and PTX were effectively encapsulated in the HAS1411 by incubation at 60 â„ƒ. Moreover, under near-infrared (NIR) light irradiation, HAS1411 enhanced the photothermal effect and cell internalization of ICG, as well as the production of reactive oxygen species in cancer cells. HAS1411-PTX-ICG displayed effective cytotoxicity and a significant tumor spheroids inhibitory effect owning to the improved internalization of PTX and ICG mediated by TfR1 and nucleolin dual receptors. Co-loaded PTX combined with ICG can produce chemo/PTT/PDT under near-infrared (NIR) light irradiation, enhancing the anti-tumor effect. The dual-targeting HAS1411 nanocarrier developed in this study can be a promising delivery system for cancer therapy and the fabricated HAS1411-PTX-ICG possesses potential application in chemo-phototherapy.

Co-Encapsulation of Hydrophilic and Hydrophobic Drugs into Human H Chain Ferritin Nanocarrier Enhances Antitumor Efficacy.

The biocompatible protein nanocarrier with homogeneous particle size is a promising candidate material for the delivery of targeted drugs to tumors. Doxorubicin (DOX) is a commonly prescribed anthracycline antitumor drug, although it may cause nephrotoxicity and cardiotoxicity. The Chinese herbal remedy ursolic acid (UA), a pentacyclic triterpenoid with anticancer action, has been used as a potential drug sensitizer to increase the effectiveness of chemotherapy and pharmacological therapy. Therefore, the dose of DOX can be reduced by compatibility with UA to lower its side effects. Ferritin binds to tumor cells through an interaction with the transferrin receptor 1 (TfR1), which is overexpressed in human cancer cells. In this study, the hydrophobic drug UA and the hydrophilic drug DOX were successfully encapsulated into the ferritin inner cavity using the thermal treatment method incubated at 60 °C for 4 h. The results demonstrated that loaded ferritin could specifically enter breast cancer cells MCF-7 and non-small-cell lung cancer cells A549 in comparison with free UA and DOX, enhancing their therapeutic effects. The loading ratio of two drugs was optimized in the constructed nanocarriers, and the effectiveness of the constructed nanodrugs in inhibiting tumor proliferation was verified by cell apoptosis and three-dimensional (3D) tumor spheroids studies. For the first time, the hydrophilic and hydrophobic drugs were loaded simultaneously within unmodified ferritin without other addition of additives, which would reduce the toxic side effects of DOX and enhance its therapeutic effect. This study also showed that the ferritin-based nanocarrier has potential for drug delivery to tumors.

Supplementation of Schisandrin B in Semen Extender Improves Quality and Oxidation Resistance of Boar Spermatozoa Stored at 4 °C.

During cold storage, boar spermatozoa undergo oxidative stress, which can impair sperm function and fertilizing capacity. The objective of the present study was to assess the effects of Schisandrin B (Sch B) in semen extenders on the quality of boar semen stored at hypothermia. Semen was collected from twelve Duroc boars and diluted in extenders supplemented with different concentrations of Sch B (0 µmol/L, 2.5 µmol/L, 5 µmol/L, 10 µmol/L, 20 µmol/L, and 40 µmol/L). Here, we demonstrated that 10 µmol/L Sch B provided the best effects on motility, plasma membrane integrity, acrosome integrity, sperm normality rate, average movement velocity, wobbility, mitochondrial membrane potential (MMP), and DNA integrity of sperm. The results of Sch B effects on antioxidant factors in boar sperm showed that Sch B significantly elevated the total antioxidant capacity (T-AOC) and markedly decreased the reactive oxygen species (ROS) and malondialdehyde (MDA) content of sperm. The expression of catalase (CAT) and superoxide dismutase (SOD) mRNA was increased, while the expression of glutathione peroxidase (GPx) mRNA demonstrated no change compared to non-treated boar sperm. Compared to the non-treated group, Sch B triggered a decrease in Ca2+/protein kinase A (PKA) and lactic acid content in boar sperm. Similarly, Sch B led to a statistically higher quantitative expression of AWN mRNA and a lower quantitative expression of porcine seminal protein I (PSP-I) and porcine seminal protein II (PSP-II) mRNA. In a further reverse validation test, no significant difference was observed in any of the parameters, including adhesion protein mRNA, calcium content, lactic acid content, PKA, and protein kinase G (PKG) activity after sperm capacitation. In conclusion, the current study indicates the efficient use of Sch B with a 10 µmol/L concentration in the treatment of boar sperm through its anti-apoptosis, antioxidative, and decapacitative mechanisms, suggesting that Sch B is a novel candidate for improving antioxidation and decapacitation factors in sperm in liquid at 4 °C.

The Effect of Traditional Chinese Medicine on Postviral Olfactory Dysfunction: A Systematic Review and Meta-Analysis.

Objective: The aim of this study is to evaluate the efficacy and safety of traditional Chinese medicine (TCM) for postviral olfactory dysfunction (PVOD). Methods: PubMed, EMBASE, Cochrane Central Register of Controlled Trials, China Network Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), Chinese Biomedical and Medical (CBM) Database, and Wanfang Database were electronically searched from their inception to July 25, 2022. Two authors independently performed study selection, data extraction, and quality assessment to ensure systematic quality evaluation. Randomized controlled trials (RCTs) comparing TCM with olfactory training and/or drug therapy (OTDT) were included. The outcomes were the effective rate, QOD-P, TDI score, UPSIT score, and adverse effects. Cochrane RoB was the guideline used to evaluate the methodological quality of the included trials. RevMan 5.3 software was used for statistical analysis. Results: A total of 6 RCTs involving 467 patients with PVOD were selected. Compared with OTDT, TCM plus OTDT decreased QOD-P (MD = -1.73, 95% CI (-2.40, -1.06), P < 0.0001) but did not increase the effective rate (T&T) (RR = 1.28, 95% CI (0.86, 1.90), P=0.22, I 2 = 61%). Compared with no treatment, TCM seemed to increase the treatment success rate (UPSIT) (RR = 3.17, 95% CI (1.78, 5.65), P < 0.0001, I 2 = 0%), but there was no statistically significant difference in improving the UPSIT score (MD = 3.44, 95% CI (-1.36, 8.24), P=0.16). Compared with drug therapy, TCM plus drug therapy appeared to increase the effective rate (ΔVAS) (RR = 2.36, 95% CI (1.41, 3.94), I 2 = 0%), but there was no statistically significant difference in improving the TDI score (MD = 2.10, 95% CI (-1.99, 6.19), P=0.31). No significant differences in adverse reactions were reported between TCM and OTDT. Conclusion: TCM may be an effective treatment for PVOD. With a lack of high-quality RCTs, further large-scale and high-quality RCTs are still warranted.

Gut microbiota mediates the pharmacokinetics of Zhi-zi-chi decoction for the personalized treatment of depression.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhi-zi-chi decoction (ZZCD), from "Treatise on Febrile Diseases", is a typical traditional Chinese medicine herb pair, which consists of Gardeniae Fructus (GF) and Semen Sojae Praeparatu (SSP). In clinical research, ZZCD was widely used to fight depression, remove annoyance. Many studies have reported that gut microbiota is critical target for the influence of depress through gut-brain axis, and our previously studies have found that ZZCD exhibiting antidepressant effect was through the gut-brain axis. However, the specific mechanism by which gut microbiota mediates the pharmacokinetics parameters of active compounds from ZZCD during the process of depression treatment has not yet been studied. AIM OF THE STUDY: To explore the differences in pharmacokinetics characters of bioactive iridoids from ZZCD and study the changes of gut microbiota at different stages of depression with the personalized medicine of ZZCD. MATERIALS AND METHODS: A new strategy exploring the relationship among disease phenotypes (D), intestinal microbiota (I), enzymes (E) and traits of metabolism (T) named as "DIET" was established. Firstly, a fast, selective and sensitive ultra-performance liquid chromatography coupled with tandem mass spectrometer (UPLC-MS/MS) was established and validated to quality the main bioactive compounds from ZZCD and compare the pharmacokinetics and bioavailability of different iridoids prototypes and metabolites from ZZCD between normal and chronic unpredictable mild stress rats. Subsequently, the activity of corresponding metabolic enzymes of anti-depressive compounds, ß-glucosidases and sulfotransferases, were analyzed by ρ-nitrophenyl-ß -D-glucopyranoside and sulfotransferases ELISA kits, respectively. Finally, 16S rRNA gene sequencing was adopt to analyze intestinal bacteria composition for the treatment of depression by ZZCD. RESULTS: The antidepressant effect of ZZCD was promoted due to the increased exposures and reduced eliminations of anti-depressive compounds, especially geniposide and genipin 1-gentiobioside, under the depression state. With the ZZCD treatment, the depression was improved, but the exposures of anti-depressive compounds from ZZCD gradually decreased. Meanwhile, there were the corresponding decreased trends on the activity of ß-glucosidases and sulfotransferases. With the consumption of ZZDC and the improvement of depression, the exposures of anti-depressive iridoid glycosides decreased and the activity of metabolism enzymes restored. Meanwhile, the dysbiosis of pathogenic bacteria (Bacteroidota) induced by depression was ameliorated and the probiotics (Firmicutes) at the phylum and genus level raised, the two phyla are closely related to the production of ß-glucosidase and sulfotransferases. CONCLUSIONS: It is the first proposed that ZZCD could personalized to treat depression at different stages targeting gut microbiota and gut microbiome could emerged as a potential diagnostic and therapeutic biomarker in depression.

Effective extraction of bioactive alkaloids from the roots of Stephania tetrandra by deep eutectic solvents-based ultrasound-assisted extraction.

The efficient and green extraction of bioactive ingredients from natural plants play a vital role in their corresponding drug effects and subsequent studies. Recently, deep eutectic solvents (DESs) have been considered promising new green solvents for efficiently and selectively extracting substances from varied plants. In this work, an environment-friendly DESs-based ultrasonic-assisted extraction (DESs-UAE) procedure was developed for highly efficient and non-polluting extraction of alkaloids from the roots of Stephania tetrandra (ST). A total of fifteen different combinations of DESs, compared with traditional organic solvents (methanol and 95% ethanol) and water, were evaluated for extraction of bioactive alkaloids (FAN and TET) from ST, and the results revealed that DESs system made up of choline chloride and ethylene glycol with mole ratio of 1:2 exhibited the optimal extraction efficiency for alkaloids. Additionally, a four-factor and three-level Box-Behnken design (BBD), a particular pattern of response surface methodology (RSM), was used to optimize extraction conditions. RSM results indicated that the maximum extraction yields of FAN, TET, and TA were attained 7.23, 13.36, 20.59 mg/g, respectively, within extraction temperature of 52 °C, extraction time of 82 min, DES water content of 23% (v/v), and liquid-solid ratio of 23 mL/g. The measured results were consistent with the predicted values. Notably, the optimized DES extraction efficiency of TA, according to the experimental data analysis, is 2.2, 3.3 and 4.1 times higher than methanol, 95% ethanol and water, respectively. Meanwhile, based on 3D response surface plots, interactive effects plots and contour maps, the effects of the aforementioned four essential factors on the extraction yield and their interactions on the response were visualized. The results revealed that the mutual interactions between extraction temperature and liquid-solid ratio exhibited positive effects on all responses, while extraction time and water content in DES posed a negative effect. Therefore, these results suggest that DESs, as a class of novel green solvents, with the potential to substitute organic solvent and water, can be widely and effectively applied to extract bioactive compounds from natural plants.

Cidan Capsule in Combination with Adjuvant Transarterial Chemoembolization Reduces Recurrence Rate after Curative Resection of Hepatocellular Carcinoma: A Multicenter, Randomized Controlled Trial.

OBJECTIVE: To evaluate the efficacy and safety of Cidan Capsule combined with adjuvant transarterial chemoembolization (TACE) in patients with a high risk of early recurrence after curative resection of hepatocellular carcinoma (HCC). METHODS: A multicenter, randomized controlled trial was conducted in patients with high-risk recurrence factors after curative resection of HCC from 9 medical centers between July 2014 and July 2018. Totally 249 patients were randomly assigned to TACE with or without Cidan Capsule administration groups by stratified block in a 1:1 ratio. Postoperative adjuvant TACE was given 4-5 weeks after hepatic resection in both groups. Additionally, 125 patients in the TACE plus Cidan group were administrated Cidan Capsule (0.27 g/capsule, 5 capsules every time, 4 times a day) for 6 months with a 24-month follow-up. Primary endpoints included disease-free survival (DFS) and tumor recurrence rate (TRR). Secondary endpoint was overall survival (OS). Any drug-related adverse events (AEs) were observed and recorded. RESULTS: As the data cutoff in July 9th, 2018, the median DFS was not reached in the TACE plus Cidan group and 234.0 days in the TACE group (hazard ratio, 0.420, 95% confidence interval, 0.290-0.608; P<0.01). The 1- and 2-year TRR in the TACE plus Cidan and TACE groups were 31.5%, 37.1%, and 60.8%, 63.4%, respectively (P<0.01). Median OS was not reached in both groups. The 1- and 2-year OS rates in TACE plus Cidan and TACE groups were 98.4%, 98.4%, and 89.5%, 87.9%, respectively (P<0.05). The most common grade 3-4 AEs included fatigue, abdominal pain, lumbar pain, and nausea. One serious AE was reported in 1 patient in the TACE plus Cidan group, the death was due to retroperitoneal mass hemorrhage and hemorrhagic shock, and was not related to study drug. CONCLUSIONS: Cidan Capsule in combination with TACE can reduce the incidence of early recurrence in HCC patients at high-risk of recurrence after radical hepatectomy and may be an appropriate option in postoperative anti-recurrence treatment. (Registration No. NCT02253511).

Therapeutic massage/Tuina for treatment of functional dyspepsia: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: A systematic review of randomized controlled trials (RCTs) was conducted to assess the potential effect of therapeutic massage/Tuina on functional dyspepsia (FD) patients. METHOD: Twelve databases and three clinical trial registries were searched until December 2021, for RCTs that compared Tuina combined with or without conventional therapy versus conventional therapy in FD. We assessed the methodological quality of included trials by the Cochrane Risk of Bias tool, and graded the quality of the evidence. The data were presented as risk ratio (RR) or mean difference (MD) respectively with their 95% confidence interval (CI). RESULTS: In total, 14 RCTs with 1128 FD participants were included. Compared with conventional therapy, Tuina showed significant beneficial effects on improving overall symptom (RR = 1.12, 95% CI 1.06 to 1.19, low certainty evidence), and early satiation (MD -0.44 scores, 95% CI -0.72 to -0.16, very low certainty evidence). Compared with conventional therapy, Tuina plus conventional therapy also significantly improved overall symptom (RR = 1.14, 95% CI 1.06-1.23, low certainty evidence), quality of life (MD 10.44 scores, 95% CI 7.65-13.23, low certainty evidence), and epigastric pain (MD -0.76 scores, 95% CI -1.11 to -0.41, low certainty evidence). No adverse events related to Tuina and cost-effectiveness were reported. CONCLUSION: Low certainty evidence showed that Tuina significantly improved overall symptom of FD participants compared with conventional therapy. Low certainty evidence showed that Tuina plus conventional therapy obviously improved overall symptom and quality of life of FD participants compared with conventional therapy.

Pollen samples from a bumble bee (Hymenoptera: Apidae) collection show historic foraging on introduced and native plants in the South Island of New Zealand.

Historic pollination networks are important to understand interactions between different plant and pollinator species, as well as to differentiate between causes and consequences of present insect population decline. Natural history collections in museums store biological proxy data, which is used to reconstruct historic pollination networks of bumble bees. Four bumble bee species (Bombus terrestris, B. ruderatus, B. hortorum and B. subterraneus) were introduced to Aotearoa New Zealand in 1885 specifically for pollination purposes. Pollen samples were collected from museum specimens of three of the four NZ species of bumble bee (excluding B. subterraneus) collected between 1954 and 1972 from 56 locations across the South Island, New Zealand. The most common plants identified on all three bumble bee species were Calluna vulgaris (heather), Ulex (gorse), Cytisus (broom), and Trifolium repens (white clover). However, all three bumble bee species also carried pollen from several native plants (e.g. Arthropodium, Weinmannia, Plagianthus, Quintinia, Veronica, Melicytus) and potentially had been involved in the pollination of these species. This study adds new plant species known to be foraged upon by bumble bees in Aotearoa New Zealand. Further studies on pollination networks in New Zealand will help us understand any changes in host plant preferences over time and after the time period covered by this study.

[Regulatory Effect of Vitamin D on Renin Expression at Maternal-Fetal Interface].

Objective: To investigate the regulatory effect and mechanism of vitamin D on the local renin-angiotensin system at maternal-fetal interface in the pathological process of preeclampsia (PE). Methods: The mRNA and protein expression of renin in decidua of normal pregnancy and PE placentas was determined by RT-PCR and Western blot. Normal decidual tissues were treated with active and inactive vitamin D for 48 h in vitro and the expressions of renin and vitamin D deactivating enzyme CYP24A1 were determined by RT-PCR and Western blot. Normal decidual stromal cells and glandular epithelial cells were isolated and purified, and identified by immunocytochemical staining. RT-PCR was used to examine the mRNA of vdr, cyp27 b1, cyp24 a1, and renin in the two types of cells and in decidual tissue, and the mRNA products were subjected to gel electrophoresis. These two cell types were treated with active and inactive vitamin D in vitro and the expressions of renin and vitamin D deactivating enzyme CYP24A1 were determined by RT-PCR and Western blot. Decidual gland epithelial cells were treated with protein kinase A (PKA) activator forskolin or inhibitor H89 to explore the interaction between PKA pathway and vitamin D in the regulation of renin expression. Results: The expression of renin in PE decidua was significantly higher than that of normal control at transcriptional and translational levels ( P<0.05). Vitamin D treatment could significantly down-regulate the expression of renin in normal decidua tissues ( P<0.05), while it significantly up-regulated CYP24A1 expression ( P<0.001). Decidual stromal cells and gland epithelial cells were successfully isolated from decidual tissue. Compared with that in decidual stromal cells, the mRNA level of vitamin D-related molecules in gland epithelial cells was more similar to that in decidual tissue. Active or inactive vitamin D treatment significantly inhibited the expression of renin in glandular epithelial cells ( P<0.05), but the expression of renin in decidual stromal cells was not affected. However, the treatment of active or inactive vitamin D in these two kinds of cells significantly increased the expression of CYP24A1 ( P<0.001). Active vitamin D could significantly inhibit the upregulation of renin by PKA agonist forskolin, and could inhibit the expression of renin through synergy with PKA inhibitor H89. Conclusion: The expression of renin in placental decidua is up-regulated in patients with PE, and the activation of local renin-angiotensin system at the maternal-fetal interface may be involved in the pathogenesis of PE. Vitamin D can specifically down-regulate renin expression in human decidual gland epithelial cells by competing with the PKA pathway. Vitamin D supplementation may have potential value for clinical intervention of PE.