The protective effect and mechanism of glycosides of cistanche deserticola on rats in middle cerebral artery occlusion (MCAO) model.

Cerebral ischemia-reperfusion injury (CIRI) occurs frequently clinically as a complication following cardiovascular resuscitation resulting in neuronal damage specifically to the hippocampal CA1 region with consequent cognitive impairment. Apoptosis and oxidative stress were proposed as major risk factors associated with CIRI development. Previously, glycosides obtained from Cistanche deserticola (CGs) were shown to play a key role in counteracting CIRI; however, the underlying mechanisms remain to be determined. This study aimed to investigate the neuroprotective effect of CGs on subsequent CIRI in rats. The model of CIRI was established for 2 hr and reperfusion for 24 hr by middle cerebral artery occlusion (MCAO) model. The MCAO rats were used to measure the antioxidant and anti-apoptotic effects of CGs on CIRI. Neurological function was evaluated by the Longa neurological function score test. 2,3,5-Triphenyltetrazolium chloride (TTC) staining was used to detect the area of cerebral infarction. Nissl staining was employed to observe neuronal morphology. TUNEL staining was used to detect neuronal apoptosis, while Western blot determined protein expression levels of factors for apoptosis-related and PI3K/AKT/Nrf2 signaling pathway. Data demonstrated that CGs treatment improved behavioral performance, brain injury, and enhanced antioxidant and anti-apoptosis in CIRI rats. In addition, CGs induced activation of PI3K/AKT/Nrf2 signaling pathway accompanied by inhibition of the expression of apoptosis-related factors. Evidence indicates that CGs amelioration of CIRI involves activation of the PI3K/AKT/Nrf2 signaling pathway associated with increased cellular viability suggesting these glycosides may be considered as an alternative compound for CIRI treatment.

[Role of mitochondrial autophagy and the curative effect of rehmannia glutinosa leaves total glycoside capsules on nucleos(t)ide drug-induced renal injury].

Objective: To study the curative effect of rehmannia glutinosa leaves total glycoside capsules and the role of mitochondrial autophagy on nucleos(t)ide drug-induced renal injury. Methods: Adefovir dipivoxil (ADV) was used to construct a hepatitis B virus (HBV) transgenic mouse model for renal injury. Renal function was measured in each group at one and two weeks of modeling. Mitochondrial autophagy indicators were measured at two weeks of modeling in renal tissue. Transmission electron microscopy was used to detect mitochondrial autophagy phenomena in renal tissue. The model was established for two weeks. Mouse with renal injury were treated with rehmannia glutinosa leaves total glycoside capsules or isotonic saline for eight weeks by intragastric administration. Renal function was measured. Renal tissue morphology was observed. Mitochondrial autophagy indicators were detected in renal tissue. The protective effect of different concentrations of verbascoside (the main active ingredient of rehmannia glutinosa capsule) was observed on HK-2 cell damage induced by ADV. HK-2 cells were divided into control, ADV, and ADV plus verbascoside groups. The effects of verbascoside at different times and concentrations were observed on the HK-2 mitochondrial autophagy indicators. Fifty patients with chronic hepatitis B were collected who presented with renal injury after treatment with nucleos(t)ide analogs. The random number method was used to divide 29 cases into a control group that received conventional treatment. The treatment group of 21 cases was treated with rehmannia glutinosa leaves total glycoside capsules on the basis of the control group. Serum creatinine (Scr) and urinary protein were detected at eight weeks.The χ(2) test or t-test was used for statistical analysis. Results: Compared with the control group, two weeks of modeling in the ADV group induced renal function injury in HBV mice. The expression of autophagy indicators was higher in the renal tissue of the ADV group than that of the control group. Transmission electron microscopy had revealed mitochondrial autophagy in the renal tissue of the ADV group. Compared with the control group, the renal function of HBV mice treated with rehmannia glutinosa leaves total glycoside capsules improved for two months, and the expressions of autophagy indicators were down-regulated.Verbascoside promoted proliferation in ADV-damaged HK-2 cells, and the expression of autophagy indicators was down-regulated compared with the ADV alone group. In 50 patients with renal function injury, the urinary protein improvement was significantly superior in the treatment group than that in the control group, with eighteen and three cases being effective and ineffective in the treatment group and 12 and 17 cases being effective and ineffective in the control group, with a statistically significant difference (χ(2) = 9.975 0, P = 0.001 6). Serum creatinine was decreased in the treatment group compared with the control group, with 11 and 10 cases being effective and ineffective in the treatment group and 12 and 17 cases being effective and ineffective in the control group, with no statistically significant difference (χ(2) = 0.593 5, P = 0.441 1). Conclusion: Rehmannia glutinosa leaves total glycoside capsule can improve the nucleos(t)ide drug-induced renal function injury in chronic hepatitis B, possibly playing a role via inhibiting PINK1/Parkin-mediated mitochondrial autophagy.

The chemometrics analysis and integrated pharmacology approach to decipher the effect and mechanism between raw and processed cistanche tubulosa.

ETHNOPHARMACOLOGICAL RELEVANCE: Cistanche tubulosa (CT) is the dried fleshy stem with scaly leaves of Cistanche tubiflora (Schenk) Wight, which has the effects of tonifying the kidney-yang, benefiting the vital essence and blood, and moisturizing the intestines and laxatives. There are differences in the activity of CT before and after processing, but the mechanism of processing is not clear. AIM OF THE STUDY: The study aimed to compare the strength of action of CT before and after yellow-wine processing in the treatment of constipation and kidney yang deficiency and to identify the active ingredients responsible for the differences in activity before and after yellow-wine processing. MATERIALS AND METHODS: This study established the fingerprints of CT and PCT using HPLC to identify their shared components. Then efficacy of KYDS and FC were carried out to compare the differences between CT and PCT in terms of efficacy. Next, this study established the spectrum-effect relationship between the shared chemical components and the medical effects of CT and PCT using the gray correlation analysis and entropy methods. Ultimately, the activity of the analyzed chemical components was verified using the zebrafish model. RESULTS: CT was more effective than PCT in promoting intestinal peristalsis, regulating gastrointestinal hormone levels, and thus treating FC. PCT was more effective than CT in improving the level of hormone indexes of the hypothalamus-pituitary-target gland axis, replenishing blood, and enhancing immunity. Through the analysis of the spectrum-effect relationship, it was finally found that 5, 6, 12 (tubuloside A), and 13 (isoacteoside) might be more closely related to the activity of tonifying kidney yang, and peaks 9, 10, and 11 (acteoside) are more closely associated with the treatment of constipation, and peaks 3 (salidroside), 4, 1, 2 (geniposidic acid), and 8 (echinacoside) were associated with both kidney yang tonic and treatment of constipation. At the same time, an activity verification experiment showed that echinacoside, geniposidic acid, and salidroside were effective in the treatment of FC and KYDS, while acteoside was very effective in the treatment of FC, and tubuloside A was significant in supplementing the blood, which validated the spectrum-effect relationship analysis. CONCLUSION: This study proved that the raw CT had a better laxative effect, while the yellow-wine processed CT had a better kidney-yang tonic effect; moreover, spectrum-effect relationships were established to analyze the chemical components leading to changes in the activity of CT before and after yellow-wine processing.

Therapeutic potential of CB1R activation by Qingyangshen glycoside M1 for seizure relief.

ETHNOPHARMACOLOGICAL RELEVANCE: Cynanchum otophyllum C.K.Schneid.PI.Wilson, commonly referred as ''Qingyangshen'' (QYS), is a traditional folk medicine from Yunnan, renowned for its efficacy in neurological and psychiatric disorders. Glycosides isolated from QYS have shown promise in alleviating epilepsy, however, mechanisms of action and specific molecular targets remain to be elucidated. AIM OF THE STUDY: The study aimed to evaluate the anticonvulsant effects of Qingyangshen glycosides M1 (M1), a C21 steroidal glycoside from QYS, on pentylenetetrazol (PTZ)-induced convulsions in zebrafish (Danio rerio), and its neuroprotective effect on Glutamate (Glu)-induced damage to PC12 cells, and importantly to identify its potential molecular targets. MATERIALS AND METHODS: To evaluate anticonvulsant activity of M1, 7 days-post-fertilization (7-dpf) animals were pretreated (by immersion) and then exposed to PTZ (10 mM) solution. Furthermore, Glu-induced PC12 cell damage was employed to investigate the neuroprotective and anti-apoptotic capacity. Cells were pretreated with various concentrations of M1 (0-10 µM) for 12 h and then co-treated with Glu (15 mM) for an additional 24 h. The cell viability, apoptosis rate and apoptosis-related proteins (p-PI3K, PI3K, Akt, p-Akt, CREB, p-CREB, BDNF, Bax and Bcl-2) were measured using CCK-8, annexin V/PI and Western blot assays. To model the expected interaction between M1 and candidate cannabinoid receptor type 1 (CB1R), ERK phosphorylation, molecular docking, and drug affinity responsive target stability (DARTS) techniques were employed. Finally, CB1R antagonist Rimonabant (Rim) was validated by co-administration in both zebrafish and cells to confirm the requirement of CB1R for M1 efficacy. RESULTS: At a concentration of 400 µM, M1 dramatically reversed PTZ-induced convulsive-like behaviors in zebrafish, as evidenced by a significant reduction in locomotor activity. In the context of Glu-induced cytotoxicity, M1 (10 µM) demonstrated a notable increase in cell viability and suppressed apoptosis through modulation of the Bax/Bcl-2 ratio and activation of the PI3K/Akt/CREB/BDNF signaling axis. These effects were facilitated through CB1R activation. In contrast, Rim dampened the beneficial activities of M1 as a cannabinoid agonist. CONCLUSIONS: These results demonstrated that M1 as a potential CB1R activator, exhibiting anticonvulsive effects in a PTZ-induced zebrafish model and neuroprotective properties via the PI3K/Akt/CREB/BDNF signaling axis in a Glu-induced PC12 cell injury model. Notably, the observed seizure relief attenuated by CB1R chemical antagonism.

Sotagliflozin and Kidney Outcomes, Kidney Function, and Albuminuria in Type 2 Diabetes and CKD: A Secondary Analysis of the SCORED Trial.

BACKGROUND: In the initial analysis of the Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial, because of early trial termination and suspension of adjudication, reconciliation of eGFR laboratory data and case report forms had not been completed. This resulted in a small number of kidney composite events and a nominal effect of sotagliflozin versus placebo on this outcome. This exploratory analysis uses laboratory eGFR data, regardless of case report form completion, to assess the effects of sotagliflozin on the predefined kidney composite end point in the SCORED trial and additional cardiorenal composite end points. METHODS: SCORED was a multicenter, randomized trial evaluating cardiorenal outcomes with sotagliflozin versus placebo in 10,584 patients with type 2 diabetes and CKD. This exploratory analysis used laboratory data to derive the eGFR components and case report form data for the non-laboratory-defined components that together made up the kidney and cardiorenal composites. AKI was also assessed in this dataset. RESULTS: Using laboratory data, 223 events were identified, and sotagliflozin reduced the risk of the composite of first event of sustained ≥50% decline in eGFR, eGFR <15 ml/min per 1.73 m 2 , dialysis, or kidney transplant with 87 events (1.6%) in the sotagliflozin group and 136 events (2.6%) in the placebo group (hazard ratio [95% confidence interval], 0.62 [0.48 to 0.82]), P < 0.001). Sotagliflozin reduced the risk of a cardiorenal composite end point defined as the abovementioned composite plus cardiovascular or kidney death with 239 events (4.5%) in the sotagliflozin group and 306 events (5.7%) in the placebo group (hazard ratio [95% confidence interval], 0.77 [0.65 to 0.91], P = 0.0023). The results were consistent when using different eGFR decline thresholds and when only including kidney death in composites (all P < 0.01). The incidence of AKI was similar between treatment groups. CONCLUSIONS: In this exploratory analysis using the complete laboratory dataset, sotagliflozin reduced the risk of kidney and cardiorenal composite end points in patients with type 2 diabetes and CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT03315143 .

The Lnc-ENST00000602558/IGF1 axis as a predictor of response to treatment with tripterygium glycosides in rheumatoid arthritis patients.

AIMS: Growing clinical evidence suggests that not all patients with rheumatoid arthritis (RA) benefit to the same extent by treatment with tripterygium glycoside (TG), which highlights the need to identify RA-related genes that can be used to predict drug responses. In addition, single genes as markers of RA are not sufficiently accurate for use as predictors. Therefore, there is a need to identify paired expression genes that can serve as biomarkers for predicting the therapeutic effects of TG tablets in RA. METHODS: A total of 17 pairs of co-expressed genes were identified as candidates for predicting an RA patient's response to TG therapy, and genes involved in the Lnc-ENST00000602558/GF1 axis were selected for that purpose. A partial-least-squares (PLS)-based model was constructed based on the expression levels of Lnc-ENST00000602558/IGF1 in peripheral blood. The model showed high efficiency for predicting an RA patient's response to TG tablets. RESULTS: Our data confirmed that genes co-expressed in the Lnc-ENST00000602558/IGF1 axis mediate the efficacy of TG in RA treatment, reduce tumor necrosis factor-α induced IGF1 expression, and decrease the inflammatory response of MH7a cells. CONCLUSION: We found that genes expressed in the Lnc-ENST00000602558/IGF1 axis may be useful for identifying RA patients who will not respond to TG treatment. Our findings provide a rationale for the individualized treatment of RA in clinical settings.

Review of molecular biological research on the treatment of membranous nephropathy with Tripterygium glycosides based on TCM theory.

To explore the mechanism of Tripterygium wilfordii polyglycoside (TWP) in the treatment of membranous nephropathy (MN) by network pharmacology. TCMSP and DrugBank databases were used to screen the main targets of the main active components of Tripterygium glycosides, and OMIM and Gene Cards databases were used to search the gene targets of MN. UniProt database was used to normalize all the targets to get the intersection targets of TGs and MNs. Synergistic genes were uploaded to the STRING platform to construct a protein-protein interaction network and screen related core targets. Gene Ontology and Kyoto Genome Encyclopedia analyses of core targets were performed using the DAVID database. AutoDockTools software was used to verify the molecular docking between the active components of TGs and the synergistic genes. We identified 126 potential targets for the active component of Tripterygium glycosides, 584 MN-associated disease targets, and 28 co-acting genes. It mainly involves AGE-RAGE signaling pathway, lipid and atherosclerosis, IL-17 signaling pathway, fluid shear stress and atherosclerosis, NF-kappa B signaling pathway and other pathways and biological pathways in diabetic complications. The active component of that Tripterygium glycosides and the active site of the synergistic core target can the bond energy is less than -5kJ/mol. Tripterygium glycosides can regulate the release of inflammatory factors to treat MN through multiple active components, multiple disease targets, multiple biological pathways and multiple pathways, which provides a basis for broadening the clinical use of traditional Chinese medicine in the treatment of MN.

Echinacoside: A promising active natural products and pharmacological agents.

Echinacoside, a natural phenylethanoid glycoside, was discovered and isolated from the garden plant Echinacea angustifolia DC., belonging to the Compositae family, approximately sixty years ago. Extensive investigations have revealed that it possesses a wide array of pharmacologically beneficial activities for human health, particularly notable for its neuroprotective and anticancer activity. Several crucial concerns surfaced, encompassing the recognition of active metabolites that exhibited inadequate bioavailability in their prototype form, the establishment of precise molecular signal pathways or targets associated with the aforementioned effects of echinacoside, and the scarcity of dependable clinical trials. Hence, the question remains unanswered as to whether scientific research can effectively utilize this natural compound. To support future studies on this natural product, it is imperative to provide a systematic overview and insights into potential future prospects. The current review provides a comprehensive analysis of the existing knowledge on echinacoside, encompassing its wide distribution, structural diversity and metabolism, diverse therapeutic applications, and improvement of echinacoside bioavailability for its potential utilization.

Tripterygium glycosides sensitizes cisplatin chemotherapeutic potency by modulating gut microbiota in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is a fatal gynecological malignancy with limited therapeutic options. Previous research has demonstrated that Tripterygium glycosides (GTW) can enhance effectiveness of cisplatin (DDP) chemotherapy against EOC. However, the underlying mechanism of GTW alleviating EOC still remains unclear. In this article, an ID8 cell-derived xenograft mouse model was established to evaluate the anti-tumor efficacy of GTW combined with DDP. Consistent with previous findings, the results suggested that GTW combined with DDP can exhibit a stronger tumor suppressive effect than DDP alone. Additionally, GTW was found can further exert gastrointestinal protection against DDP by reducing pathological damage on colon tissue. Secondly, to verify whether gut microbiota play an instrumental role in GTW's anticancer effect, we treated mice models with antibiotic to eliminate gut microbiota. And our experimental results indicated that all drug groups showed a weaker tumor suppressive effect and more severe gastrointestinal damage post antibiotic supplement. At genus level, the relative abundance of Lactobacillus was dramatically diminished by the antibiotic treatment, while combined treatment of GTW and DDP can significantly restore the level. Moreover, we performed Lactobacillus acidophilus transplantation and healthy mice fecal microbiota transplantation experiments to further investigate the link between the anticancer effect of GTW and gut microbiota. Our results suggested that both cisplatin-sensitizing and intestinal barrier-protecting effects of GTW can be recovered to a different extent. In conclusion, our results indicated that GTW is a promising chemosensitization and intestinal barrier repair drug for EOC, and the potential mechanism may corelate with the restoration of the compromised intestinal microbial balance.

The potential effects and mechanism of echinacoside powder in the treatment of Hirschsprung's Disease.

Possible complications, such as intestinal obstruction and inflammation of the intestinal tract, can have a detrimental effect on the prognosis after surgery for Hirschsprung disease. The aim of this study was to investigate the potential targets and mechanisms of action of echinacoside to improve the prognosis of Hirschsprung disease. Genes related to the disease were obtained through analysis of the GSE96854 dataset and four databases: OMIM, DisGeNET, Genecard and NCBI. The targets of echinacoside were obtained from three databases: PharmMapper, Drugbank and TargetNet. The intersection of disease genes and drug targets was validated by molecular docking. The valid docked targets were further explored for their expression by using immunohistochemistry. In this study, enrichment analysis was used to explore the mechanistic pathways involved in the genes. Finally, we identified CA1, CA2, CA9, CA12, DNMT1, RIMS2, RPGRIP1L and ZEB2 as the core targets. Except for ZEB2, which is predominantly expressed in brain tissue, the remaining seven genes show tissue specificity and high expression in the gastrointestinal tract. RIMS2 possesses a high mutation phenomenon in pan-cancer, while a validated ceRNA network of eight genes was constructed. The core genes are involved in several signaling pathways, including the one-carbon metabolic process, carbonate dehydratase activity and others. This study may help us to further understand the pharmacological mechanisms of echinacoside and provide new guidance and ideas to guide the treatment of Hirschsprung disease.

Efficacy of verbascoside, echinacoside, crenatoside on altitude-induced fatigue in rats and possible mechanism.

OBJECTIVE: To study the efficacy and mechanism of three phenylethanoid glycosides (PhGs) (verbascoside, echinacoside, and crenatoside) on altitude-induced fatigue in rats. METHODS: Altitude-induced fatigue model rats were established in a large hypobaric chamber. Swimming time, energy storage substances, metabolic enzymes, and metabolites were used to evaluate the anti-fatigue activities and mechanism of three PhGs (verbascoside, echinacoside, and crenatoside) (150 mg/kg, intragastric administration) in the hypoxic environment. RESULTS: The three PhGs, especially verbascoside, could prolong the swimming time of rats, ameliorate the edema and inflammatory infiltration of liver and skeletal muscle, increase the level of energy storage substances, reduce the decomposition of proteins, and exhibit positive effects on the metabolism-related enzyme activity and metabolites. CONCLUSIONS: The PhGs, especially verbascoside, are very potential with anti-fatigue activity in hypoxia. The mechanism may be explained with regulation of energy metabolism and reduction of oxidative stress.

Enhanced efficacy with reduced toxicity of tripterygium glycoside tablet by compatibility with total glucosides of paeony for rheumatoid arthritis therapy.

BACKGROUND AND AIMS: Drug-induced liver injury remains a critical issue to hinder clinical application of Tripterygium Glycosides Tablets (TGTs) for rheumatoid arthritis (RA) therapy. Combination of TGTs with Total Glucosides of Peony (TGP) may be the most common therapeutic strategy for enhancing TGTs' efficacy and reducing its toxicity. Herein, we aimed to investigate the efficacy-enhancing and toxicity-reducing properties and mechanisms of TGT-TGP combination. METHODS: Both TGT-induced acute and chronic liver injury animal models were established. ELISA, transmission electron microscopy, immunohistochemistry, western blot and quantitative PCR were performed to determine the efficacy, toxicity and regulatory mechanisms of TGT-TGP combination. RESULTS: The compatibility of TGP significantly reduced the abnormal serum ALT and AST levels, and improved liver histopathological changes in both acute and chronic DILI animal models induced by TGTs, with the most effective dosage of TGP-M (medium-dose TGP, 450 mg/kg). Additionally, TGP and TGT synergistically alleviated joint swelling and improved the elevation of serum inflammatory factors, in line with the positive changes in joint histopathological features of collagen induced arthritis mice, with the same effective dosage of TGP-M following 5 weeks' drug combination treatment. Mechanically, TGT significantly increased the number of autophagosomes and the expression of LC3II protein while reducing p62 protein expression in the liver tissues, which were significantly reversed by the compatibility with TGP, similar to the findings based on the inflamed joint tissues. CONCLUSIONS: These findings suggest an enhanced efficacy with reduced toxicity of TGT by the compatibility with TGP for RA therapy, possibly through regulating various autophagy-related proteins.

Comparing four immunosuppressive agents for chronic spontaneous urticaria-A network meta-analysis.

BACKGROUND: Immunosuppression is an integral part of treating chronic spontaneous urticaria (CSU), but there is no literature to evaluate the efficacy of multiple immunosuppressive agents. OBJECTIVE: The comparison of the efficacy, safety, and incidence of adverse effects of four immunosuppressive medicines (tripterygium glycosides, methotrexate, cyclosporine A, and azathioprine) in combination with antihistamines in treating CSU provides a clinical reference and evidence-based medicine for treating CSU. METHODS: PUBMED, The Cochrane Library, EMBASE, WANFANG, CNKI, CBM, and clinical trial registration platform were searched to collect relevant randomized controlled trials (RCT) and cohort studies of four immunosuppressive medicines combined with antihistamines for treating CSU. The primary outcomes were the efficacy of weekly urticaria activity score 7 (UAS7) and adverse effects. RESULTS: This study pooled data from seven randomized clinical trials with 410 participants. The standardized mean differences for change in UAS7 were 0.10 (95% confidence interval (CI), 0.01 to 0.68) for cyclosporine A plus antihistamine; 0.03 (95% CI, 0.00 to 0.23) for azathioprine plus antihistamine; 0.52 (95% CI, 0.32 to 0.85) for tripterygium glycosides plus antihistamine; and 1.54 (95% CI, 0.64 to 3.67) for methotrexate plus antihistamine. There were no significant differences in side effects between these medicines in the limited number of trials and clinical samples. CONCLUSION: Our results indicate that cyclosporine A combined with antihistamine resulted in greater improvements regarding the UAS7 in CSU patients and that tripterygium glycosides are also effective in treating CSU.

Glycosides of Buyang Huanwu decoction inhibits pyroptosis associated with cerebral ischemia-reperfusion through Nrf2-mediated antioxidant signaling pathway both in vivo and in vitro.

BACKGROUND: Glycosides are the pharmacodynamic substances of Buyang Huanwu Decoction (BYHWD) and they exert a protective effect in the brain by inhibiting neuronal pyroptosis of cerebral ischemia-reperfusion (CIR). However, the mechanism by which glycosides regulate neuronal pyroptosis of CIR is still unclear. PURPOSE: A significant part of this study aimed to demonstrate whether glycosides have an anti-pyroptotic effect on CIR by nuclear factor erythroid 2-related factor (Nrf2)-mediated antioxidative mechanism. METHODS: Rats were used in vivo models of middle cerebral artery occlusion and reperfusion (MCAO/R). Neuroprotective effect of glycosides after Nrf2 inhibiting was observed by nerve function score, Nissl staining, Nrf2 fluorescence staining and pyroptotic proteins detection. SH-SY5Y cells were used in vitro models of oxygen-glucose deprivation/reperfusion (OGD/R). Glycosides was evaluated for their effects by measuring cell morphology, survival rate, lactate dehydrogenase (LDH) rate and expression of pyroptotic proteins. Nrf2 si-RNA 54-1 interference with lentivirus was used to create silenced Nrf2 SH-SY5Y cells (si-Nrf2-SH-SY5Y). Glycosides were evaluated on si-Con-SH-SY5Y and si-Nrf2-SH-SY5Y cells based on the expression of Nrf2 signaling pathway, pyroptotic proteins and cell damage manifestation. RESULTS: In vivo, glycosides significantly promoted the fluorescence level of nuclear Nrf2, added more Nissl bodies, reduced neurological function scores and inhibited the pyroptotic proteins level. In vitro, glycosides significantly repaired the morphological damage of cells, promoted the survival rate, reduced the LDH rate, inhibited the pyroptosis. Moreover, antioxidant activity of glycosides was enhanced via Nrf2 activation. Both Nrf2 blocking in vivo and Nrf2 silencing in vitro significantly weakened the pyroptosis inhibitory and neuroprotective effects of glycosides. CONCLUSION: These results suggested for the first time that glycosides inhibited neuronal pyroptosis by regulating the Nrf2-mediated antioxidant stress pathway, thereby exerting brain protection of CIR. As a result of this study, This study improved understanding of the pharmacodynamics and mechanism of BYHWD, as well as providing a Traditional Chinese Medicine (TCM) treatment strategy for CIR .

Chitosan based macromolecular hydrogel loaded total glycosides of paeony enhances diabetic wound healing by regulating oxidative stress microenvironment.

Oxidative stress microenvironment caused by reactive oxygen species (ROS) accumulation seriously hinders wound healing in diabetes, which brings great burden to global health. Various wound dressings on the market focus on delivering active substances to promote wound healing in diabetes. However, the complex pathological microenvironment of diabetic wounds often leads to the inactivation of delivery factors, which often leads to treatment failure, and thus, emerging therapeutic approaches are urgently needed. In this study, a macromolecular hydrogel synthesized by crosslinking N-carboxyethyl chitosan, hyaluronic acid-aldehyde, and adipic acid dihydrazide, with self-healing and injectable abilities was used to deliver total glycosides of paeony (TGP). The TGP incorporated hydrogel could obviously induce fibroblasts proliferation and secretion of various extracellular matrix proteins and growth factors, induce migration and angiogenesis of vein endothelial cells, and enhance macrophages polarization to M2 phenotype by eliminating accumulated ROS. In diabetic wound models, the ROS-scavenging hydrogel efficiently enhanced proliferation, re-epithelialization, collagen deposition, as well as angiogenesis in the wound area. Besides, the dressing induced the macrophages polarization from M1 phenotype (pro-inflammatory) to M2 phenotype (anti-inflammatory) and decreased the levels of inflammatory cytokines, thereby enhancing the diabetic wound healing. The wounds treated with TGP incorporated hydrogel almost completely healed 16 days after treatment. However, the residual wound areas in the groups of Con, INTRA, and Gel are 55.2 ± 4.6 %, 33.7 ± 6.5 %, and 34.9 ± 6.1 % on the 16th day, respectively. This hydrogel with pathological microenvironment improvement ability affords a novel therapeutic strategy for enhancing healing of chronic diabetic wound.

Glycosides as Potential Medicinal Components for Ulcerative Colitis: A Review.

Ulcerative colitis (UC) is a chronic, non-specific disease of unknown etiology. The disease develops mainly in the rectum or colon, and the main clinical symptoms include abdominal pain, diarrhea, and purulent bloody stools, with a wide variation in severity. The specific causative factors and pathogenesis of the disease are not yet clear, but most scholars believe that the disease is caused by the interaction of genetic, environmental, infectious, immune, and intestinal flora factors. As for the treatment of UC, medications are commonly used in clinical practice, mainly including aminosalicylates, glucocorticoids, and immunosuppressive drugs. However, due to the many complications associated with conventional drug therapy and the tendency for UC to recur, there is an urgent need to discover new, safer, and more effective drugs. Natural compounds with biodiversity and chemical structure diversity from medicinal plants are the most reliable source for the development of new drug precursors. Evidence suggests that glycosides may reduce the development and progression of UC by modulating anti-inflammatory responses, inhibiting oxidative stress, suppressing abnormal immune responses, and regulating signal transduction. In this manuscript, we provide a review of the epidemiology of UC and the available drugs for disease prevention and treatment. In addition, we demonstrate the protective or therapeutic role of glycosides in UC and describe the possible mechanisms of action to provide a theoretical basis for preclinical studies in drug development.

Transcriptomic analysis the mechanisms of anti-osteoporosis of desert-living Cistanche herb in ovariectomized rats of postmenopausal osteoporosis.

Desert-living Cistanche herb (DC), as a traditional Chinese medicine for tonifying kidney yang, is often used to treat postmenopausal osteoporosis (PMOP). Total phenylethanoid glycosides are instruction ingredients for discrimination and assay according to the China pharmacopoeia for DC. This research aimed to reveal the anti-osteoporosis mechanism of total phenylethanoid glycosides of DC (PGC) by transcriptomic analysis of ovariectomized rats. Serum levels of BGP were evaluated by ELISA, the bone weight was measured, and transmission electron microscopy was used to examine the ultrastructure of osteoblasts in rats. In addition, micro-CT was used to detect the bone volume (Tb.BS/BV), bone mineral density (Tb.BMD), and bone mineral content (Tb.BMC) in trabecular bone, and the ratio of cortical bone area to total area (Ct.ar/Tt.ar), and the level of bone mineral content (Ct.BMC) in cortical bone. Differential expressed genes (DEGs) after PGC treatment were analyzed by transcriptomics. Then, a bioinformatics analysis of DEGs was carried out through GO enrichment, KEGG enrichment, and selection of the nucleus gene through the protein-protein interaction network. Through qRT-PCR analysis, the DEGs were verified. The analysis results indicated that PGC increased the secretion of osteogenic markers, and ultrastructural characterization of osteoblasts and bone morphology were improved in ovariectomized rats. A total of 269 genes were differentially expressed, including 201 genes that were downregulated and 68 genes that were upregulated between the model group and the PGC group. Bioinformation analysis results prompt the conclusion that PGC could promote the bone metabolism by muscle cell development, myofibril assembly, etc. In addition, our study also found that PGC has a good effect on osteoporosis complicated with cardiomyopathy, and it also provided evidence for the correlation between sarcopenia and osteoporosis.

[Effects of intranasal administration of tripterygium glycoside-bearing liposomes on behavioral cognitive impairment of mice induced by central nervous system inflammation].

Tripterygium glycosides liposome(TPGL) were prepared by thin film-dispersion method, which were optimized accor-ding to their morphological structures, average particle size and encapsulation rate. The measured particle size was(137.39±2.28) nm, and the encapsulation rate was 88.33%±1.82%. The mouse model of central nervous system inflammation was established by stereotaxic injection of lipopolysaccharide(LPS). TPGL and tripterygium glycosides(TPG) were administered intranasally for 21 days. The effects of intranasal administration of TPG and TPGL on behavioral cognitive impairment of mice due to LPS-induced central ner-vous system inflammation were estimated by animal behavioral tests, hematoxylin-eosin(HE) staining of hippocampus, real-time quantitative polymerase chain reaction(RT-qPCR) and immunofluorescence. Compared with TPG, TPGL caused less damage to the nasal mucosa, olfactory bulb, liver and kidney of mice administered intranasally. The behavioral performance of treated mice was significantly improved in water maze, Y maze and nesting experiment. Neuronal cell damage was reduced, and the expression levels of inflammation and apoptosis related genes [tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß), BCL2-associated X(Bax), etc.] and glial activation markers [ionized calcium binding adaptor molecule 1(IBA1) and glial fibrillary acidic protein(GFAP)] were decreased. These results indicated that liposome technique combined with nasal delivery alleviated the toxic side effects of TPG, and also significantly ameliorated the cognitive impairment of mice induced by central nervous system inflammation.

Anti-inflammatory and pro-regenerative effects of a monoterpene glycoside on experimental periodontitis in a rat model of diabetes.

OBJECTIVE: Paeoniflorin (Pae) is a monoterpene glycoside with immune-regulatory effects. Several studies have already demonstrated the impact of Pae on periodontitis, but its effect on diabetic periodontitis is unclear. In this study, our aim was to test the hypothesis that Pae had a strong anti-inflammatory effect that prevented bone loss in diabetic periodontitis. METHODS: Thirty male Wistar albino rats were randomly divided into control (healthy, n = 10), periodontitis (PD) + diabetes (DM; n = 10), and PD + DM + Pae (n = 10) groups. Ligature-induced periodontitis was created by placing 4-0 silk ligatures around the lower first molars on both sides of the mandibulae. Experimental DM was created via an injection of 50 mg/kg and streptozotocin (STZ). Hyperglycemia was confirmed by the blood glucose levels of rats (>300 mg/dL). The bone mineral density (BMD), trabecular number, trabecular thickness, and bone loss were measured by micro-CT. The expression levels of IL-1ß, IL-6, and TNF-α were measured in tissue homogenates by ELISA. RESULTS: The PD + DM + Pae group had significantly less alveolar crest resorption when compared to the PD + DM group. There was also a significant difference between the PD + DM + Pae group compared to PD + DM group in trabecular thickness, BMD, and the number of trabeculae. Pae application led to a statistically significant decrease in IL-1ß, IL-6, and TNF-α levels in diabetic periodontitis. CONCLUSION: Systemic application of Pae suppressed inflammation caused by PD and DM, leading to reduced bone loss and enhanced bone quality.