Lycorine inhibits Ang II-induced heart remodeling and inflammation by suppressing the PI3K-AKT/NF-κB pathway.

BACKGROUND: Ang II induces hypertensive heart failure (HF) via hemodynamic and non-hemodynamic actions. Lycorine (LYC) is an alkaloid derived from Lycoris bulbs, and it possesses anti-cardiovascular disease-related activities. Herein, we explored the potential LYC-mediated regulation of Ang II-induced HF. METHODS: Over 4 weeks, we established a hypertensive HF mouse model by infusing Ang II into C57BL/6 mice using a micro-osmotic pump. For the final two weeks, mice were administered LYC via intraperitoneal injection. The LYC signaling network was then deduced using RNA sequencing. RESULTS: LYC administration strongly suppressed hypertrophy, myocardial fibrosis, and cardiac inflammation. As a result, it minimized heart dysfunction while causing no changes in blood pressure. The Nuclear Factor kappa B (NF-κB) network/phosphoinositol-3-kinase (PI3K)-protein kinase B (AKT) was found to be a major modulator of LYC-based cardioprotection using RNA sequencing study. We further confirmed that in cultured cardiomyocytes and mouse hearts, LYC reduced the inflammatory response and downregulated the Ang II-induced PI3K-AKT/NF-κB network. Moreover, PI3K-AKT or NF-κB axis depletion in cardiomyocytes completely abrogated the anti-inflammatory activities of LYC. CONCLUSION: Herein, we demonstrated that LYC safeguarded hearts in Ang II -stimulated mice by suppressing the PI3K-AKT/NF-κB-induced inflammatory responses. Given the evidence mentioned above, LYC is a robust therapeutic agent for hypertensive HF.

Preparation and Properties of GO/ZnO/nHAp Composite Microsphere Bone Regeneration Material.

The purpose of this study is to explore the possibility of using graphene-zinc oxide-hydroxyapatite (GO/ZnO/nHAp) composite microspheres as bone regeneration materials by making use of the complementary advantages of nanocomposites, so as to provide reference for the clinical application of preventing and solving bacterial infection after implantation of synthetic materials. Firstly, GO/ZnO composites and hydroxyapatite nanoparticles were synthesized using the hydrothermal method, and then GO/ZnO/nHAp composite microspheres were prepared via high-temperature sintering. The graphene-zinc oxide-calcium phosphate composite microspheres were characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), X-ray photoelectron spectroscopy (XPS), energy dispersion spectroscopy (EDS), water contact angle measurement, degradation and pH determination, and differential thermal analysis (DiamondTG/DTA). The biocompatibility, osteogenic activity, and antibacterial activity of GO/ZnO/nHAp composite microspheres were further studied. The results of the cell experiment and antibacterial experiment showed that 0.5% and 1% GO-ZnO-nHAp composite microspheres not only had good biocompatibility and osteogenic ability but also inhibited Escherichia coli and Staphylococcus aureus by more than 45% and 70%. Therefore, GO/ZnO/nHAp composite microspheres have good physical and chemical properties and show good osteogenic induction and antibacterial activity, and this material has the possibility of being used as a bone regeneration material.

Probiotic-Fermented Distillers Grain Alters the Rumen Microbiome, Metabolome, and Enzyme Activity, Enhancing the Immune Status of Finishing Cattle.

A total of 30 Simmental crossbred cattle (6.50 months old, 265.0 ± 22.48 kg) were randomly divided into three groups, with 10 heads per group, and fed for 45 days. The diet treatments consisted of the Control group without PFDG supplementation, the PFDG-15% group with 15% PFDG substituting for 15% concentrate, and PFDG-30% group with 30% PFDG substituting for 30% concentrate. The results showed that compared with the Control group, the average daily gain (ADG) of the cattle in the PFDG-30% group decreased significantly (0.890 vs. 0.768 kg/d, p = 0.005). The serum malondialdehyde content of cattle in the PFDG-15% and PFDG-30% groups decreased significantly (p = 0.047) compared to that of the Control group. However, the serum superoxide dismutase activity of cattle in the PFDG-30% group was significantly higher than that of the Control group (p = 0.047). Meanwhile, both the PFDG-15% and PFDG-30% groups (1758.47 vs. 2061.30 µg/mL) showed higher serum levels of immunoglobulin G, while the interleukin-10 concentration was lower in the PFDG-30% group (p = 0.027). In addition, the PFDG-15% and PFDG-30% groups shifted the rumen microbiota by improving the abundances of F082 (related to propionic acid production) and fiber-degrading bacteria (Lachnospiraceae_UGG-009 and Prevotellaceae_UCG-001) and reducing the abundance of the disease-associated bacteria Selenomonas. A Kyoto encyclopedia of genes and genomes (KEGG) analysis illustrated that three key metabolic pathways, including phenylalanine metabolism, pyrimidine metabolism, and tryptophan metabolism, were enriched in the PFDG-15% group, but eight key metabolic pathways, including arachidonic acid metabolism, were enriched in the PFDG-30% group. Importantly, both the PFDG-15% and PFDG-30% groups increased (p < 0.01) the activities of cellulase, lipase, and protease in the rumen. Finally, the different bacterial abundance in the rumen was associated with changes in the ADG, serum antioxidant capacity, immune status, rumen enzyme activity, and metabolites. These results suggest that PFDG alters rumen microbiome abundance, metabolome, and enzyme activity for enhancing serum antioxidant capacity and the immune status, but when the supplemental level reaches 30%, it has a negative effect on ADG and the anti-inflammatory factors in finishing cattle.

Antibacterial activities of anthraquinones: structure-activity relationships and action mechanisms.

With the increasing prevalence of untreatable infections caused by antibiotic-resistant bacteria, the discovery of new drugs from natural products has become a hot research topic. The antibacterial activity of anthraquinones widely distributed in traditional Chinese medicine has attracted much attention. Herein, the structure and activity relationships (SARs) of anthraquinones as bacteriostatic agents are reviewed and elucidated. The substituents of anthraquinone and its derivatives are closely related to their antibacterial activities. The stronger the polarity of anthraquinone substituents is, the more potent the antibacterial effects appear. The presence of hydroxyl groups is not necessary for the antibacterial activity of hydroxyanthraquinone derivatives. Substitution of di-isopentenyl groups can improve the antibacterial activity of anthraquinone derivatives. The rigid plane structure of anthraquinone lowers its water solubility and results in the reduced activity. Meanwhile, the antibacterial mechanisms of anthraquinone and its analogs are explored, mainly including biofilm formation inhibition, destruction of the cell wall, endotoxin inhibition, inhibition of nucleic acid and protein synthesis, and blockage of energy metabolism and other substances.

Mechanisms underlying soil microbial regulation of available phosphorus in a temperate forest exposed to long-term nitrogen addition.

With exogenous nitrogen (N) input into soil, phosphorus (P) could become a limiting nutrient for plant growth. Soil microbes play a crucial role in regulating soil P cycle and availability. P functional genes, further, regulate soil P availability. It is unclear how the addition of N in different chemical forms and rates influences the composition of soil microbes associated with P cycling and the abundance of P functional genes. A long-term experiment of N addition in three chemical forms with two levels in a temperate forest was performed to reveal the influences and the underlying mechanisms. We found that both chemical N forms and N rates selected for different P-solubilizing microbes. Ammonia form-N increased the abundances of P-solubilizing bacteria at low and high rates. Continuous N deposition included a significant decrease in soil pH and inhibited the viability and activity of bacterial communities in soil, especially the P-solubilizing bacteria. Thus, it restricted inorganic P mobilization and led to a decrease in soil available P. In addition, ammonium-N enhanced the relative abundance of most of the functional genes related to organic P mineralization, while nitrate-N presented a decrease trend. Ammonium-N significantly decreased most of the functional genes relevant to P transportation, whereas the other chemical N forms did not change them. Although N-addition consistently decreased the functional genes relevant to inorganic P solubilization, two of them (ppx and ppa) were the exceptions and showed an increase trend. N addition also decreased soil pH and altered soil properties, and indirectly contributed to the changes in community composition of P-solubilizing microbes and the abundances of multiple P functional genes. Our results provide a mechanistic explanation for the regulation of microbes on N-induced available P limitation via tuning the compositions of P-solubilizing microbes and the abundances of multiple P functional genes.

Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia.

Glucose is the basic fuel essential for maintenance of viability and functionality of all cells. However, some neurons - namely, glucose-inhibited (GI) neurons - paradoxically increase their firing activity in low-glucose conditions and decrease that activity in high-glucose conditions. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here, we showed that currents mediated by the anoctamin 4 (Ano4) channel are only detected in GI neurons in the ventromedial hypothalamic nucleus (VMH) and are functionally required for their activation in response to low glucose. Genetic disruption of the Ano4 gene in VMH neurons reduced blood glucose and impaired counterregulatory responses during hypoglycemia in mice. Activation of VMHAno4 neurons increased food intake and blood glucose, while chronic inhibition of VMHAno4 neurons ameliorated hyperglycemia in a type 1 diabetic mouse model. Finally, we showed that VMHAno4 neurons represent a unique orexigenic VMH population and transmit a positive valence, while stimulation of neurons that do not express Ano4 in the VMH (VMHnon-Ano4) suppress feeding and transmit a negative valence. Together, our results indicate that the Ano4 channel and VMHAno4 neurons are potential therapeutic targets for human diseases with abnormal feeding behavior or glucose imbalance.

Asprosin promotes feeding through SK channel-dependent activation of AgRP neurons.

Asprosin, a recently identified adipokine, activates agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARH) via binding to protein tyrosine phosphatase receptor δ (Ptprd) to increase food intake. However, the intracellular mechanisms responsible for asprosin/Ptprd-mediated activation of AgRPARH neurons remain unknown. Here, we demonstrate that the small-conductance calcium-activated potassium (SK) channel is required for the stimulatory effects of asprosin/Ptprd on AgRPARH neurons. Specifically, we found that deficiency or elevation of circulating asprosin increased or decreased the SK current in AgRPARH neurons, respectively. AgRPARH-specific deletion of SK3 (an SK channel subtype highly expressed in AgRPARH neurons) blocked asprosin-induced AgRPARH activation and overeating. Furthermore, pharmacological blockade, genetic knockdown, or knockout of Ptprd abolished asprosin's effects on the SK current and AgRPARH neuronal activity. Therefore, our results demonstrated an essential asprosin-Ptprd-SK3 mechanism in asprosin-induced AgRPARH activation and hyperphagia, which is a potential therapeutic target for the treatment of obesity.

Tubiechong patching promotes tibia fracture healing in rats by regulating angiogenesis through the VEGF/ERK1/2 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The external use of traditional Chinese medicine (TCM) to treat fractures has a long history of clinical application and theoretical basis, and is also one of the characteristic treatment methods of TCM with significant efficacy and many advantages. Among the commonly used external Chinese medicines, Tubiechong is noteworthy. AIM OF THE STUDY: To elucidate whether local patching of Tubiechong can promote fracture healing and explore its mechanism of action. MATERIALS AND METHODS: A rat tibia fracture model was constructed by the modified Einhorn modeling method. X-ray films were taken to evaluate the progress of fracture healing. Serum bone alkaline phosphatase (BALP), osteocalcin (BGP) and the C-terminal content of collagen type I (CTX-I) were analyzed by ELISA. CD31 immunohistochemistry was used to evaluate angiogenesis in the tibia segment. The effects of Tubiechong decoction (TD) on HUVEC proliferation, migration and invasion were detected by MTT assay, wound healing assay and Transwell migration assay, respectively. RNA-seq was performed to identify differentially expressed genes (DEGs). Enrichment of functions and signaling pathway analysis were performed based on the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Quantitative real time polymerase chain reaction (qRT-PCR) was used to study gene expression levels. Western blotting (WB) was used to detect the expression of relevant regulatory proteins. RESULTS: The healing time of rat tibia fractures in the three TD dose groups was shortened. The serum levels of BALP, BGP and CTX- I in the TD-treated group were higher than those in the NC group. The X-ray results showed that on the 7th day after surgery, the fracture healing degree of the high-dose TD group was significantly better than that of the NC group, and the fracture healing degrees of each TD treatment group were significantly higher than those of the NC group on the 14th, 17th, and 21st days after the operation. The CD31 immunohistochemistry results showed that the number of blood vessels and the vascular area in the TD treatment group were higher than those in the NC group. In vitro, TD promoted the proliferation, wound healing and migration of HUVECs. GO analysis of transcriptome sequencing results showed that TD significantly altered the expression of genes related to cell growth, metabolism, and motility. According to KEGG annotations, VEGFA was upregulated. Eight DEGs were enriched in the VEGFA-VEGFR2 signaling pathway, of which six were upregulated. KEGG signaling pathway analysis showed that the most abundant DEGs were in mitogen-activated protein kinase (MAPK) signaling pathway. qRT-PCR showed that VEGFA gene expression in HUVECs was 7.8 times that of the control group after 1 mg/mL TD treatment for 24 h, and WB experiments showed that its protein expression was 3 times that of the control group. WB results showed that the phosphorylated ERK gene was highly expressed, while the expression levels of phosphorylated P38 and phosphorylated JNK protein remained unchanged. CONCLUSION: Tubechong patching therapy promotes tibia fracture healing in rats by regulating angiogenesis through the VEGF/ERK1/2 signaling pathway.

Tubiechong：A review on ethnomedicinal uses, bioactive chemical constituents and pharmacological activities.

ETHNOPHARMACOLOGICAL RELEVANCE: Tubiechong comprises mainly Eupolyphaga and Steleophaga is widely distributed in China. It has been used in the traditional medicine systems in Asian countries specially in China，Japan and Singapore for thousand years. AIM OF THE REVIEW: The aim of this work is to review the scientific work about Tubiechong regarding their ethnomedicinal uses, bioactive chemical constituents and pharmacological activities. MATERIALS AND METHODS: Relevant literature of Tubiechong was collected for its traditional uses, pharmacological activities, and bioactive compounds released from inception until May 2022. The online databases such as Web of Science, PubMed, Google Scholar, Science Direct, Scopus, SciFinder Scholar, Springer Link, China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP database were used as electronic search engines for articles with the various specific keywords. Additionally, references from ancient texts and local information such as PhD and MSc theses, books, and Chinese journals were also included. RESULTS: The clinical researches have revealed that Tubiechong alone has been successfully used to treat bone disease, ache, sprain, herpes zoster, paronychia and so on. Tubichong's main clinical application is to form formulations with other herbs. The most widely used 34 kinds of Chinese patent medicine containing Tubiechong were included in Chinese Pharmacopoeia (2020 Edition) for the treatment of traumatic injury, low back pain, cardiovascular disease, tumors or mass and nodule, cervical spondylopathy, osteoarthritis and psoriasis. Its other derived formulas have been used in the clinical treatment of various diseases, such as blood stasis, hepatic cirrhosis, cyclomastopathy, chronic active hepatitis, nephropathy, gynaecopathia, cancer diseases. To date, the bioactive substances reported are limited to protein and peptides, fatty acids, polysaccharides and alkaloids from Eupolyphaga sinensis Walker. So far, the pharmacological activities of Tubiechong and its various extracts have been evaluated, including anticoagulant and antithrombotic, anticancer, bone repair, immunomodulation, analgesia, antioxidant, antihyperlipidemic, antimicrobial and protective and repair functions for damage to the liver, heart, brain and skin. As an edible insect, its safety has also been confirmed by acute toxicity tests and 30-day feeding trials. CONCLUSION: Tubiechong is an important insect medicine with the effect of promoting blood circulation and removing blood stasis, which has been used in traditional Chinese medicine for thousands of years for the treatment of trauma and abdominal lumps, and has now been clinically extended to the treatment of a variety of diseases. Its multiple pharmacological activities indicate that it has great potential for development and application. However, its chemical constituents with pharmacological activity require further excavation and detailed study. In addition, the in-depth molecular pharmacological mechanisms deserve further explanation.

Protective Effect of Anwulignan on Gastric Injury Induced by Indomethacin in Mice.

Anwulignan (AN) is a monomer lignan from Schisandra sphenanthera Rehd. et Wits (Schisandra sphenanthera fructus, Schisandra sphenanthera). The protective effect of AN against the indomethacin (IND)-induced gastric injury to mice and the related mechanism of action was investigated in this study. The effect of AN was mainly assessed by observing the gastric tissue morphology, gastric ulcer index (GUI), ulcer inhibition rate (UIR), gastric juice volume (GJV) and pH value. Chemical colorimetry, immunofluorescence, ELISA, and Western blot were used to detect related factors in the gastric tissue. The results showed that AN reduced the GUI, increased the UIR, inhibited the GJV, and increased the gastric pH value. AN significantly increased cyclooxygenase-1, cyclooxygenase-2, and prostaglandin E2 expression levels in the gastric tissue, activated nuclear factor (erythroid-derived 2)-like 2 (Nrf2), increased heme oxygenase-1 expression, enhanced the activity of superoxide dismutase and glutathione peroxidase, and decreased the malondialdehyde content. AN reduced the phosphorylation of nuclear factor-κ gene binding (NF-κB) p65 and its nuclear translocation, the key protein of NF-κB signaling pathway in the gastric tissue, and the content of the pathway downstream signaling molecules, including interleukin-6, interleukin-1ß, and tumor necrosis factor-α, to play an anti-inflammatory role. AN inhibited the downstream signals B-cell lymphoma 2-associated x protein and cleaved caspase-3 in gastric tissue, and activated B-cell lymphoma 2, to play an antiapoptotic role, which were further verified by Hoechst staining. Therefore, AN has a significant protection against the gastric injury induced by IND in mice, and the mechanism may be concerned in its activation of Nrf2, inhibition of NF-κB signaling pathway, and anti-apoptotic effect. SIGNIFICANCE STATEMENT: Anwulignan (AN) significantly reduced the indomethacin-induced gastric injury in mice, and its antioxidation, anti-inflammation, and antiapoptosis were considered to be involve in the effect, suggesting that AN should be a potential drug or food supplement for gastric injury induced by indomethacin.

Prevention of Deep Vein Thrombosis by Panax Notoginseng Saponins Combined with Low-Molecular-Weight Heparin in Surgical Patients.

OBJECTIVE: To evaluate the efficacy of deep vein thrombosis (DVT) prevention among real-world surgical inpatients who received panax notoginseng saponins (PNS) combined with low-molecular-weight heparin (LMWH). METHODS: A prospective cohort study was conducted among surgical patients between January 2016 and November 2018 in Xuanwu Hospital, Capital Medical University, Beijing, China. Participants received LMWH alone or PNS combined with LMWH for preventing DVT. The primary outcome was incidence of lower extremity DVT, which was screened once a week. Participants in the LMWH group were given LMWH (enoxaparin) via hypodermic injection, 4000-8000 AxalU once daily. Participants in the exposure group received PNS (Xuesaitong oral tablets, 100 mg, 3 times daily) combined with LMWH given the same as LMWH group. RESULTS: Of the 325 patients screened for the study, 281 participants were included in the final analysis. The cohort was divided into PNS + LMWH group and LMWH group with 134 and 147 participants, respectively. There was a significant difference of DVT incidence between two groups (P=0.01), with 21 (15.7%) incident DVT in the PNS + LMWH group, and 41 (27.9%) incident DVT in the LMWH group. Compared with participants without DVT, the participants diagnosed with DVT were older and had higher D-dimer level. The multivariate logistic regression model showed a significant lower risk of incident DVT among participants in the PNS + LMWH group compared with the LMWH group (odds ratio 0.46, 95% confidence interval, 0.25-0.86). There were no significant differences in thromboelaslography values (including R, K, Angle, and MA) and differences in severe bleeding between two groups. No symptomatic pulmonary embolism occurred during the study. CONCLUSION: Combined application of PNS and LMWH can effectively reduce the incidence of DVT among surgical inpatients compared with LMWH monotherapy, without increased risk of bleeding.

Pharmacokinetics and Main Metabolites of Anwulignan in Mice.

Anwulignan is a representative component of Chinese traditional medicine Schisandra sphenanthera, with strong pharmacological activities. However, there are few reports on its pharmacokinetics and metabolites in the body. In this study, a metabolomic method based on UHPLC-Q-Orbitrap-MS was used to study the pharmacokinetics of anwulignan in the blood, organs, urine, and feces samples of mice after the intragastric administration of anwulignan (10 mg/kg). The pharmacokinetic parameters were calculated, and the distribution characteristics and main metabolites of anwulignan in the body of mice were analyzed. The results showed that the retention time of anwulignan in the body of mice was longer (t 1/2 = 7.1 h), and anwulignan was widely distributed in the body (Vz/F = 32.81 L/kg), especially in the liver. The order of anwulignan concentration in the tissues of mice from high to low was the liver > heart > brain > kidney > lung > spleen. Anwulignan was mainly excreted through the digestive tract in the form of its prototype and metabolites, indicating that it might experience an enterohepatic circulation. A total of seven metabolites were identified, and the demethylation, hydroxylation, dehydroxylation, and demethoxylation were considered to be the main metabolic ways of anwulignan in the body of mice.

Impact of insufficient doses of medications on Helicobacter pylori eradication: a retrospective observational study.

BACKGROUND AND AIMS: The doses of medications may influence the success of Helicobacter pylori (H. pylori) eradication. This real-world observational study aimed to explore the impact of insufficient doses of medications prescribed for the bismuth-containing quadruple therapy (BQT) regimen on successful H. pylori eradication. METHODS: We retrospectively screened the patients who were diagnosed with H. pylori infection and received BQT regimens for H. pylori eradication at our department between January 2017 and July 2020. The rate of successful H. pylori eradication was compared according to the doses of medications prescribed. Standard doses were defined according to the clinical guidelines. RESULTS: Overall, 1054 patients were included. The rate of successful H. pylori eradication was 78.2% (824/1054). Among them, proton pump inhibitors (PPIs) and antibiotics were prescribed at insufficient doses in 37.0% (390/1054) and 6.7% (71/1054) of patients, respectively. Furthermore, pantoprazole (98.7% [385/390]) was the most common type of PPIs prescribed at insufficient doses, and nitroimidazoles (85.9% [61/71]) were the most common type of antibiotics prescribed at insufficient doses. Among the patients receiving colloidal bismuth pectin (CBP) (200 mg tid) and standard-dose antibiotics, the rate of successful H. pylori eradication was lower in insufficient-dose PPIs group than standard-dose PPIs group (78.1% [271/347] versus 82.6% [438/530], P = 0.095). Among the patients receiving CBP (200 mg tid) and standard-dose PPIs, the rate of successful H. pylori eradication was significantly lower in insufficient-dose antibiotics group than standard-dose antibiotics group (37.8% [14/37] versus 82.6% [438/530], P < 0.0001). Among the patients receiving CBP 200 mg tid, the rate of successful H. pylori eradication was significantly lower in patients receiving both PPIs and antibiotics at insufficient doses than those at standard doses (46.4% [13/28] versus 82.6% [438/530], P < 0.0001). CONCLUSION: Among the BQT regimens, PPIs and/or antibiotics, especially pantoprazole and metronidazole, are often prescribed at insufficient doses, compromising the success of H. pylori eradication. ABBREVIATIONS: H. pylori, Helicobacter pylori; UBT, urea breath test; DPM, disintegrations per minute; BQT, bismuth-containing quadruple therapy; PPI, proton pump inhibitor; CBP, colloidal bismuth pectin; qd, once daily; bid, twice daily; tid, three times daily; qid, four times daily.

Hypothalamic steroid receptor coactivator-2 regulates adaptations to fasting and overnutrition.

The neuroendocrine system coordinates metabolic and behavioral adaptations to fasting, including reducing energy expenditure, promoting counterregulation, and suppressing satiation and anxiety to engage refeeding. Here, we show that steroid receptor coactivator-2 (SRC-2) in pro-opiomelanocortin (POMC) neurons is a key regulator of all these responses to fasting. POMC-specific deletion of SRC-2 enhances the basal excitability of POMC neurons; mutant mice fail to efficiently suppress energy expenditure during food deprivation. SRC-2 deficiency blunts electric responses of POMC neurons to glucose fluctuations, causing impaired counterregulation. When food becomes available, these mutant mice show insufficient refeeding associated with enhanced satiation and discoordination of anxiety and food-seeking behavior. SRC-2 coactivates Forkhead box protein O1 (FoxO1) to suppress POMC gene expression. POMC-specific deletion of SRC-2 protects mice from weight gain induced by an obesogenic diet feeding and/or FoxO1 overexpression. Collectively, we identify SRC-2 as a key molecule that coordinates multifaceted adaptive responses to food shortage.

Study on the effect of active components of Schisandra chinensis on liver injury and its mechanisms in mice based on network pharmacology.

The aim of this study was to analyze the active components of Schisandra chinensis on liver injury and its mechanism in mice by network pharmacology. The active components of S. chinensis were found through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and their corresponding targets were predicted. The targets of liver injury were searched through Therapeutic Targets Database (TTD), DisGeNET and drugbank databases, and the Venn diagram was constructed to obtain the action targets. The "drug-active component-target" network and protein-protein interaction network (PPI) were constructed by using STRING database and Cytoscape software, and the key targets were further screened by the enrichment analysis of relevant KEGG pathways. Finally, a CCl4-induced mouse liver injury model was established to verify the efficacy and related targets of S. chinensis and clarify its mechanism. Eight active components and 56 related targets of S. chinensis were screened out based on their oral bioavailability (OB) and drug likeness (DL). Five targets of S. chinensis related to liver injury were found by using the Venn diagram. The key targets, namely Ptgs2 and Nos2 genes, were further screened out by constructing a PPI network, and Schisandrol B (SCB) was considered the key component most closely related to the liver injury in S. chinensis. The results indicate that SCB may play a role in the treatment of the CCl4-induced liver injury by down-regulating the expression of iNOS and COX-2, and regulating the expression of NF-κB and IL-17 signaling pathway to inhibit the expression of proinflammatory factors.

Anwulignan alleviates d-galactose induced renal damage by regulating Nrf2/ARE signaling pathway in mice.

Free radical accumulation in the body will cause oxidative stress damages including the renal damage. Schisandrae Sphenantherae Fructus (Schisandra), a traditional Chinese herbal medicine, has been used throughout the world. Anwulignan, a monomer extracted from Schisandra, has been shown in our previous studies to possess antioxidant and protective effects on the liver, brain and spleen damages in the aging mice. However, its effect on the renal damage caused by aging is not clear. This study showed that anwulignan could significantly increase the kidney index, the creatinine clearance, the activities of superoxide dismutase, catalase and glutathione peroxidase; reduce the urinary protein concentration, the serum urea nitrogen and creatinine content, the content of malondialdehyde and 8-hydroxylated deoxyguanosine in the renal tissue; and improve the renal tissue damage. Moreover, anwulignan increased the production of Nrf2, HO-1 and NQO1 proteins and decreased the production level of Keap1 protein in the renal tissue in the d-galactose induced aging mice. These results suggest that anwulignan significantly alleviates the renal damage by its antioxidant effect through regulating the production of Nrf2/ARE pathway-related proteins in the renal tissue in the d-galactose induced aging mice. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10068-021-00951-7.

Protective Effects of Anwulignan against HCl/Ethanol-Induced Acute Gastric Ulcer in Mice.

Gastric ulcer is one of the most common gastrointestinal diseases. Anwulignan (AN) is a major active component of Schisandra sphenanthera Rehd. This study was designed to evaluate the protective effect of AN against the acute gastric ulcer induced by HCl/ethanol in mice. The mice were given HCl/ethanol by gavage to establish an acute gastric ulcer model. Then, the serum and gastric tissue samples were taken for biochemical analyses. The results showed that the pretreatment with AN could significantly reduce the gastric ulcer index (GUI) and increase the ulcer inhibition rate, indicating that AN can protect against gastric ulcers. AN showed its antioxidant roles by decreasing the content of reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxydeoxyguanosine (8-OHdG) and increasing the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) and anti-inflammatory roles by decreasing the content of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and myeloperoxidase (MPO) and increasing the content of interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-10 (IL-10), prostaglandin E2 (PGE2), and nitric oxide (NO) in both serum and gastric tissue. Furthermore, AN also activated the NRF2/ARE signaling pathway and inhibited the MAPK/NF-κB signaling pathway. AN improves the acute gastric ulcer induced by HCl/ethanol in mice, which may be mainly through its antioxidant capacity and anti-inflammatory effect.

Relaxation Effect of Schisandra Chinensis Lignans on the Isolated Tracheal Smooth Muscle in Rats and Its Mechanism.

Schisandra chinensis (S. chinensis) is one of the core drugs used for relieving cough and asthma in traditional Chinese medicine. However, there are few basic studies on the treatment of respiratory diseases with S. chinensis in modern pharmacology, and the material basis and mechanism of its antiasthmatic effect are still unclear. Lignans are the main active components of S. chinensis. The aim of this study was to observe the relaxation effect of S. chinensis lignans (SCL) on the tracheal smooth muscle of rats by in vitro tracheal perfusion experiments, and to explore the mechanism by preincubation with L-type calcium channel blocker verapamil, four potassium channel blockers glibenclamide, tetraethylamine, 4-aminopyridine and barium chloride (BaCl2), ß-adrenoceptor blocker propranolol, nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME), and the cyclooxygenase inhibitor indomethacin, respectively. The results showed that SCL (0.25-1.75 mg/mL) reduced the contraction of isolated tracheal smooth muscle induced by acetylcholine, the preincubation with verapamil and glibenclamide could attenuate the relaxation effect, whereas propranolol, 4-aminopyridine, BaCl2, tetraethylamine, L-NAME, and indomethacin had no such effect. These results suggest that SCL has a significant relaxation effect on the isolated tracheal smooth muscle of rats, and the mechanism may be related to the inhibition of extracellular calcium influx and intracellular calcium release from the sarcoplasmic reticulum, as well as the activation of ATP-sensitive potassium channels. These findings may provide a pharmacological basis for the traditional use of S. chinensis to treat asthma.

Schisantherin A ameliorates liver fibrosis through TGF-ß1mediated activation of TAK1/MAPK and NF-κB pathways in vitro and in vivo.

BACKGROUD: Schisandra chinensis, a traditional Chinese medicine for liver protection, can significantly improve liver fibrosis. However, it is still unclear which active components in Schisandra chinensis play an anti-fibrosis role. PURPOSE: The purpose of present study was to observe the anti-fibrosis effect of schisantherin A (SCA) on liver fibrosis and explore its underlying mechanism. METHODS: The liver fibrosis model of mice was constructed by the progressive intraperitoneal injection of thioacetamide (TAA), and SCA (1, 2, and 4 mg/kg) was administered by gavage for 5 weeks. The biochemical indicators and inflammatory cytokines were measured, changes in the pathology of the mice liver were observed by hematoxylin & eosin (H&E) and Masson stainings for studying the anti-fibrosis effect of SCA. A hepatic stellate cell (HSCs) activation model induced by transforming growth factor-ß1 (TGF-ß1) was established, and the effect of SCA on the HSCs proliferation was observed by MTT assay. The expressions of target proteins related to transforming growth factor-ß-activated kinase 1 (TAK1)/mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways were evaluated by western blotting, immunohistochemistry or immunofluorescence analysis, to explore the potential mechanism of SCA. RESULTS: SCA could significantly ameliorate the pathological changes of liver tissue induced by TAA, and reduce the serum transaminase level, the hydroxyproline level and the expression of α-smooth muscle actin (α-SMA) and collagen 1A1 (COL1A1) proteins in the liver tissue. SCA could significantly lower the levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in the serum and liver tissue, and down-regulate the expression of target proteins related to TAK1/MAPK and NF-κB pathways in the liver tissue. The in vitro studies demonstrated that SCA significantly inhibited the proliferation and activation of HCS-T6 cells induced by TGF-ß1, decreased TNF-α and IL-6 levels, and inhibited the TAK1 activation induced by TGF-ß1 and then the expression of MAPK and NF-κB signaling pathway-related proteins. CONCLUSION: Together, SCA can ameliorate the liver fibrosis induced by TAA and the HSC-T6 cell activation induced by TGF-ß1 in mice, and its mechanism may be to inhibit the HSCs activation and inflammatory response by inhibiting TGF-ß1 mediated TAK1/MAPK and signal pathways.

Sorafenib plus partial splenic embolism for treatment of hepatocellular carcinoma Barcelona stage C combined with hypersplenism: a case series.

BACKGROUND: Sorafenib is mainly used to treat patients with hepatocellular carcinoma (HCC) Barcelona Clinic Liver Cancer (BCLC) stage C, many of whom also have severe cirrhosis. However, hypersplenism and digestive tract hemorrhage are common complications of cirrhosis, which increase the risk and difficulty of treatment. METHODS: Nineteen patients with HCC BCLC stage C with hypersplenism were treated with sorafenib plus partial splenic embolism at Chongqing University Cancer Hospital, Chongqing, China, between January 2015 and June 2018. We analyzed the therapeutic effect and clinical safety of this treatment in these patients. RESULT: Hypersplenism was rectified in all patients. The incidence rates of hemorrhage and myelosuppression were 0%, and the mean survival time was 11.2 months. CONCLUSION: Sorafenib plus partial splenic embolism could relieve hypersplenism and prolong survival in patients with BCLC stage C HCC.