Vitamin D and prebiotics for intestinal health in cystic fibrosis: Rationale and design for a randomized, placebo-controlled, double-blind, 2 x 2 trial of administration of prebiotics and cholecalciferol (vitamin D3) (Pre-D trial) in adults with cystic fibrosis.

Individuals with cystic fibrosis (CF) have dysfunctional intestinal microbiota and increased gastrointestinal (GI) inflammation also known as GI dysbiosis. It is hypothesized that administration of high-dose cholecalciferol (vitamin D3) together with a prebiotic (inulin) will be effective, and possibly additive or synergistic, in reducing CF-related GI and airway dysbiosis. Thus, a 2 x 2 factorial design, placebo-controlled, double-blinded, pilot and feasibility, clinical trial was proposed to test this hypothesis. Forty adult participants with CF were block-randomized into one of four groups: 1) high-dose oral vitamin D3 (50,000 IU weekly) plus oral prebiotic placebo daily; 2) oral prebiotic (12 g inulin daily) plus oral placebo vitamin D3 weekly; 3) combined oral vitamin D3 weekly and oral prebiotic inulin daily; and 4) oral vitamin D3 placebo weekly and oral prebiotic placebo. The primary endpoints included 12-week changes in the microbial bacterial communities, gut and airway microbiota richness and diversity before and after the intervention. This pilot study examined whether vitamin D3 with or without prebiotics supplementation was feasible, changed airway and gut microbiota, and reduced dysbiosis, which in turn, may improve health outcomes and quality of life of patients with CF.

Echinacoside ameliorates post-stroke depression by activating BDNF signaling through modulation of Nrf2 acetylation.

BACKGROUND: Post-stroke depression (PSD) affects approximately one-third of stroke survivors, leading to adverse outcomes in rehabilitation, reduced quality of life, and increased mortality rates. Despite these implications, the underlying causes of PSD remain unclear, posing challenges for prevention and treatment. Echinacoside (ECH), a natural compound with known neuroprotective and antidepressant properties, holds significant therapeutic potential for PSD. However, the precise mechanism of its action remains unknown. PURPOSE: To unravel the specific mechanism through which ECH alleviates PSD by exploring the intricate interplay between ECH and Nrf2, as well as its impact on the BDNF/TrkB signaling axis. STUDY DESIGN AND METHODS: A rat PSD model was established though middle cerebral artery occlusion coupled with chronic unpredictable mild stress, followed by ECH treatment. The rats' depressive state was evaluated using the sucrose preference test and force swimming test. Brain damage was assessed through TTC staining, Nissl staining, and TUNEL assay. The multifaceted mechanism of ECH in PSD was investigated using immunofluorescence, immunohistochemistry, RT-qPCR, dual-luciferase assay, and western blotting. Additionally, the interaction between ECH and Nrf2 was explored through molecular docking and microscale thermophoresis. RESULTS: Our findings unveiled a novel facet of ECH action, demonstrating its unique ability to upregulate Nrf2 through acetylation within the hippocampus of PSD-affected rats (p < 0.05). Moreover, ECH showcased its distinctive potential by enhancing BDNF transcriptional activity, activating the BDNF/TrkB signaling axis, and orchestrating a comprehensive response against oxidative stress and apoptosis, thereby alleviating PSD symptoms in rats (p < 0.05). CONCLUSIONS: This study not only provides insights into the pivotal role of Nrf2 in mediating the BDNF/TrkB axis activation by ECH but also highlights the novelty of ECH's mechanism in addressing PSD. The elucidation of these unique aspects positions ECH as a groundbreaking candidate for further exploration and development in the realm of PSD intervention.

Monomeric pilose antler peptide improves depression-like behavior in mice by inhibiting FGFR3 protein expression.

ETHNOPHARMACOLOGICAL RELEVANCE: It has been found that pilose antler peptide has an antidepressant effect on depression. However, the exact molecular mechanism of its antidepressant effect is still unclear. AIM OF THE STUDY: The study sought to determine the impact of monomeric pilose antler peptide (PAP; sequence LVLVEAELRE) on depression as well as investigate potential molecular mechanisms. MATERIALS AND METHODS: Chronic unexpected mild stress (CUMS) was used to establish the model, and the effect of PAP on CUMS mice was detected by the behavioral test. The influence of PAP on neuronal cells and dendritic spine density was observed by immunofluorescence and Golgi staining. FGFR3 and the CaMKII-associated pathway were identified using quantitative real-time polymerase chain reaction, and Western blot analysis was utilized to measure their proteins and gene expression levels. Molecular docking and microscale thermophoresis were applied to detect the binding of PAP and FGFR3. Finally, the effect of FGFR3's overexpression on PAP treatment of depression was detected. RESULTS: PAP alleviated the changes in depressive behavior induced by CUMS, promoted the growth of nerve cells, and the density of dendritic spines was increased to its original state. PAP therapy successfully downregulated the expression of FGFR3 and ERK1/2 while upregulating the expression of CREB, BDNF, and CaMKII. CONCLUSION: Based on the current research, PAP has a therapeutic effect on depression brought on by CUMS by inhibiting FGFR3 expression and enhancing synaptic plasticity.

Vitamin D and Prebiotics for Intestinal Health in Cystic Fibrosis: Rationale and design for a randomized, placebo-controlled, double-blind, 2 × 2 trial of administration of prebiotics and cholecalciferol (vitamin D3) (Pre-D Trial) in adults with cystic fibrosis.

Individuals with cystic fibrosis (CF) have dysfunctional intestinal microbiota and increased gastrointestinal (GI) inflammation also known as GI dysbiosis. It is hypothesized that administration of high-dose cholecalciferol (vitamin D3) together with a prebiotic (inulin) will be effective, and possibly additive or synergistic, in reducing CF-related GI dysbiosis and improving intestinal functions. Thus, a 2 × 2 factorial design, placebo-controlled, double-blind, clinical trial was proposed to test this hypothesis. Forty adult participants with CF will be block-randomized into one of four groups: 1) high-dose oral vitamin D3 (50,000 IU weekly) plus oral prebiotic placebo daily; 2) oral prebiotic (12 g inulin daily) plus oral placebo vitamin D3 weekly; 3) combined oral vitamin D3 weekly and oral prebiotic inulin daily; and 4) oral vitamin D3 placebo weekly and oral prebiotic placebo. The primary endpoints will include 12-week changes in the reduced relative abundance of gammaproteobacteria, and gut microbiota richness and diversity before and after the intervention. This clinical study will examine whether vitamin D3 with or without prebiotics will improve intestinal health and reduce GI dysbiosis, which in turn, should improve health outcomes and quality of life of patients with CF.

Ginsenoside Rg1 modulates PI3K/AKT pathway for enhanced osteogenesis via GPER.

BACKGROUND: Osteoporosis is a systemic skeletal disorder characterized by decreased bone density and the degradation of bone tissue microarchitecture. Ginsenoside Rg1, derived from Panax ginseng, has been a part of traditional Chinese medicine in China for centuries, particularly for treating osteoporosis. However, there remains limited research on the osteogenic potential of Rg1 within the glucocorticoid-induced osteoporosis (GIOP) model and its specific mechanisms. PURPOSE: The primary objective of this study is to investigate the osteogenic potential of Rg1 within the GIOP model and explore the signaling pathways associated with its in vivo and in vitro effects. METHODS: Cell proliferation, differentiation and mineralization were evaluated by the Cell counting kit 8(CCK8) assay, alkaline phosphatase (ALP) test and Alizarin Red S staining, respectively. The qPCR technique was used to determine the relative expression of mRNA and the western blot was used to determine the relative expression of protein. In vivo experiments, spinal vertebrae staining in zebrafish larvae was accomplished by alizarin red S staining. RESULTS: Zebrafish larvae's hatching, survival, malformation, and heart rate were unaffected by 50 µM of Rg1 in vivo, while the MEC3T3-E1 cell line's proliferation was unaffected by 50 µM of Rg1 in vitro. Meanwhile, Rg1 was shown to improve osteogenic differentiation or bone formation as well as the level of mRNA expression of osteogenic markers in vivo and in vitro. Treatment with Rg1 significantly increased the expression of G protein-coupled estrogen receptor (GPER) and pAKT. In addition, the GPER inhibitor G15 could significantly reduce the mRNA and protein expression levels of GPER and phosphorylated AKT, LY294002, a PI3K/AKT pathway inhibitor, markedly suppresses the expression of phosphorylated AKT, yet shows no significant impact on GPER expression. Both G15 and LY294002 can significantly blocked the Rg1-mediated enhancement of osteogenesis capacity in the GIOP model. In contrast, when both the agonists G1 of GPER and LY294002 were added, G1 increased the relative expression of mRNA and protein of GPER, but not the expression of osteogenic capacity and osteogenic markers. CONCLUSIONS: This study investigates the mineralization effects and mechanisms of Ginsenoside Rg1 both in vitro and in vivo. For the first time, we propose that Rg1 might regulate osteogenesis by modulating AKT phosphorylation through mediating GPER expression within the PI3K/AKT pathway in the GIOP model. This discovery introduces novel targets and avenues for osteoporosis treatment.

Exogenous Selenium and Biochar Application Modulate the Growth and Selenium Uptake of Medicinal Legume Astragalus Species.

Astragalus species have a certain capacity to enrich selenium (Se) and are the strongest Se hyperaccumulator legumes known globally at present. The biochar application to medicinal plants has been reported to affect plant metabolites. In this study, we aimed to employ hyperaccumulating Astragalus species in the plant growth of selenium-lacked soil, while also investigating the impact of varying selenium doses and biochar application on legumes growth, selenium content, and secondary metabolite production. Applying biochar to soil, along with a Se concentration of 6 mg/kg, significantly enhanced the growth, Se content, total polysaccharide content, and calycosin-7-glucoside content of Astragalus species (p < 0.05). Importantly, the Se and biochar application also led to a significant improvement in Se content in ABH roots (p < 0.05). Meanwhile, the content of total flavonoids in ABH roots could be promoted by a Se concentration of 3 mg/kg and biochar application in soil. Additionally, the Se enrichment coefficients of Astragalus species under Se treatments were significantly higher than those under control treatment, with a marked difference observed across all treatments, whether roots or above-ground (p < 0.05). Remarkably, the Se transport coefficients of Astragalus species were observed to be lower than one, except for the transport coefficient of AB in the Se concentration of the control treatment (0 mg/kg). This result showed that a medium concentration treatment of Se and biochar application in soil not only promotes the growth of Astragalus species and the uptake of exogenous Se but also increases the active component content, meanwhile enhancing the Se enrichment and transport capacity. Taken as a whole, the present findings offer a more comprehensive understanding of the interplay between distinct Se levels, as well as the addition of biochar in soil, providing valuable insight for the cultivation of Se-rich Astragalus in Se-deficient soil-plant systems.

Orchestrated feedback regulation between melatonin and sex hormones involving GPER1-PKA-CREB signaling in the placenta.

Maintaining placental endocrine homeostasis is crucial for a successful pregnancy. Pre-eclampsia (PE), a gestational complication, is a leading cause of maternal and perinatal morbidity and mortality. Aberrant elevation of testosterone (T0 ) synthesis, reduced estradiol (E2 ), and melatonin productions have been identified in preeclamptic placentas. However, the precise contribution of disrupted homeostasis among these hormones to the occurrence of PE remains unknown. In this study, we established a strong correlation between suppressed melatonin production and decreased E2 as well as elevated T0 synthesis in PE placentas. Administration of the T0 analog testosterone propionate (TP; 2 mg/kg/day) to pregnant mice from E7.5 onwards resulted in PE-like symptoms, along with elevated T0 production and reduced E2 and melatonin production. Notably, supplementation with melatonin (10 mg/kg/day) in TP-treated mice had detrimental effects on fetal and placental development and compromised hormone synthesis. Importantly, E2 , but not T0 , actively enhanced melatonin synthetase AANAT expression and melatonin production in primary human trophoblast (PHT) cells through GPER1-PKA-CREB signaling pathway. On the other hand, melatonin suppressed the level of estrogen synthetase aromatase while promoting the expressions of androgen synthetic enzymes including 17ß-HSD3 and 3ß-HSD1 in PHT cells. These findings reveal an orchestrated feedback mechanism that maintains homeostasis of placental sex hormones and melatonin. It is implied that abnormal elevation of T0 synthesis likely serves as the primary cause of placental endocrine disturbances associated with PE. The suppression of melatonin may represent an adaptive strategy to correct the imbalance in sex hormone levels within preeclamptic placentas. The findings of this study offer novel evidence that identifies potential targets for the development of innovative therapeutic strategies for PE.

Integrative Single-Cell and Bulk Transcriptomes Analyses Identify Intrinsic HNSCC Subtypes with Distinct Prognoses and Therapeutic Vulnerabilities.

PURPOSE: Tumor heterogeneity in head and neck squamous cell carcinoma (HNSCC) profoundly compromises patient stratification, personalized treatment planning, and prognostic prediction, which underscores the urgent need for more effective molecular subtyping for this malignancy. Here, we sought to define the intrinsic epithelial subtypes for HNSCC by integrative analyses of single-cell and bulk RNA sequencing datasets from multiple cohorts and assess their molecular features and clinical significance. EXPERIMENTAL DESIGN: Malignant epithelial cells were identified from single-cell RNA sequencing (scRNA-seq) datasets and subtyped on the basis of differentially expressed genes. Subtype-specific genomic/epigenetic abnormalities, molecular signaling, genetic regulatory network, immune landscape, and patient survival were characterized. Therapeutic vulnerabilities were further predicted on the basis of drug sensitivity datasets from cell lines, patient-derived xenograft models, and real-world clinical outcomes. Novel signatures for prognostication and therapeutic prediction were developed by machine learning and independently validated. RESULTS: Three intrinsic consensus molecular subtypes (iCMS1-3) for HNSCC were proposed from scRNA-seq analyses and recapitulated in 1,325 patients from independent cohorts using bulk-sequencing datasets. iCMS1 was characterized by EGFR amplification/activation, stromal-enriched environment, epithelial-to-mesenchymal transition, worst survival, and sensitivities to EGFR inhibitor. iCMS2 was featured by human papillomavirus-positive oropharyngeal predilection, immune-hot, susceptibilities to anti-PD-1, and best prognosis. Moreover, iCMS3 displayed immune-desert and sensitivities to 5-FU and MEK, STAT3 inhibitors. Three novel, robust signatures derived from iCMS subtype-specific transcriptomics features were developed by machine learning for patient prognostication and cetuximab and anti-PD-1 response predictions. CONCLUSIONS: These findings reiterate molecular heterogeneity of HNSCC and advantages of scRNA-seq in pinpointing cellular diversities in complex cancer ecosystems. Our HNSCC iCMS regime might facilitate accurate patient stratification and individualized precise treatment.

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.

[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.

Biomimetic Red Blood Cell Membrane-Mediated Nanodrugs Loading Ursolic Acid for Targeting NSCLC Therapy.

As one of the most common cancers worldwide, non-small-cell lung cancer (NSCLC) treatment always fails owing to the tumor microenvironment and resistance. UA, a traditional Chinese medicine, was reported to have antitumor potential in tumor models in vitro and in vivo, but showed impressive results in its potential application for poor water solubility. In this study, a novel biomimetic drug-delivery system based on UA-loaded nanoparticles (UaNPs) with a red blood cell membrane (RBCM) coating was developed. The RBCM-coated UANPs (UMNPs) exhibited improved water solubility, high stability, good biosafety, and efficient tumor accumulation. Importantly, the excellent antitumor efficiency of the UMNPs was confirmed both in vitro and in vivo in cancer models. In addition, we further investigated the antitumor mechanism of UMNPs. The results of Western blotting showed that UMNPs exerted an anticancer effect by inducing the apoptosis and autophagy of NSCLC cells, which makes it superior to free UA. In addition, body weight monitoring, hematoxylin and eosin (HE) analysis, and immunohistochemical (IHC) analysis showed no significant difference between UMNPs and the control group, indicating the safety of UMNPs. Altogether, the preparation of biomimetic UMNPs provides a promising strategy to improve outcomes in NSCLC.

Clinical Efficacy of Xueshuantong plus Urokinase in the Treatment of Sudden Deafness.

Objective: To investigate the clinical effect of Xueshuantong combined with urokinase in the treatment of sudden deafness. Methods: A total of 90 patients with sudden deafness who were treated in South China Hospital affiliated to Shenzhen University from June 2019 to August 2020 were recruited and assigned (1 : 1) into the control group (n = 45, urokinase) and the experimental group (n = 45, Xueshuantong plus urokinase) according to the different treatment methods. The clinical treatment effect, the degree of tinnitus, the average auditory valve of the damaged frequency, and the changes in hemorheology (plasma viscosity, whole blood high-shear reduced viscosity, whole blood low-shear reduced viscosity, hematocrit, and fibrinogen) were compared between the two groups of patients. Results: The treatment with urokinase and Xueshuangtong injection in the experimental group resulted in a significantly higher clinical treatment effect when compared with the treatment in the control group (P < 0.05). After treatment, the degree of tinnitus and the average auditory valve of the damaged frequency in the experimental group were significantly lower than those in the control group (P < 0.05). The levels of hemorheology (plasma viscosity, whole blood high-shear reduced viscosity, whole blood low-shear reduced viscosity, hematocrit, and fibrinogen) in the experimental group after treatment were significantly lower than those in the control group (P < 0.05). Conclusion: The clinical effect of Xueshuantong combined with urokinase in the treatment of patients with sudden deafness is remarkable, and it can effectively improve the hearing level and hemorheology-related indexes of patients, and it thus merits clinical application.

Influence of organoboron cross-linker and reservoir characteristics on filtration and reservoir residual of guar gum fracturing fluid in low-permeability shale gas reservoirs.

To effectively reduce the filtration rate of water-based fracturing fluid and promote the pressure holding effect of fracturing fluid in underground unconventional reservoirs, an efficient and clean organic-boron cross-linker was synthesized with boric acid and low alcohols. The results obtained that the synthesized organoboron cross-linker exhibits better fluid loss performance to water-based fracturing fluid than the commercially available cross-linker. This organoboron cross-linker allowed decreasing filtration coefficient more than 0.74 × 10-2 m3·min1/2 as a result of the network structure formed by the organoboron cross-linker and guar gum molecule. However, commercially available cross-linker exhibits a relatively large filtered mass of water more than 1.33 × 10-2 m3·min1/2 at the same condition. Meanwhile, the cross-linked guar gum fracturing fluid can significantly improve the fluid loss property with the increase of cross-linker content and pressure, and an increased fluid filtration gradually was revealed with increasing the reservoir temperature and current speed. Moreover, the damage of shale reservoir caused by the prepared boron cross-linker was only 11%, which was lower than 18% of the commercial boron cross-linker under the same conditions.

Taraxasterol prompted the anti-tumor effect in mice burden hepatocellular carcinoma by regulating T lymphocytes.

Hepatocellular carcinoma (HCC) is a common digestive malignant tumor with high morbidity and mortality worldwide, however, the treatment of HCC and prognosis of patients are not optimistic, finding more effective treatments are imperative. Taraxacum officinale (L.) Weber ex F.H.Wigg is a perennial herb of compositae, and our study has demonstrated that Taraxacum officinale polysaccharide has certain anti-tumor effect on HCC cells. Taraxasterol (TS) is a natural product extracted from Taraxacum officinale with strong physiological, pharmacological and biological activities, but the effect of TS on HCC is yet to be determined. Therefore, the aim of this study is to explore the effect of dandelion sterol on HCC in vivo and in vitro. The results showed that TS significantly inhibited the proliferation, induced apoptosis and blocked cell cycle in HCC cell lines HepG2 and Huh7 cells in vitro. TS inhibited the tumor growth of H22 bearing mice and the expression of Ki67 in vivo. More importantly, TS regulated the immunity of H22 bearing mice by elevating the ratio of CD4+ T cells in spleen, and increasing the number of T cell infiltration in tumor tissue. Except immunomodulation, the mechanism of tumor growth inhibition may be related to the regulation of apoptosis related proteins and IL-6/STAT3 pathway. TS significantly inhibited the growth of HCC cells both in vitro and in vivo. The study would provide a theoretical basis for the new application of TS and the adjuvant treatment of malignant tumor with traditional Chinese medicine.

Efficacy and Safety of Zuojin Pill for the Treatment of Chronic Nonatrophic Gastritis: A Randomized Active-Controlled Clinical Trial.

Objective: Zuojin pill (ZJP) is used as the classical prescription for a wide variety of digestive diseases. However, there is a lack of direct evidence for its use in the treatment of chronic nonatrophic gastritis (CNG). In particular, there is a lack of rigorous trials of randomized controlled designs. In this study, a randomized active-controlled clinical trial was performed to verify the efficacy and safety of ZJP in detail. Methods: Patients with CNG were divided into the ZJP group and the Marzulene-S granule group. Patients were enrolled from September 2019 to February 2021 (ChiCTR2000040549). Endoscopy and histology scores were evaluated as the primary outcome measure. The Helicobacter pylori positive rate and the disappearance rate of symptoms were also measured to reflect the outcomes. Finally, adverse events were also calculated as the index of safety. Results: A total of 68 eligible patients were enrolled in this trial and randomly divided into two groups with baseline comparability. ZJP was able to improve the red plaques as well as bile reflux scores compared with Marzulene-S granule (P=0.043 and P=0.019, respectively). Moreover, it also remarkably alleviated the active chronic inflammation score (P=0.043). However, there was no difference between the Helicobacter pylori positivity rate (P=0.752). The symptom scores of abdominal distension (P=0.004), belching (P=0.010), and loss of appetite (P=0.019) were alleviated by ZJP, but nausea and vomiting were not (P=0.616). ZJP can also be considered safe with no obvious adverse effects. Conclusion: ZJP might decrease mucosal injury and alleviate symptoms in CNG. In addition, more large-scale clinical trials should be carried out to further confirm its clinical efficacy and safety.

Overview of Microvascular Angina Pectoris and Discussion of Traditional Chinese Medicine Intervention.

Previous research and treatment of coronary heart disease mostly focused on the large epicardial vessels, with limited research on the small endocardial coronary arteries or arterioles that could not be detected by coronary angiography, especially microvascular angina caused by microvascular stenosis or microcirculation dysfunction. Conventional Western medicine therapies have no specific efficacy, but traditional Chinese medicine has significant advantages in this regard. In particular, traditional Chinese medicine of supplementing Qi and activating blood circulation protects the vascular endothelium, relaxes coronary microvessels, reduces myocardial no-reflow after ischemia-reperfusion, increases myocardial hypoxia tolerance, constrains the aggregation of platelet, and increases the rate of blood flow. Moreover, these treatments can significantly improve patients' symptoms through multitarget comprehensive intervention. Here, we analyzed the pathogenesis of microvascular angina pectoris, the treatment status of modern medicine, and the research on the multitarget intervention of traditional Chinese medicine to provide new research ideas for correctly identifying the role of coronary microcirculation in coronary artery disease to solve clinical problems and prevent cardiovascular events.

Dehydroevodiamine ameliorates indomethacin-induced gastric injury via inhibition of ERK and p38 signaling pathway.

BACKGROUND: Dehydroevodiamine (DHE), a pivotal quinazoline alkaloid isolated from Fructus Evodiae (Tetradium ruticarpum (A. Juss.) Hartley), has various pharmacological effects. However, the effect of DHE on gastric injury is still uncharted. PURPOSE: To clarify the pharmacological effect and mechanism of DHE on gastric injury (GI) induced by indomethacin (IDO). STUDY DESIGN: The gastric injury was induced in rat by oral administration of 5 mg/kg IDO for 7 days. Then the rats were treated with DHE (10, 20, 40 mg/kg, ig) for 7 days. METHODS: The changes of food intake, body weight, gastric pH and general state observation were determined. And HE staining and AB-PAS staining was analyzed. Then, the inflammatory infiltration of gastric tissue was observed through MPO immunohistochemical approach, and the expression of TNF-α, IL-6 and IL-10 were measured. Furthermore, the levels of proteins ERK, p-ERK, P38, p-P38, JNK and p-JNK were determined to elucidate the molecular mechanism of DHE. RESULTS: DHE alleviated food intake reduction, weight loss and gastric injury induced by IDO and made gastric pH and mucosal thickness return to normal. In addition, DHE could down regulate the expression of MPO, TNF-α and IL-6 and up regulate the expression of IL-10 to reduce the damage induced by inflammatory, and create a healing environment. Furthermore, DHE could significantly inhibit the phosphorylation of ERK and p38 not JNK. CONCLUSION: DHE ameliorated dyspepsia, inflammatory infiltration and tissue damage induced by IDO through ERK and p38 signaling pathways rather than JNK pathway.

Chemical Fingerprint Profiles and Pharmacodynamic Investigation for Quality Evaluation of Moxa Smoke by UHPLC in a Rat Model of Superficial Infection.

INTRODUCTION: Moxibustion, a traditional Chinese medicine technique, involves the use of moxa smoke from Folium Artemisia argyi to treat various disorders, especially superficial infections. However, there is a higher health risk for people exposed to high levels of moxa smoke for extended durations. Here, we report the first ultra-high-performance liquid chromatography (UHPLC) fingerprint profiles and pharmacodynamic evaluation of moxa smoke, as well as evaluation of its aqueous solution on a rat model of superficial infection. METHODS: A novel method for moxa smoke fingerprint profiling was developed using UHPLC under characteristic wavelength. Chromatographic peaks were further analyzed by ultra-high-performance liquid chromatography quadrupole-time-of-flight mass spectrometry (UHPLC-QTOF/MS). 12 sample batches obtained from various Chinese provinces were then analyzed using similarity evaluation, clustering analysis, and principal component analysis. The pharmacodynamics of moxa smoke and moxa aqueous solution were investigated on a rat model of acute skin wound infection. RESULTS: UHPLC fingerprint profiles of 12 batches of moxa smoke were generated at 270 nm wavelength and 21 chromatographic peaks extracted as common peaks. Similarity between the 12 batches ranged from 0.341 to 0.982. Based on cluster analysis, the 12 batches of moxa smoke samples were clustered into five groups. Principal component analysis showed that the cumulative contribution of the three principal components reached 90.17%. Eigenvalues of the first, second, and third principal components were 10.794, 6.504, and 1.638, respectively. The corresponding variance contribution rates were 51.40%, 30.97%, and 7.80%, respectively. Pharmacological analysis found that wound healing was slow in the model group relative to the mupirocin ointment, moxa smoke, and aqueous moxa smoke solution groups. Histological analysis revealed markedly reduced tissue inflammation in rats treated with moxa smoke or its aqueous solution. CONCLUSIONS: Moxa smoke and its aqueous solution significantly promote wound healing upon superficial infection. A novel quality control method for moxa smoke was established and evaluated for the first time. As its main effects are unchanged, the transformation of moxa smoke into aqueous moxa smoke improves safety and is a simple and controllable process.

Neonicotinoid insecticides triggers mitochondrial bioenergetic dysfunction via manipulating ROS-calcium influx pathway in the liver.

Extensive use of neonicotinoids insecticides (NNIs) rapidly garnered widespread attention in the toxicology, since they have been found in human samples, including urine, blood, breast milk and hair. However, the precise mechanism is not completely clear regarding the NNIs-induced hepatotoxicity. In this study, we exposed male mice to three neonicotinoids (dinotefuran (DIN), nitenpyram (NIT) and acetamiprid (ACET) for 30 days. Our results showed that NNIs remarkably induced morphological damage in the liver. Simultaneously, we found that three neonicotinoids could activate the store operated Ca2+ entry (SOCE) in the liver. Further results confirmed that reactive oxide species (ROS) scavenger n-acetylcysteine (NAC) attenuated DIN-induced calcium ion (Ca2+) overload and S-phase arrest via restoring protein expression of SOCE and S phase related genes in L02 hepatocytes. Moreover, we found that NAC obviously combated mitochondrial dysfunction caused by DIN via restoring mitochondrial membrane potential. Meanwhile, DIN treatment significantly increased pyruvate content, impaired the activities of tricarboxylic acid (TCA) cycle rate-limiting enzymes and inhibited adenosine triphosphate (ATP) generation, but these effects were reversed by Serca specific activator CDN1163. Collectively, perturbation of redox states can be recognized as the center of S-phase arrest and Ca2+ overload after NNIs exposure. In this regard, Ca2+ homeostasis dysregulation is a causative event of mitochondrial bioenergetic dysfunction in the liver. These data provides a new perspective for understanding NNI-induced hepatotoxicity mechanisms.

[Analysis of "Tianyou (TE 16) and five regions" in the human body].

Focusing on the original text record in Huangdi Neijing (Inner Canon of Yellow Emperor), the relevant theories of "Tianyou (TE 16) and five regions" are explored, e.g. acupoint names, meridians and acupoint features, and the clinical application of these acupoints has been analyzed. It is discovered that "Tianyou (TE 16) and five regions" are mainly used in treatment of the disorders in the nervous system, five sensory organs and motor system. Besides, in terms of the relevant theories, "Tianyou (TE 16) and five regions" has been compared with "root and knot" and "twelve divergent meridians". It is found that "Tianyou (TE 16) and five regions" communicates the externally-internally related meridians and is applicable in treatment of the disorders with both exterior and interior involved. It is the essential acupoint composition of the human body.