Advanced glycation end products induce skeletal muscle atrophy and insulin resistance via activating ROS-mediated ER stress PERK/FOXO1 signaling.

Skeletal muscle atrophy is often found in patients with type 2 diabetes mellitus (T2DM), which is characterized by insulin resistance. As the largest tissue in the body, skeletal muscle plays important roles in insulin resistance. Advanced glycation end products (AGEs) are a type of toxic metabolite that are representative of multiple pathophysiological changes associated with T2DM. Mice were exposed to AGEs. Forkhead box O1 (FOXO1) was silenced by using a constructed viral vector carrying siRNA. Skeletal muscle atrophy was evaluated by using hematoxylin-eosin (H&E), oil red O, myosin skeletal heavy chain (MHC), and laminin immunofluorescent stains. Reactive oxygen species (ROS) generation was assessed by using the dihydroethidium (DHE) stain. Western blotting was used to evaluate protein expression and phosphorylation. Insulin resistance was monitored via the insulin tolerance test and the glucose infusion rate (GIR). Mice exposed to AGEs showed insulin resistance, which was evidenced by reduced insulin tolerance and GIR. H&E and MHC immunofluorescent stains suggested reduced cross-sectional muscle fiber area. Laminin immunofluorescent and oil red O stains indicated increased intramuscular fibrosis and lipid deposits, respectively. Exposure to AGEs induced ROS generation, increased phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and FOXO1, facilitated FOXO1 nuclear translocation, and elevated expression of muscle atrophy F-box (MAFbx) in gastrocnemius muscle. foxo1 silencing significantly suppressed skeletal muscle atrophy and insulin resistance without affecting ROS production. AGEs exacerbated skeletal muscle atrophy and insulin resistance by activating the PERK/FOXO1 signaling pathway in skeletal muscle.NEW & NOTEWORTHY In this study, we proposed a molecular mechanism underlying the skeletal muscle atrophy-associated insulin resistance in type 2 diabetes mellitus (T2DM). Our investigation suggests that exposure to AGEs, which are characteristic metabolites of T2DM pathology, induces the activation of reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, leading to the upregulation of the protein kinase RNA-like ER kinase (PERK)/forkhead box O1 (FOXO1)/muscle atrophy F-box pathway and subsequent skeletal muscle atrophy, ultimately resulting in insulin resistance.

Dissolved organic matter and bacterial population changes during the treatment of solid potato waste in a microbial fuel cell.

This study investigated the effect of mixed feeding of anaerobically cultured waste activated sludge (WAS) on the performance of microbial fuel cells (MFCs) in the treatment of solid potato waste. The maximum current densities of the four MFCs was estimated as 36, 5, 10 and 150 mA/m2, with the columbic efficiencies of 6.1, 0.3, 0.9 and 31.1%, respectively. Composition changes of dissolved organic matter (DOM) coupled with its interrelation with electricity generation and total and viable bacterial population at the end of the operation were investigated. The experimental results demonstrated that mixing WAS into solid potato enhanced the presence of the tyrosine-like aromatic amino acids and aromatic protein-like substances from the beginning of the operation and promoted hydrolysis and humification of the solid potato. In the final solution of the anodic chamber, more viable bacteria were detected for the reactors treating solid potato alone and the mixed feedstock with the smaller amount of sludge, where distinct electricity generation was observed.

Preliminary study of Yinhuapinggan granule against H1N1 influenza virus infection in mice through inhibition of apoptosis.

CONTEXT: Yinhuapinggan granule (YHPG) is frequently used for treating fever, cough, and viral pneumonia in traditional Chinese medicine. OBJECTIVE: This study investigated the antiviral effects of YHPG in H1N1 influenza virus (IFV)-infected mice and its possible mechanism. MATERIALS AND METHODS: ICR mice were intranasally infected with 10 LD50 viral dose of IFV and then oral administration of YHPG (6, 12, and 18 g/kg) or oseltamivir (positive control) once a day for 2 or 4 consecutive days, six mice in each group. The lung, spleen and thymus indexes of IFV-infected mice, the expression of viral loads and pathological changes in lung tissues were performed to evaluate the antiviral effects of YHPG. Real-time PCR, immunohistochemistry and western blot assays were used to determine the expression of Bax, Bcl-2 and caspase-3. RESULTS: LD50 in mice was 10-3.5/0.02 mL. YHPG (6, 12, and 18 g/kg) dose-dependently decreased the lung index and viral load; the inhibition ratio of lung index was 5.31, 18.22, and 34.06%, respectively. Further detection revealed that YHPG (12 and 18 g/kg) significantly attenuated lung pathological changes, and increased the spleen and thymus indexes. Moreover, YHPG significantly down-regulated the mRNA and protein expression of Bax and caspase-3 in lung tissues of mice infected with IFV, and up-regulated the expression of Bcl-2. CONCLUSIONS: YHPG has significant antiviral effects in IFV-infected mice, partially by inhibiting influenza virus replication and regulating the occurrence of apoptosis induced by influenza virus infection, suggesting that YHPG may be a promising antiviral agent with potential clinical application prospects.

[Lipid-lowering effect and mechanism of Danhong Injection on hyperlipidemia rats based on lipid metabolism disorder].

The animal model of hyperlipidemia in rats was established to investigate the lipid-lowering effect and mechanism of Danhong Injection on hyperlipidemic rats. SD rats were selected as the research object. The rats in normal group were fed with basic diet, and the rats in other groups were fed with high-fat diet to establish hyperlipidemia model. The successfully modeled rats were randomly divided into model group, Danhong Injection low, medium, high dose(1.0, 2.0, 4.0 mL·kg~(-1)) groups, and simvastatin(2.0 mg·kg~(-1)) group. Danhong Injection groups received intraperitoneal administration, and simvastatin group received intragastrical administration, once a day for 4 weeks. At the first, second, third, and fourth weekends after administration, blood was collected from the orbital vein to detect the levels of total cholesterol(TC), triglyceride(TG), low-density lipoprotein cholesterol(LDL-C), and high-density lipoprotein cholesterol(HDL-C), and then the atherosclerosis index(AI) was calculated. After 4 weeks of administration, the animals were sacrificed, and their heart, liver, spleen, lung, kidney and adipose tissue were extracted and weighed respectively to calculate the organ index of each group. The expressions of acyl-coaoxidase 1(Acox1), adenosine 5'-monophosphate(AMP)-activated protein kinase alpha(AMPK-α), bile salt export pump(BSEP), peroxisome proliferator-activated receptor gamma(PPAR-γ), catalase(CAT) and superoxide dismutase(SOD) mRNA in liver tissues were detected by fluorescence quantitative PCR; the content of cholesteryl ester transfer protein(CETP) and lecithin cholesterol acyltransferase(LCAT) in serum was detected by ELISA. The results showed that as compared with the normal group, the levels of serum TC, TG and LDL-C in the model group were significantly increased, and the level of HDL-C was significantly decreased, indicating that the hyperlipidemia rat model was successfully constructed. As compared with the model group, Danhong Injection could decrease the contents of TC, TG, LDL-C and increase the content of HDL-C in hyperlipidemia rats; reduce the body weight of hyperlipidemia rats, and reduce the liver weight, liver index, fat weight and fat index; it had no significant effect on the main organ indexes such as heart, spleen, lung and kidney; but it could increase the expressions of Acox1, AMPK-α, BSEP, PPAR-γ, CAT and SOD mRNA in liver tissues of rats; it could also reduce the level of CETP and increase the level of LCAT in serum; and the regulatory effect of Danhong Injection groups all showed a dose-dependent effect. It can be concluded that Danhong Injection can regulate the blood lipid contents, reduce the blood lipid levels and alleviate the accumulation of body fat in rats with hyperlipidemia. The mechanism may be related to inhibiting lipid metabolism disorder and oxidative stress induced by high-fat diet feeding, and improving the imbalance of lipid transport system.

Yangyin Tongnao granules enhance neurogenesis in the peri-infarct area and upregulate brain-derived neurotrophic factor and vascular endothelial growth factor after focal cerebral ischemic infarction in rats.

Yangyin Tongnao granules (YYTNG) have been extensively applied in the treatment of brain injury, mainly due to its antioxidant effects, inhibition of apoptosis, and enhancement of blood circulation. To analyze the effect of YYTNG on the recovery of neurological function and neurogenesis in the peri-infarct area after cerebral ischemic infarction in rats and to elucidate its role in the neuroprotective mechanism of stroke, Sprague-Dawley (SD) rats were subjected to middle cerebral artery occlusion (MCAO) for 90 min followed by reperfusion. Rats were randomly divided into five groups: sham, MCAO, and YYTNG-treated rats given doses of 0.83, 1.65, or 3.3 g kg-1 day-1. The YYTNG-treated groups (1.65 and 3.3 g kg-1 day-1) showed higher neurological scores and a lower infarct volume than the MCAO group on day 3 after MCAO. Furthermore, the YYTNG-treated groups (0.83, 1.65, and 3.3 g kg-1 day-1) showed higher neurological scores on day 7 after MCAO. The number of BrdU+/nestin+, BrdU+/NeuN+, and BrdU+/GFAP+ cells in the peri-infarct area 7 days after MCAO was significantly increased in the YYTNG-treated groups in a dose-dependent manner. The protein expression levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were significantly higher in all three YYTNG-treated groups than in the MCAO group. Based on these results, administration of YYTNG post ischemia could ameliorate neurological function deficits in rats with MCAO. The therapeutic effect of YYTNG may be due to the promotion of neurogenesis in the peri-infarct area and the upregulation of neuroprotective factors BDNF and VEGF in MCAO rats.

Antiviral effects and mechanisms of Yinhuapinggan granule against H1N1 influenza virus infection in RAW264.7 cells.

Yinhuapinggan granule (YHPG), a modified prescription based on Ma-Huang-Tang (MHT), is used in traditional Chinese medicine (TCM) to treat influenza, cough, and viral pneumonia. In this study, we investigated the antiviral effects of YHPG by means of pre-, post-, and co-treatment, and its underlying mechanisms on regulating the levels of inflammatory-related cytokines, modulating the mRNA expressions of interferon-stimulated genes in influenza virus-infected murine macrophage cells (RAW264.7), and evaluating the protein expressions of key effectors in the Type I IFN and pattern recognition receptor (PRRs) signaling pathways. The results showed that YHPG markedly inhibited influenza virus (IFV) replication in pre-, post- and co-treatment assay, especially in post-treatment assay. Antiviral mechanisms studies revealed that YHPG (500 and 250 µg/mL) significantly up-regulated levels of IFN-ß, IFN-stimulated genes (Mx-1, ISG-15 and ISG-56) compared with the IFV control group, while the levels of IL-6 and TNF-α were significantly down-regulated. Furthermore, western blot analysis results revealed that the protein expressions of the phosphorylated forms of TBK1, IRF3, ERK1/2, P38 MAPK and NF-κB p65 were significantly down-regulated in RAW264.7 cells with the YHPG (500 and 250 µg/mL) treatment, while the expression of the phosphorylated form of STAT1 was significantly enhanced. Based on these results, YHPG had antiviral effects in IFV-infected RAW264.7 cells, which might be associated with regulation of the inflammatory cytokines production, evaluation of the levels of IFN-stimulated genes, and modulation of the protein expressions of key effectors in the Type I IFN and PRRs signaling pathways.

Enhancing microbial fuel cell (MFC) performance in treatment of solid potato waste by mixed feeding of boiled potato and waste activated sludge.

The effects of mixed feeding of boiled potato and waste activated sludge (WAS) on the performance of a microbial fuel cell (MFC) in treating solid potato waste were investigated. The coulombic efficiency (CE) of four MFCs fed with potato cubes containing 0, 48.7, 67.3 and 85.6% of boiled potato was 53.5, 70.5, 92.7 and 71.1%, respectively, indicating enhanced electricity generation and the existence of an optimum mixing ratio. The hydrolysis rate estimated using a first-order sequential hydrolysis model increased from 0.061 to 0.191 day-1, leading to shortening of the startup time for current density reaching its maximum from 25 to 5 days. The final chemical oxygen demand (COD) removal reached 85%. The CE of seven MFCs, fed with raw potato alone, sterilized/unsterilized WAS alone, and four mixed samples of raw potato with sterilized WAS at ratios of 2:1 and 4:1 and unsterilized WAS at 2:1 and 4:1, was found to be 6.1, 43.6, 0.3, 31.0, 16.5, 0.9 and 31.1%, respectively. The hydrolysis rate increased from 0.056 to 0.089 day-1, and the final COD removal changed from 39.5 to 89.6% following the order: potato alone > mixture of potato & WAS > sterilized WAS alone > unsterilized WAS alone.

[Immunologic mechanisms of Yinhua Pinggan granule and San-ao decoction against influenza virus in vivo].

This paper aimed to investigate the effect of Yinhua Pinggan granule and San-ao decoction on the immunologic mechanisms of influenza viral pneumonia mice in vivo, in order to study the activity of the combined administration of different formulas on influenza A/H1N1 virus. The model of pneumonia was established in mice through nasal dropping influenza virus, and then divided randomly into five groups: normal control group, influenza virus model group, oseltamivir control group, Yinhua Pinggan granule group, and San-ao decoction group. The animals were put to death at the 5th day after gavage administration with the corresponding drugs. The contents in mice serum of TNF-α, IL-6 and IFN-γ were respectively measured by ELISA. The mRNA expressions of TLR3/7, MyD88, JNK, p38MAPK and NF-κB p65 in lung tissues were respectively detected by RT-PCR. The protein expressions of JNK, p38MAPK and NF-κB p65 in lung tissues were determined by immunohistochemical analysis, respectively. According to the results, Yinhua Pinggan granule and San-ao decoction could significantly decrease the levels of TNF-α and IL-6, increase the level of IFN-γ in mice serum of lung tissues, significantly reduce the gene expressions of TLR3/7, MyD88, JNK, p38MAPK and NF-κB p65 in influenza virus-infected mice lung tissues, and significantly reduce the protein expressions of JNK, p38MAPK and NF-κB p65 in lung tissues. Furthermore, the regulatory effect of Yinhua Pinggan granule was superior to that of San-ao decoction. In conclusion, Yinhua Pingan granule and San-ao decoction have the therapeutic effect on pneumonia mice infected by H1N1 virus in vivo. The anti-influenza mechanisms of Yinhua Pinggan granule and San-ao decoction may be the results of interactions by regulating the immunologic function of influenza virus-infected mice and TLR3/7 signaling pathway with multiple links of the gene and protein expressions. Moreover, the combined administration of warm-natured and cold-natured Yinhua Pinggan granule with the effects of detoxification and exhalation has a better effect than the single administration of warm-natured San-ao decoction.

Efficacy and safety of Danhong injection for treating myocardial infarction: a systematic review and meta-analysis of randomized controlled trials.

Objective: Danhong injection (DHI) is widely used in the treatment of myocardial infarction (MI). We aimed to systematically review the efficacy and safety of DHI in a randomized controlled experiment on MI. Methods: We searched the randomized controlled trials (RCTs) of DHI for MI published before 2 April 2023 in China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Wanfang database, China Science and Technology Journal Database (VIP), PubMed, Web of Science, Cochrance Library, and Embase databases. The methodological quality of the included studies was evaluated using the Cochrane Handbook 5.3 criteria using the RevMan software, and meta-analysis was performed and a forest map was drawn. Results: A total of 38 trials included 3877 patients, including 2022 cases in the DHI treatment group and 1855 cases in the control group. Meta-analysis showed that the total effective rate (RR = 1.18%, 95% CI [1.14-1.12]) during treatment with DHI was higher than that of the control group. The prevalence of cardiac arrhythmia (RR = 0.55%, 95% CI [0.46-0.65]) was lower than that of the control group. The incidence of heart rate failure (RR = 0.45%, 95% CI [0.30-0.70]) was lower than that of the control group. The prevalence of cardiogenic shock (RR = 0.33%, 95% CI [0.11-1.04]) was p > 0.05, and the difference was not statistically significant. There was no statistically significant difference in LVEF between the two groups (MD = 0.00%, 95% CI [0.00-0.00]). CK-MB (MD = -0.81%, 95% CI [-0.92∼ -0.69]) was lower than the control group. hs-CRP (MD = -1.09, 95% CI [-1.22∼ -0.97]) was lower than the control group. The incidence of adverse reactions (RR = 0.37, The 95% CI [0.17-0.82]) was lower than that in the control group. Conclusion: Basing on our study, the use of DHI in the treatment of myocardial infarction patients is effective, can improve cardiac function, reduce the incidence of adverse reactions, and improve the overall quality of life. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023390973.

Social Support and Psychological Capital Mediate the Effect of Personalities on the Mental Health of Professional Staff in China During COVID-19 Pandemic.

Objective: COVID-19-related lockdown can lead to mental health problem, which displays heterogeneous between individuals. The aim of this study was to explore the association between mental health, social support and psychological capital state of professional staff with different personalities during the COVID-19 pandemic in China. Methods: A cross-section study was conducted via online survey using the questionnaires of General Health Questionnaire (GHQ-12), Multidimensional Scale of Perceived Social Support (MSPSS), Psychological Capital Questionnaire (PCQ), Eysenck Personality Questionnaire-Revision Short Scale of China (EPQ-RSC). A total of 626 employees were included. Multiple regression analysis was performed to investigate the association of psychological capital, perceived social support, EPQ-N and EPQ-E and their interactions in general mental health. Results: About 2.7% of professionals had mental health. The married had a higher mental health score than the single (P<0.05). The regular exercising workers had the lowest mental health score (P<0.05), and higher psychological capital and social support scores than the non-exercising ones (P<0.01). Multivariate analysis showed that the interaction between social support, psychological capital and neuroticism was statistically significant (ß=-0.161, P<0.001) in general mental health with neuroticism ranking the top (ß=0.352, P<0.001). Mediation analysis showed that social support modified the effect of psychological capital on mental health, accounting for 25.5% of the total effect, and that both social support and psychological capital mediated the effect of neuroticism or extroversion differentially on mental health. Conclusion: Neuroticism is an influencing factor on mental health of professional staff. Social support and psychological capital played a partial mediating role in the effect of neuroticism or extroversion differentially on mental health in China. The findings suggest that during the COVID-19 pandemic, more social support and psychological capital are needed for the professional individuals with neuroticism to alleviate their stress and improve mental health.

Amygdalin prevents multidrug-resistant Staphylococcus aureus-induced lung epithelial cell injury by regulating inflammation and oxidative stress.

Methicillin-resistant Staphylococcus aureus (MRSA) is an opportunistic pathogen that can cause severe bacterial pneumonia. Amygdalin is the main active pharmaceutical ingredient of bitter almond, which has broad-spectrum antibacterial, anti-inflammatory, anti-oxidation and immunomodulatory effects. It is also the main ingredient of Yinhua Pinggan granule, which is commonly used to moisten the lung and relieve cough. However, little is known about the effects of amygdalin on MRSA. In this study, we found that amygdalin exhibited good antimicrobial activity in vitro against MRSA. Amygdalin has a protective effect on MRSA infected cells, and the effect is better when combined with levofloxacin. It also can reduce the adhesion and invasion of MRSA to cells. Amygdalin has anti-inflammatory and antioxidant effects, which can significantly reduce the increase of inflammatory factors and the production of ROS caused by infection. The protective mechanism of amygdalin on cells may be related to inhibiting the expression of NLRP3, ASC and IL-1ß pyroptosis pathways. Taken together, our study suggests that amygdalin exerts antibacterial effects by affecting biofilm formation, the expression of virulence factors, and drug resistance genes. Amygdalin combined with levofloxacin has a protective effect on A549 cells infected with MRSA, and the mechanism may be related to the inhibition of inflammatory response, oxidative damage and pyroptosis.

Therapeutic Suppression of Atherosclerotic Burden and Vulnerability via Dll4 Inhibition in Plaque Macrophages Using Dual-Targeted Liposomes.

Atherosclerosis, characterized by chronic inflammation within the arterial wall, remains a pivotal concern in cardiovascular health. We developed a dual-targeted liposomal system encapsulating Dll4-targeting siRNA, designed to selectively bind to pro-inflammatory M1 macrophages through surface conjugation with anti-F4/80 and anti-CD68 antibodies. The Dll4-targeting siRNA is then delivered to the macrophages, where it silences Dll4 expression, inhibiting Notch signaling and reducing plaque vulnerability. Emphasizing accuracy in targeting, the system demonstrates effective suppression of Dll4, a key modulator of atherosclerotic progression, and vulnerability via VSMCs phenotypic conversion and senescence. By employing liposomes for siRNA delivery, we observed enhanced stability and specificity of the siRNA. Alongside the therapeutic efficacy, our study also evaluated the safety profile and pharmacokinetics of the dual-targeted liposomal system, revealing favorable outcomes with minimal off-target effects and optimal biodistribution. The integration of RNA interference techniques with advanced nanotechnological methodologies signifies the importance of targeted delivery in this therapeutic approach. Preliminary findings suggest a potential attenuation in plaque development and vulnerability, indicating the therapeutic promise of this approach. This research emphasizes the potential of nanocarrier-mediated precision targeting combined with a reassuring safety and pharmacokinetic profile for advancing atherosclerosis therapeutic strategies.

The mediating effect of psychological flexibility on fatigue and depressive symptoms among nursing staff.

Objectives: To explore the relationship between depressive symptoms, fatigue and psychological flexibility, as well as their interactions on depression in Chinese nurses. Material and Methods: Using convenience sampling, a cross-sectional survey of 796 nurses in municipal hospitals of Zhengzhou, Henan Province, China, was conducted. The questionnaires of Work-related Acceptance and Action Questionnaire, Center for Epidemiological Studies Depression Scale and Fatigue Assessment Instrument were used. Hierarchical regression and bootstrap methods were used to examine the mediating effect of psychological flexibility between fatigue and depression. Results: More than 51.8% of the nurses were at risk of depression and 62.3% were at risk of fatigue. There was a significantly positive and moderate correlation between depression and fatigue severity, situation specificity, and consequences (r = 0.43, r = 0.24 and r = 0.31, respectively, p < 0.01). Depression was negatively correlated with psychological flexibility (r = -0.28, p < 0.01). Psychological flexibility had a negative impact on depression with the explained variance increased by 4.2% (ß = -0.211, p < 0.001). The bootstrap method showed that the mediating effect of psychological flexibility accounting for 8.5% and 12.3% on fatigue and depressive symptoms, respectively. Conclusions: Psychological flexibility plays a partial mediating role between the fatigue severity, consequences of fatigue and depressive symptoms of nurses. Hospital managers should improve medical staff work acceptance to alleviate their depressive symptoms. Int J Occup Med Environ Health. 2023;36(4):563-74.

Calycosin alleviates cerebral ischemia/reperfusion injury by repressing autophagy via STAT3/FOXO3a signaling pathway.

BACKGROUND: As a common cerebrovascular disease (CVD) of the elderly, ischemic stroke (IS) is characterized by high disability and mortality. Excessive autophagy induced by IS is implicated in neuronal death, therefore, the inhibition of immoderate autophagy is viewed as a potential therapeutic avenue to treat IS. Calysoin (CA) is a bioactive component of Radix Astragali, which has been widely used to treat CVDs. However, the mechanism of the treatment of IS by CA is still problematic. PURPOSE: Based on the result of network pharmacology, whether CA inhibited autophagy by regulating the STAT3/FOXO3a pathway to alleviate cerebral ischemia-reperfusion injury (CIRI) was investigated in vivo and in vitro for the first time. STUDY DESIGN: Integrate computational prediction and experimental validation based on network pharmacology. METHODS: In current study, network pharmacology was applied to predict the mechanism of the treatment of IS by CA, and it was shown that CA alleviated CIRI by inhibiting autophagy via STAT3/FOXO3a signaling pathway. One hundred and twenty adult male specific pathogen-free Sprague-Dawley rats in vivo and PC12 cells in vitro were used to verify the above prediction results. The rat middle cerebral artery occlusion/reperfusion (MCAO/R) model was established by suture method, and oxygen glucose deprivation/re-oxygenation (OGD/R) model was used to simulate cerebral ischemia in vivo. The content of MDA, TNF-α, ROS and TGF-ß1 in rat serum were detected by ELISA kits. The mRNA and protein expressions in brain tissue were detected by RT-PCR and Western Blotting. The expressions of LC3 in brain were detected immunofluorescent staining. RESULTS: The experimental results demonstrated that administration of CA dosage-dependently improved rat CIRI as evidenced by the reduction in the cerebral infarct volume, amelioration of the neurological deficits. HE staining and transmission electron microscopy results revealed that CA ameliorated cerebral histopathological damage, abnormal mitochondrial morphology, and damaged mitochondrial cristae structure in MCAO/R rats. CA treatment exerted protective effects in CIRI by inhibiting inflammation response, oxidative stress injury, and cell apoptosis in rat and PC12 cells. CA relieved excessive autophagy induced by MCAO/R or OGD/R through downregulating the LC3Ⅱ/LC3Ⅰ ratio and upregulating the SQSTM1 expression. CA treatment also decreased p-STAT3/STAT3 and p-FOXO3a/FOXO3a ratio in the cytoplasm and modulated the autophagy-related gene expression both in vivo and in vitro. CONCLUSION: Treatment with CA attenuated CIRI by reducing excessive autophagy via STAT3/FOXO3a signal pathway in rat and PC12 cells.

Danhong injection alleviates cerebral ischemia-reperfusion injury by inhibiting mitochondria-dependent apoptosis pathway and improving mitochondrial function in hyperlipidemia rats.

Cerebral ischemia threatens human health and life. Hyperlipidemia is a risk of cerebral ischemia. Danhong injection (DHI) is a traditional Chinese medical preparation for the treatment of cerebrovascular diseases. However, the effects of DHI on mitochondria-dependent apoptosis and mitochondrial function following cerebral ischemia in hyperlipidemia rats are not clear. In this study, SD rats were fed by high-fat diet for six weeks to establish the hyperlipidemia model, except for the sham and ischemia-reperfusion (I/R) groups. Hyperlipidemia rats were assigned into I/R + high-fat diet (HFD) group, DHI 1 mL/kg group, and DHI 2 mL/kg group. DHI was administrated to the drug group via caudal vein for seven consecutive days (once per day). Subsequently, rats underwent middle cerebral artery occlusion (MCAO) for 1 h and reperfusion for 24 h. The results showed that DHI significantly reduced cerebral infarction volume, ameliorated neurological function, improved pathological changes, and inhibited apoptosis. DHI could significantly restore the levels of mitochondrial respiratory chain complexes I-IV, increase the ATP content and COX activity, and decrease the level of OFR in the ischemic brain mitochondria of hyperlipidemia rats after I/R. DHI significantly regulated the levels of cytochrome c (Cyt c), Apaf1, Bax, Bcl-2, Caspase-3, and Caspase-9 in brain tissue, and improved mitochondrial dynamics (Mfn1, Mfn2, OPA1, Drp1, and Fis1). The results indicate that DHI could alleviate ischemic brain injury in hyperlipidemia rats, and the mechanism may be to improve mitochondrial function by restoring the mitochondrial respiratory chain and changing the protein balance of mitochondrial fusion and fission, and inhibiting mitochondria-dependent apoptosis.

Yinhuapinggan granule ameliorates lung injury caused by multidrug-resistant Acinetobacter baumannii via inhibiting NF-κB/NLRP3 pathway.

Yinhuapinggan granule (YHPG) is a traditional Chinese medicine prescription with rich clinical experience for the treatment of colds and coughs. The aim of this study is to investigate the protective effect of YHPG on multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) infection in vivo and its potential anti-inflammatory mechanism. BALB/c mice were intranasally inoculated with MDR A. baumannii strain to establish the pneumonia infection model, and received intraperitoneally cyclophosphamide to form immunosuppression before attack. YHPG (6, 12 and 18 g/kg) was administered by gavage once a day for 3 consecutive days after infection. The protective effect of YHPG was evaluated by lung index, spleen index, thymus index, pathological changes of lung tissue and inflammatory factors (IL-1ß, IL-6 and TNF-α) in serum. The expression of key targets of NF-κB/NLRP3 signaling pathway in vivo was analyzed by immunohistochemistry, immunofluorescence, reverse transcription quantitative PCR (RT-qPCR) and Western blot. The results showed that YHPG improved the lung index and its inhibition rate, immune organ indexes and lung pathological changes in infected mice, and significantly reduced IL-1ß, IL-6 and TNF-α levels in serum. In addition, YHPG significantly down-regulated the mRNA and protein expression of NF-κB p65, NLRP3, ASC, Caspase-1, TNF-α, IL-6 and IL-1ß in mice lung tissue. The results of the current study demonstrated that YHPG has significant protective effects on mice infected with MDR A.baumannii, which may be related to the regulation of inflammatory factors and NF-κB/NLRP3 signaling pathway, indicating that YHPG has a wide range of clinical application value and provides a theoretical basis for its treatment of MDR A.baumannii infection.

Multi-omics research strategies in ischemic stroke: A multidimensional perspective.

Ischemic stroke (IS) is a multifactorial and heterogeneous neurological disorder with high rate of death and long-term impairment. Despite years of studies, there are still no stroke biomarkers for clinical practice, and the molecular mechanisms of stroke remain largely unclear. The high-throughput omics approach provides new avenues for discovering biomarkers of IS and explaining its pathological mechanisms. However, single-omics approaches only provide a limited understanding of the biological pathways of diseases. The integration of multiple omics data means the simultaneous analysis of thousands of genes, RNAs, proteins and metabolites, revealing networks of interactions between multiple molecular levels. Integrated analysis of multi-omics approaches will provide helpful insights into stroke pathogenesis, therapeutic target identification and biomarker discovery. Here, we consider advances in genomics, transcriptomics, proteomics and metabolomics and outline their use in discovering the biomarkers and pathological mechanisms of IS. We then delineate strategies for achieving integration at the multi-omics level and discuss how integrative omics and systems biology can contribute to our understanding and management of IS.

Effectiveness and safety of selected traditional Chinese medicine injections in patients with combined diabetes mellitus and coronary heart disease: A systematic review and network meta-analysis of randomized clinical trials.

Background: In view of the high morbidity and mortality of Diabetes mellitus-Coronary heart disease (DM-CHD) in diabetics, the combination therapy of traditional Chinese medicine injections (TCMIs) and conventional therapy (CT) is receiving extensive attention. Therefore, the effectiveness and security of conventional therapy with traditional Chinese medicine injections in the therapy of diabetes mellitus-coronary heart disease were compared by systematical review and network meta-analysis. Methods: According to the preset inclusion criteria and exclusion criteria, we searched seven electronic literature databases from their inception to JAN 5,2022, to obtain the relevant RCT literature on the therapy of diabetes mellitus-coronary heart disease with traditional Chinese medicine injections. Two researchers independently reviewed the papers, two other researchers worked in extracting data and quality assessment of the included literature. The primary outcomes were total effective rate. The secondary outcomes included electrocardiogram (EGG)effective rate, the effective rate of angina pectoris, fasting blood glucose (FBG), 2-h postprandial blood glucose (PBG), hemoglobinA1c (HbA1c), total cholesterol (TC) and triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), frequency of angina pectoris, and duration of angina pectoris. We adopted stata16.0 software for the systematic review and network meta-analysis. Results: A total of 53 trials involved 4,619 patients and one of the following 16 traditional Chinese medicine injections: Danhong, Danshen, Gualoupi, Gegen, Chuanxiongqin, Danshenchuanxiongqin, Shenmai, Shenqi, Xixin, Xuesaitong, Shuxuetong, Guanxinning, Kudiezi, Ciwujia, Xingding, Shuxuening. The meta-analysis revealed that Chuanxiongqin injection was superior to all other therapies in improving the total effective rate, [vs. conventional therapy odds ratio (OR): 14.52, 95% confidence interval (CI): 4.13-51.02], vs. Xuesaitong injection (odds ratio: 7.61, confidence interval: 1.25-46.40), and vs. Danshenchuanxiongqin injection (odds ratio: 3.98, confidence interval: 1.03-15.28)]. Xixin injection + conventional therapy was superior to conventional therapy only for electrocardiogram effective rate (odds ratio: 5.44, confidence interval: 1.55-19.18). Shenmai injection + conventional therapy was superior to conventional therapy in effective rate of angina (odds ratio: 11.05, confidence interval: 2.76-44.28). There was not different significantly in the comparisons of frequency of angina pectoris and duration of angina pectoris, we considered that this may be due to the lack of sufficient data. As most of the included RCTs did not monitor Adverse Events, the safety of those traditional Chinese medicine injections remains to be further explored. Conclusion: Basing on our study, traditional Chinese medicine injections combined with conventional therapy takes important role in the treatment of diabetes mellitus-coronary heart disease, and its curative effect is better than conventional therapy. Nevertheless, properly designed RCTs are required to validate our conclusions in the future. Systematic Review Registration: [https://inplasy.com/inplasy-2021-12-0125/], identifier [INPLASY2021120125].

Matrine inhibits advanced glycation end products-induced macrophage M1 polarization by reducing DNMT3a/b-mediated DNA methylation of GPX1 promoter.

Advanced glycation end products (AGEs) are characterized diabetic metabolites inducing macrophage M1 polarization which is crucial in diabetes-exacerbated atherosclerosis. Matrine was proved anti-atherosclerotic. The current study was aimed to investigate the inhibitory effects of matrine on AGEs- induced macrophage M1 polarization and underlying molecular mechanisms. Primary mouse macrophages were exposed to AGEs. Receptor for AGEs (RAGE) and toll-like receptor 4 (TLR4) were over-expressed by vectors. Matrine was used to treat these cells. Inducible nitric oxide synthase (iNOS) expression and pro-inflammatory cytokine production were used to evaluate macrophage M1 polarization. Oxidative stress was assessed by intracellular reactive oxygen species (ROS) generation, total antioxidant capacity (TAC) and malondialdehyde (MDA) contents. Relative mRNA expression level was determined by real-time PCR. Western blotting was used to evaluate protein and protein phosphorylation levels. Bisulfite sequencing PCR (BSP) was used to evaluate DNA methylation. Matrine reduced AGEs exposure-elevated expressions of DNA methyltransferase (DNA MTase, DNMT)3a and DNMT3b in macrophages which were not affected by RAGE or TLR4 over expressions. DNA methylation rate of GPX1 promoter was reduced from 97.22% to 66.67% in AGEs- exposed macrophages treated by matrine. GPX1 expression was up-regulated by matrine, which further suppressed AGEs/RAGE-mediated oxidative stress. Thus, the activation of down-stream TLR4/STAT1 signaling pathway was inhibited by matrine treatment which eventually suppressed AGEs- induced macrophage M1 polarization. However, these effects of matrine were impaired by RAGE and TLR4 overexpression. Results from this study suggested that matrine inhibited AGEs- induced macrophage M1 polarization by suppressing RAGE-induced oxidative stress-mediated TLR4/STAT1 signaling pathway. Matrine exerted anti-oxidant effects via increasing GPX1 expression by inhibiting DNMT3a/b-induced GPX1 promoter DNA methylation.

Clinical Efficacy Protocol of Yinhuapinggan Granules: A Randomized, Double-Blind, Parallel, and Controlled Clinical Trial Program for the Intervention of Community-Acquired Drug-Resistant Bacterial Pneumonia as a Complementary Therapy.

Background: Community-acquired bacterial pneumonia (CABP) is an important health care concern in the worldwide, and is associated with significant morbidity, mortality, and health care expenditure. Streptococcus pneumoniae is the most frequent causative pathogen of CABP. Common treatment for hospitalized patients with CABP is empiric antibiotic therapy using ß-lactams in combination with macrolides, respiratory fluoroquinolones, or tetracyclines. However, overuse of antibiotics has led to an increased incidence of drug-resistant S. pneumoniae, exacerbating the development of community-acquired drug-resistant bacterial pneumonia (CDBP) and providing a challenge for physicians to choose empirical antimicrobial therapy. Methods: Traditional Chinese medicine (TCM) is widely used as a complementary treatment for CDBP. Yinhuapinggan granules (YHPG) is widely used in the adjuvant treatment of CDBP. Experimental studies and small sample clinical trials have shown that YHPG can effectively reduce the symptoms of CDBP. However, there is a lack of high-quality clinical evidence for the role of YHPG as a complementary drug in the treatment of CDBP. Here, we designed a randomized, double-blind, placebo-controlled clinical trial to explore the efficacy and safety of YHPG. A total of 240 participants will be randomly assigned to the YHPG or placebo group in a 1:1 ratio. YHPG and placebo will be added to standard treatment for 10 days, followed by 56 days of follow-up. The primary outcome is the cure rate of pneumonia, and the secondary outcomes includes conversion rate of severe pneumonia, lower respiratory tract bacterial clearance, lactic acid (LC) clearance rate, temperature, C-reactive protein (CRP), criticality score (SMART-COP score), acute physiological and chronic health assessment system (APACHEII score) and clinical endpoint events. Adverse events will be monitored throughout the trial. Data will be analyzed according to a pre-defined statistical analysis plan. This research will disclose the efficacy of YHPG in acquired drug-resistant pneumonia. Clinical Trial Registration: https://clinicaltrials.gov, identifier ChiCTR2100047501.