Targeting the Tumor Immune Microenvironment Could Become a Potential Therapeutic Modality for Aggressive Pituitary Adenoma.

OBJECT: This study aimed to explore the relationship between the aggressiveness and immune cell infiltration in pituitary adenoma (PA) and to provide the basis for immuno-targeting therapies. METHODS: One hundred and three patients with PA who underwent surgery at a single institution were retrospectively identified. The infiltration of macrophages and T-lymphocytes was quantitatively assessed. RESULTS: The number of CD68+ macrophages was positively correlated with Knosp (p = 0.003) and MMP-9 expression grades (p = 0.00). The infiltration of CD163+ macrophages differed among Knosp (p = 0.022) and MMP-9 grades (p = 0.04). CD8+ tumor-infiltrating lymphocytes (TILs) were also positively associated with Knosp (p = 0.002) and MMP-9 grades (p = 0.01). Interestingly, MGMT expression was positively correlated with MMP-9 staining extent (p = 0.000). The quantities of CD8+ TILs (p = 0.016), CD68+ macrophages (p = 0.000), and CD163+ macrophages (p = 0.043) were negatively associated with MGMT expression levels. The number of CD68+ macrophages in the PD-L1 negative group was significantly more than that in the PD-L1 positive group (p = 0.01). The rate of PD-L1 positivity was positively correlated with the Ki-67 index (p = 0.046) and p53 expression (p = 0.029). CONCLUSION: Targeted therapy for macrophages and CD8+ TILs could be a helpful treatment in the future for aggressive PA. Anti-PD-L1 therapy may better respond to PAs with higher Ki-67 and p53 expression and more infiltrating CD68+ macrophages. Multiple treatment modalities, especially combined with immunotherapy could become a novel therapeutic strategy for aggressive PA.

Resveratrol glycoside mediates microglial endoplasmic reticulum stress to mitigate LPS-induced sepsis-associated cognitive dysfunction.

BACKGROUND: As a common complication of sepsis, sepsis-associated encephalopathy (SAE) is characterized by diffuse brain dysfunction and neurological damage and closely associated with long-term cognitive dysfunction. The dysregulated host response triggered by neurotoxicity of microglia is an important cause of diffuse brain dysfunction in SAE. Resveratrol glycoside has anti-inflammatory and antioxidant effects. However, there is no evidence whether resveratrol glycoside could alleviate SAE. METHODS: LPS administration was used to induce SAE in mice. Step-down test (SDT) and Morris water maze test (MWM) were performed to evaluate the cognitive function of mice with SAE. Western blot and immunofluorescence were used to reveal the endoplasmic reticulum stress (ERS) regulation. Microglia cell line BV-2 was used to validate the effect of resveratrol glycoside on LPS-stimulated ERS in vitro. RESULTS: Compared with the control group, LPS-stimulated mice had decreased cognitive function, but this phenomenon was well reversed by resveratrol glycoside administration, in which the SDT assay showed longer retention time, both in short-term memory (STM) and long-term memory (LTM). Western blot indicated that the expression of ER stress-related protein PERK/CHOP in LPS-stimulated mice were significantly increased, while that in the resveratrol glycoside-treated group were relieved. Furthermore, Immunofluorescence revealed resveratrol glycoside mainly worked on microglia in mediating the ER stress, in which the expression of PERK/CHOP were significantly inhibited in resveratrol glycoside group mice. In vitro, BV2 showed consistent results with the aforementioned. CONCLUSION: Resveratrol glycoside could alleviate the cognitive dysfunction caused by LPS-induced SAE, mainly by inhibiting the ER stress and maintaining the homeostasis of ER function of microglia.

Mechanistic insights into the ameliorative effects of hypoxia-induced myocardial injury by Corydalis yanhusuo total alkaloids: based on network pharmacology and experiment verification.

Introduction: Corydalis yanhusuo total alkaloids (CYTA) are the primary active ingredients in yanhusuo, known for their analgesic and cardioprotective effects. However, the mechanisms underlying the treatment of Myocardial ischemia (MI) with CYTA have not been reported. The purpose of this study was to explore the protective effect of CYTA on MI and its related mechanisms. Methods: A network pharmacology was employed to shed light on the targets and mechanisms of CYTA's action on MI. The protective effect of CYTA against hypoxia damage was evaluated in H9c2 cells. Furthermore, the effects of CYTA on L-type Ca2+ current (ICa-L), contractile force, and Ca2+ transient in cardiomyocytes isolated from rats were investigated using the patch clamp technique and IonOptix system. The network pharmacology revealed that CYTA could regulate oxidative stress, apoptosis, and calcium signaling. Cellular experiments demonstrated that CYTA decreased levels of CK, LDH, and MDA, as well as ROS production and Ca2+ concentration. Additionally, CYTA improved apoptosis and increased the activities of SOD, CAT, and GSH-Px, along with the levels of ATP and Ca2+-ATPase content and mitochondrial membrane potential. Moreover, CYTA inhibited ICa-L, cell contraction, and Ca2+ transient in cardiomyocytes. Results: These findings suggest that CYTA has a protective effect on MI by inhibiting oxidative stress, mitochondrial damage, apoptosis and Ca2+ overload. Discussion: The results prove that CYTA might be a potential natural compound in the field of MI treatment, and also provide a new scientific basis for the its utilization.

Liquiritin Protects Against Cardiac Fibrosis After Myocardial Infarction by Inhibiting CCL5 Expression and the NF-κB Signaling Pathway.

Purpose: Despite significant advances in interventional treatment, myocardial infarction (MI) and subsequent cardiac fibrosis remain major causes of high mortality worldwide. Liquiritin (LQ) is a flavonoid extract from licorice that possesses a variety of pharmacological properties. However, to our knowledge, the effects of LQ on myocardial fibrosis after MI have not been reported in detail. The aim of our research was to explore the potential role and mechanism of LQ in MI-induced myocardial damage. Methods: The MI models were established by ligating the left anterior descending branch of the coronary artery. Next, rats were orally administered LQ once a day for 14 days. Biochemical assays, histopathological observations, ELISA, and Western blotting analyses were then conducted. Results: LQ improved the heart appearance and ECG, decreased cardiac weight index and reduced levels of cardiac-specific markers such as CK, CK-MB, LDH, cTnI and BNP. Meanwhile, LQ reduced myocardial infarct size and improved hemodynamic parameters such as LVEDP, LVSP and ±dp/dtmax. Moreover, H&E staining showed that LQ attenuated the pathological damage caused by MI. Masson staining showed that LQ alleviated myocardial cell disorder and fibrosis while reducing collagen deposition. LQ also decreased the levels of oxidative stress and inflammation. Western blotting demonstrated that LQ significantly down-regulated the expressions of Collagen I, Collagen III, TGF-ß1, MMP-9, α-SMA, CCL5, and p-NF-κB. Conclusion: LQ protected against myocardial fibrosis following MI by improving cardiac function, and attenuating oxidative damage and inflammatory response, which may be associated with inhibition of CCL5 expression and the NF-κB pathway.

Expression level comparison of marker genes related to early embryonic development and tumor growth.

In tumor research, the occurrence and origin of tumors are the fundamental problems. In the 1970s, the basic discussion of the developmental biology problem of tumors was proposed, and it was believed that tumorigenesis is closely related to developmental biology. Tumors are abnormal biological structures in organisms, and their biological behavior is very similar to that of the early embryo. Many tumor-related genes also serve regulatory roles in the normal development and differentiation of embryos. However, it remains unclear whether gene expression in early embryos has any similarities with tumor cells. In this study, to compare the similarities and differences in gene expression between early embryos and tumor cells, reverse transcription-quantitative PCR was conducted to determine and compare the relative expression levels of nine tumor-related genes in the brain glioma cell line, T98G, and in the early embryo of Spodoptera litura, which is fast-growing, low-cost, easily accessible and easy to observe. The expression of tumor-related genes in early embryos and the similarity of regulatory mechanisms between early embryonic development and tumor growth were explored. In conclusion, tumor growth may be regarded as an abnormal embryogenic activation that happens in the organs of adult individuals.

Clinical Characteristics and Prognostic Risk Factors of Parasellar Chondrosarcoma.

Background: Parasellar chondrosarcomas are extremely rare. This study describes the characteristics of parasellar chondrosarcoma and analyzes the risk factors and prognosis based on the resection degree. Methods: Fifteen patients with pathologically diagnosed parasellar chondrosarcoma were retrospectively analyzed for the clinical data, surgical methods, and prognosis to identify relationships between the surgical resection degree, tumor recurrence, and imaging characteristics. Results: Twelve patients had eye dysfunction and ptosis. Differentiation from other parasellar tumors by imaging is difficult. The preoperative Karnofsky Performance Scale (KPS) score positively correlated with the tumor resection degree (p = 0.026) and negatively correlated with the maximum tumor diameter (p = 0.001). Tumor recurrence negatively correlated with the resection degree (p = 0.009). The postoperative KPS score positively correlated with the preoperative KPS score (p < 0.001) and tumor resection degree (p = 0.026), and negatively correlated with the maximum tumor diameter (p = 0.016) and age (p = 0.047). An improved KPS score positively correlated with the tumor resection degree (p = 0.039). Patients who underwent total resection of the chondrosarcoma had longer progression-free survival than those who underwent partial resection (p = 0.0322). Conclusion: Parasellar chondrosarcomas are difficult to resect completely. Preoperative KPS score is an important factor for the degree of resection. KPS score, age, maximum tumor diameter, and resection degree may be important prognostic factors.

Influence of Evidence-Based Nursing on Psychological Status, Neurological Function, and Life Quality of Patients with Acute Poststroke Depression.

Objective: This research sets out to elucidate the influence of evidence-based nursing (EBN) on psychological status (PSY), neurological function, and quality of life (QoL) of patients with acute poststroke depression (PSD). Methods: One hundred and fifty stroke patients who received treatment in the Characteristic Medical Center of PLA Rocket Force between December 2019 and December 2021 were enrolled, including 100 cases (Group A) treated with comprehensive EBN and 50 patients (Group B) with routine nursing. Anxiety and depression (Self-Rating Anxiety Scale [SAS] and Self-Rating Depression Scale [SDS] scores), neurological function (National Institutes of Health Stroke Scale [NIHSS] and Scandinavian Stroke Scale [SSS] scores), QoL (Generic Quality Of Life Inventory-74 [GQOLI-74] score), and complication rate of both groups were evaluated, as well as total effective rate and nursing satisfaction. Results: Group A outperformed Group B with lower scores of NIHSS, SSS, SAS, and SDS and higher GOOLI-74 scores. Besides, lower complication rate and higher total effective rate and nursing satisfaction were determined in Group A. Conclusions: EBN can better improve the PSY of patients with acute PSD, restore their neurological function, and effectively improve their QoL.

The cardioprotective effects and mechanisms of naringenin in myocardial ischemia based on network pharmacology and experiment verification.

Naringenin (Nar) is a natural flavonoid extracted from citrus fruits with abundant pharmacological properties against cardiac diseases, but existing studies are unsystematic and scattered. The present research systematically investigates the mechanism of action of Nar in the treatment of myocardial ischemia (MI). Network pharmacology was used to analyze the relevant targets of Nar against MI as well as the biological mechanisms. The protective effect of Nar was initially assessed in H9c2 cells induced by CoCl2. In acutely isolated rat cardiomyocytes, Nar was further explored for effects on L-type Ca2+ currents, cell contractility and Ca2+ transients by using patch-clamp technique and Ion Optix system. Network pharmacology analysis indicated that Nar improved apoptosis, mitochondrial energy metabolism, inflammation and oxidative stress. Experimental validation demonstrated that Nar decreased ROS and MDA levels and increased antioxidant activity (e.g., GSH-PX, SOD, and CAT), mitochondrial membrane potential, ATP and Ca2+-ATPase contents. Nar also markedly reduced inflammatory factor levels, apoptosis, and intracellular Ca2+ concentrations in H9c2 cells. Based on the experimental results, it is speculated that Ca2+ signals play an essential role in the process of Nar against MI. Thus, we further confirmed that Nar significantly inhibited the L-type Ca2+ currents, contractility and Ca2+ transients in acutely isolated cardiomyocytes. The inhibition of Ca2+ overload by Nar may be a novel cardioprotective mechanism. The present study may serve as a basis for future clinical research, and Nar as a Ca2+ channel inhibitor may provide new perspectives for the treatment of myocardial ischemic diseases.

Process Parameter Modeling and Optimization of Abrasive Water Jet Dressing Fixed-Abrasive Pad Based on Box-Behnken Design.

Clarifying the influence of the dress process parameters of the abrasive water jet on the dressing effect of fixed-abrasive pads (FAPs) is a prerequisite for online controllable dressing of abrasive water jets. This paper uses three factors and three horizontal response surface methods to explore the influence of jet pressure, abrasive concentration, and nozzle angle on FAP dressing quality. The prediction model of the material removal rate of a FAP machined using three process parameters is established. The influence of pairwise interactions of the three process parameter variables on the dressing effect and the optimal process parameters under each target is analyzed. Finally, the optimal process parameters predicted by the model are verified by experiments. The results show that the best dressing parameters with the MRR of the workpiece as the response value are as follows: jet pressure 3.8 MPa, abrasive concentration 3%, and nozzle angle 73°. The predicted value of the optimal process performance is 464.574 nm/min, and the experimental verification result is 469.136 nm/min; the error between the experimental value and the predicted value is within a reasonable range.

Resveratrol ameliorates iron overload induced liver fibrosis in mice by regulating iron homeostasis.

This study is intended to explore the protective effects of resveratrol (RES) on iron overload-induced liver fibrosis and its mechanism. Iron dextran (50 mg/kg) was injected intraperitoneally in all groups except the control group. Mice in the L-RES, M-RES and H-RES groups were gavaged with RES solution at 25, 50 mg/kg and 100 mg/kg, respectively, 4 h before injection of iron dextran every day; mice in the deferoxamine (DFO) group were injected with DFO intraperitoneally (100 mg/kg); mice in the control group received isovolumetric saline. After seven weeks of RES administration, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) activities and liver hydroxyproline (Hyp) levels were reduced; the malondialdehyde (MDA) activities decreased and the levels of superoxide dismutase (SOD) and glutathione (GSH) were raised. Hematoxylin and eosin (H&E), Prussian, and Masson staining indicated that RES treatment could improve cell damage and reduce hepatic iron deposition and collagen deposition in iron-overload mice. The expression of Bcl-2 was increased, the expression levels of Bax and caspase-3 were decreased under RES treatment. Moreover, RES reduced the expression of hepcidin, ferritin (Ft), divalent metal transporter-1 (DMT-1), transferrin receptor-2 (TFR-2), and raised the expression of ferroprotein-1 (FPN-1). In conclusion, RES could ameliorate iron overload-induced liver fibrosis, and the potential mechanisms may be related to antioxidant, anti-inflammatory, anti-apoptotic, and more importantly, regulation of iron homeostasis by reducing iron uptake and increasing iron export.

Protective effects and possible mechanism of 6-gingerol against arsenic trioxide-induced nephrotoxicity based on network pharmacological analysis and experimental validation.

BACKGROUND AND OBJECTIVE: Nephrotoxicity induced by the chemotherapeutic drug arsenic trioxide (ATO) is often overlooked, and the underlying mechanisms remain poorly understood. Based on network pharmacology and experimental validation, this study investigates the protection of 6-gingerol (6G) against ATO-induced nephrotoxicity and the potential mechanisms. METHODS: We screened and collected 6G and disease-related targets and then imported the interaction targets into a String database to construct protein-protein interaction (PPI) networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Mice were injected intraperitoneally with ATO (5 mg/kg) for seven days to induce nephrotoxicity, and then the histological morphology of the kidneys, biochemical indices of serum and tissues, and associated protein expressions were observed. RESULTS: The network pharmacology results revealed that the effects of 6G against nephrotoxicity are closely related to apoptosis, and the MAPKs pathway was screened for validation. In animal experiments, 6G improved the histopathological morphology of the kidneys, reduced the levels of renal function markers, enhanced antioxidant activity, and decreased the levels of inflammation. Furthermore, 6G reduced apoptotic cells in kidney tissues, decreased the levels of Bax and c-Caspase-3, and increased the level of Bcl-2. The results of immunohistochemistry and western blotting revealed that 6G significantly inhibited the expressions of p-p38, p-ERK, and p-JNK. CONCLUSION: The results comprehensively demonstrate the protective effects of 6G against ATO-induced nephrotoxicity. The effects are related to anti-oxidant, anti-inflammatory, and anti-apoptotic properties, possibly through inhibition of the MAPKs pathway.

Protective Effects of 6-Gingerol on Cardiotoxicity Induced by Arsenic Trioxide Through AMPK/SIRT1/PGC-1α Signaling Pathway.

Background and Objective: Arsenic trioxide (As2O3) induced cardiotoxicity to limit the clinical applications of the effective anticancer agent. 6-Gingerol (6G) is the main active ingredient of ginger, a food with many health benefits. The present study aims to investigate the potential pharmacological mechanisms of 6G on As2O3-induced myocardial injury. Methods and Results: Fifty KunMing mice were divided into five groups (n = 10) receiving: 1) physiological saline; 2) 6G (20 mg/kg) alone; 3) As2O3 (5 mg/kg); 4) 6G (10 mg/kg) and As2O3 (5 mg/kg); 5) 6G (20 mg/kg) and As2O3 (5 mg/kg). 6G was given orally and As2O3 was given intraperitoneally once per day for seven consecutive days. Biochemical, histopathological, transmission electron microscopy, ELISA, and western blotting analyses were then performed. Based on the resultant data, As2O3 was found to induce cardiotoxicity in mice. 6G significantly ameliorated As2O3-induced heart injury, histopathological changes, oxidative stress, myocardial mitochondrial damage, inflammation, and cardiomyocyte apoptosis, while reversed As2O3-induced inhibition of the AMPK/SIRT1/PGC-1α pathway. Conclusion: Our experimental results reveal that 6G effectively counteracts As2O3-induced cardiotoxicity including oxidative stress, inflammation and apoptosis, which might be attributed to its activation action on AMPK/SIRT1/PGC-1α signaling pathway.

Protective mechanisms of 10-gingerol against myocardial ischemia may involve activation of JAK2/STAT3 pathway and regulation of Ca2+ homeostasis.

10-Gingerol (10-Gin), an active ingredient extracted from ginger, has been reported to have beneficial effects on the cardiovascular system. However, its protective effects on myocardial ischemia (MI) and the underlying cellular mechanisms are still unclear. To investigate the protection conferred by 10-Gin against MI injury and its potential mechanisms in cardiomyocytes via patch-clamp and molecular biology techniques. A rat MI model was established using the subcutaneous injection of isoproterenol (85 mg/kg) administered on two consecutive days. 10-Gin was pre-administered to rats for seven days to assess its cardio-protection. The patch-clamp and IonOptix Myocam detection techniques were used to investigated 10-Gin's effects on L-type Ca2+ channels (LTCCs), Ca2+ transients and cell contractility in isolated rat cardiomyocytes. 10-Gin administration alleviated MI injury, improved cardiac function and myocardial histopathology, reduced myocardial infarct area, downregulated oxidative stress and Ca2+ levels, and decreased the expression of apoptotic factors. Importantly, 10-Gin led to an increase in phosphorylated Janus kinase 2 and signal transducer and activator of transcription 3 (JAK2 and STAT3, respectively) expressions. Furthermore, 10-Gin inhibited LTCCs in a concentration-dependent manner with a half-maximal inhibitory concentration of 75.96 µM. Moreover, 10-Gin administration inhibited Ca2+ transients and cell contractility. Our results suggest that 10-Gin exerts cardioprotective effects on MI in vivo and in vitro in connection with the inhibition of oxidative stress and apoptosis via activation of the JAK2/STAT3 signalling pathway, and regulation of Ca2+ homeostasis by LTCCs.

Inhibition of human ether-à-go-go-related gene K+ currents expressed in HEK293 cells by three gingerol components from ginger.

OBJECTIVES: Gingerols are bioactive compounds derived from ginger, our experiment investigates the effects of 6-, 8- and 10-Gin on the human ether-à-go-go-related gene (hERG) K+ channels by using patch clamp technology. KEY FINDINGS: hERG K+ currents were suppressed by 6-, 8- and 10-Gin in a concentration-dependent manner. The IC50 values of 6-, 8- and 10-Gin were 41.5, 16.1 and 86.5 µM for the hERG K+ currents, respectively. The maximum inhibitory effects caused by 6-, 8- and 10-Gin were 44.3% ± 2.0%, 88.6% ± 1.3% and 63.1% ± 1.1%, respectively, and the effects were almost completely reversible. CONCLUSION: These findings suggest that 8-Gin is the most potent hERG K+ channel inhibitor among gingerol components and may offer a new approach for understanding and treating cancer.

Protein disulfide isomerase modulation of TRPV1 controls heat hyperalgesia in chronic pain.

Protein disulfide isomerase (PDI) plays a key role in maintaining cellular homeostasis by mediating protein folding via catalyzing disulfide bond formation, breakage, and rearrangement in the endoplasmic reticulum. Increasing evidence suggests that PDI can be a potential treatment target for several diseases. However, the function of PDI in the peripheral sensory nervous system is unclear. Here we report the expression and secretion of PDI from primary sensory neurons is upregulated in inflammatory and neuropathic pain models. Deletion of PDI in nociceptive DRG neurons results in a reduction in inflammatory and neuropathic heat hyperalgesia. We demonstrate that secreted PDI activates TRPV1 channels through oxidative modification of extracellular cysteines of the channel, indicating that PDI acts as an unconventional positive modulator of TRPV1. These findings suggest that PDI in primary sensory neurons plays an important role in development of heat hyperalgesia and can be a potential therapeutic target for chronic pain.

Baicalein Ameliorates Myocardial Ischemia Through Reduction of Oxidative Stress, Inflammation and Apoptosis via TLR4/MyD88/MAPKS/NF-κB Pathway and Regulation of Ca2+ Homeostasis by L-type Ca2+ Channels.

Background: Baicalein (Bai) is the principal ingredient of Scutellaria baicalensis Georgi. Reports concerning the therapeutic advantages in treating cardiovascular diseases have been published. However, its protective mechanism towards myocardial ischemia (MI) is undefined. Objective: The aim of this study was to investigate the protective mechanisms of Bai on mouse and rat models of MI. Methods: Mice were pre-treated with Bai (30 and 60 mg/kg/day) for 7 days followed by subcutaneous injections of isoproterenol (ISO, 85 mg/kg/day) for 2 days to establish the MI model. Electrocardiograms were recorded and serum was used to detect creatine kinase (CK), lactate dehydrogenase (LDH), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondialdehyde (MDA). Cardiac tissues were used to detect Ca2+ concentration, morphological pathologies, reactive oxygen species (ROS), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). In addition, the expression levels of Bcl-2-associated X (Bax), B cell lymphoma-2 (Bcl-2), Caspase-3, Toll-like receptor-4 (TLR4), myeloid differentiation protein 88 (MyD88), nuclear factor-kappa B (NF-κB), p-p38, p-extracellular signal-regulated kinase1/2 (p-ERK1/2) and c-Jun N-terminal kinase (p-JNK) were assessed by western blots in myocardial tissues. The effects of Bai on L-type Ca2+ currents (ICa-L), contractility and Ca2+ transients in rat isolated cardiomyocytes were monitored by using patch clamp technique and IonOptix system. Moreover, ISO-induced H9c2 myocardial injury was used to detect levels of inflammation and apoptosis. Results: Bai caused an improvement in heart rate, ST-segment and heart coefficients. Moreover, Bai led to a reduction in CK, LDH and Ca2+ concentrations and improved morphological pathologies. Bai inhibited ROS generation and reinstated SOD, CAT and GSH activities in addition to inhibition of replenishing MDA content. Also, expressions of IL-6 and TNF-α in addition to Bax and Caspase-3 were suppressed, while Bcl-2 expression was upregulated. Bai inhibited protein expressions of TLR4/MyD88/MAPKS/NF-κB and significantly inhibited ICa-L, myocyte contraction and Ca2+ transients. Furthermore, Bai caused a reduction in inflammation and apoptosis in H9c2 cells. Conclusions: Bai demonstrated ameliorative actions towards MI, which might have been related to attenuation of oxidative stress, inflammation and apoptosis via suppression of TLR4/MyD88/MAPKS/NF-κB pathway and adjustment of Ca2+ homeostasis via L-type Ca2+ channels.

Exploring the Mechanism of Danshensu in the Treatment of Doxorubicin-Induced Cardiotoxicity Based on Network Pharmacology and Experimental Evaluation.

Background: Doxorubicin (DOX) is one of the most effective chemotherapeutic agents available; however, its use is limited by the risk of serious cardiotoxicity. Danshensu (DSS), an active ingredient in Salvia miltiorrhiza, has multiple cardioprotective effects, but the effect of DSS on DOX-induced cardiotoxicity has not been reported. Objectives: Predicting the targets of DOX-induced cardiotoxicity and validating the protective effects and mechanisms of DSS. Methods: (1) Using methods based on network pharmacology, DOX-induced cardiotoxicity was analyzed by data analysis, target prediction, PPI network construction and GO analysis. (2) The cardiotoxicity model was established by continuous intraperitoneal injection of 15 mg/kg of DOX into mice for 4 days and the protective effects and mechanism were evaluated by treatment with DSS. Results: The network pharmacology results indicate that CAT, SOD, GPX1, IL-6, TNF, BAX, BCL-2, and CASP3 play an important role in this process, and Keap1 is the main target of DOX-induced cardiac oxidative stress. Then, based on the relationship between Keap1 and Nrf2, the Keap1-Nrf2/NQO1 pathway was confirmed by animal experiments. In the animal experiments, by testing the above indicators, we found that DSS effectively reduced oxidative stress, inflammation, and apoptosis in the damaged heart, and significantly alleviated the prolonged QTc interval caused by DOX. Moreover, compared with the DOX group, DSS elevated Keap1 content and inhibited Nrf2, HO-1, and NQO1. Conclusion: The results of network pharmacology studies indicated that Keap1-Nrf2/NQO1 is an important pathway leading to DOX-induced cardiotoxicity, and the results of animal experiments showed that DSS could effectively exert anti-oxidative stress, anti-inflammatory and anti-apoptotic therapeutic effects on DOX-induced cardiotoxicity by regulating the expression of Keap1-Nrf2/NQO1.

Mechanisms of cinnamic aldehyde against myocardial ischemia/hypoxia injury in vivo and in vitro: Involvement of regulating PI3K/AKT signaling pathway.

To investigate the protection of cinnamic aldehyde (CA) against myocardial ischemia/hypoxia (I/H) injury and its potential mechanisms in vivo and in vitro. Mice were pretreated with CA for 7 days, and then isoproterenol (85 mg/kg) was administered for 2 consecutive days to assess its cardioprotection. Furthermore, an in vitro myocardial I/H model was established by administering CoCl2 (600 µM) to H9c2 cells for 24 h. H9c2 cells were pretreated with CA for 12 h to assess its protection. We observed that CA improved electrocardiogram and histopathological changes and decreased creatine kinase and lactate dehydrogenase activities and oxidative stress levels. The TUNEL results showed that CA reduced the degree of apoptosis. Furthermore, CA could lead to a down-regulation of the Caspase-3 and Bax protein expressions, but an up-regulation of the Bcl-2 protein expressions. Importantly, CA increased p-PI3K and p-AKT protein expressions, indicating the activation of the PI3K/AKT signaling pathway. Moreover, treatment with CA improved the cell viability rate and mitochondrial membrane potential while markedly decreasing apoptosis and oxidative stress levels in vitro. Our results suggested that CA exerts cardioprotection on myocardial I/H injury, which possibly occurred in connection with inhibition of oxidative stress and apoptosis via activation of the PI3K/AKT signaling pathway.

Removal Modeling and Experimental Verification of Magnetorheological Polishing Fused Silica Glass.

Compared to conventional polishing methods, magnetorheological polishing has no subsurface damage and a has good polishing effect, which is suitable for fused silica glass surface processing. However, the existing magnetorheological polishing material removal model has low processing efficiency and uneven removal, which cannot realize the deterministic processing of parts. The material removal (MR) model of fused silica glass is established by convolving the dwell time with the material removal function. The residence time is Fourier transformed. The consequence of process variable such as machining time, workpiece rotational frequency, machining gap and X-direction deflection on the MR of workpiece interface are analyzed. Experiments verify the validity of the material removal model. The surface precision PV value of the workpiece surface under the optimal process parameters was decreased from 7.959 nm to 0.609 nm for machining. The experiment results indicate that the established MR model can be implemented as the deterministic MR of the optical surface and ameliorate the surface accuracy of the workpiece surface.

Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α.

The transcription suppressor factor FBI-1 (the factor that binds to inducer of short transcripts-1) is an important regulator of hepatocellular carcinoma (HCC). In this work, the results showed that FBI-1 promoted the Warburg effect and enhances the resistance of hepatocellular carcinoma cells to molecular targeted agents. Knockdown of FBI-1 via its small-interfering RNA (siRNA) inhibited the ATP level, lactate productions, glucose uptake or lactate dehydrogenase (LDH) activation of HCC cells. Transfection of siFBI-1 also decreased the expression of the Warburg-effect-related factors: hypoxia-inducible factor-1 alpha (HIF-1α), lactate dehydrogenase A (LDHA), or GLUT1, and the epithelial-mesenchymal transition-related factors, Vimentin or N-cadherin. The positive correlation between the expression of FBI-1 with HIF-1α, LDHA, or GLUT1 was confirmed in HCC tissues. Mechanistically, the miR-30c repressed the expression of HIF-1α by binding to the 3'-untranslated region (3'-UTR) of HIF-1α in a sequence-specific manner, and FBI-1 enhanced the expression of HIF-1α and HIF-1α pathway's activation by repressing the expression of miR. By modulating the miR-30c/HIF-1α, FBI-1 promoted the Warburg effect or the epithelial-mesenchymal transition of HCC cells and promoted the resistance of HCC cells to molecular targeted agents.