Viral metagenomics combined with non-targeted serum metabolomics reveals the role of enteroviruses in a mouse model of coronary heart disease.

BACKGROUND: Coronary heart disease (CHD) is a common cardiovascular disease that is associated with altered gut microbiota. Enteroviruses, an essential component of the gut microbiome, may play an important role in disease progression. However, the relationship between enteroviruses and CHD remains unclear. The development of high-throughput sequencing technologies has facilitated research on the interconnections between viruses and disease-related metabolites. METHODS AND RESULTS: Mice were fed a high-fat diet (CHD group) or chow diet (Sham group) for 12 weeks, and ligation of the left anterior descending coronary artery was performed at the end of week 8. After 4 weeks, all animals were euthanised. Subsequently, the animals were evaluated for basic haemato-biochemical parameters and cardiac function, and aorta staining was performed. Based on enteroviral metagenomics and serum UPLC-MS/MS metabolomics analyses, we evaluated the association between enteroviral groups and serum metabolites of CHD mouse model. A high-fat diet and coronary ligation enabled the establishment of the CHD mouse model. Notably, the enterovirus spectrum of the sham group was significantly different from that of the CHD group, with 24 viral communities of different family and species classification, such as Tsarbombavirus, Mingyongvirus, Claudivirus, and Firehammervirus, exhibiting significant differences. In addition, 731 Differential metabolites were detected in the serum of both groups of mice. Correlation network analysis revealed a close relationship between various metabolites related to lipid metabolism and different viruses, including Tsarbombavirus, Mingyongvirus, Claudivirus, and Firehammervirus. CONCLUSIONS: An animal model of CHD, characterised by lipid disturbance and myocardial ischaemia, was established using a high-fat diet and ligation of the left anterior descending branch of the coronary artery. Tsarbombavirus, Firehammervirus, Mingyongvirus, and Claudivirus were associated with metabolites in the lipid metabolism pathway. The results indicate that Tsarbombavirus may be the main genus interacting with CHD-related metabolites in mice. Conclusively, the findings of our study provide novel insights into the potential relationship enterovirus groups and metabolites associated with CHD.

[Role of lymphatic system in coronary heart disease based on theory of combined phlegm and stasis].

According to the traditional Chinese medicine(TCM) theory, coronary heart disease(CHD) is mainly caused by heart vessel obstruction due to Qi stagnation, blood stasis, and phlegm turbidity. Chest impediment with combined phlegm and stasis is a common syndrome of CHD, with the manifestations of chest tightness, chest pain, and asthma. Lymphatic system is one of the important immune systems in the human body and has a close relationship with the Qi and blood movement in TCM. The dysfunction of the lymphatic system may lead to metabolism disorders, the generation of dampness pathogen which turns into sticky and difficult-to-dissolve phlegm turbidity. Moreover, it can affect blood circulation and coagulation, causing slow blood flow, increased blood viscosity, and microcirculation disorders. Alterations in lymphatic hydrodynamics may affect the interaction between blood circulation and the lymphatic system. A variety of small molecule drugs and TCM can treat cardiovascular diseases by targeting the lymphatic system. This review discusses the role of the lymphatic system in CHD based on the theory of combined phlegm and stasis, involving the influences of mechanical factors on lymphatic function and the effects and pharmacological mechanisms of TCM and chemicals that target lymphocyte function and lymphatic circulation. By expounding the development process of combined phlegm and stasis in CHD from the lymphatic system, this paper aims to provide new ideas for deciphering pharmacological mechanisms of TCM for resolving phlegm and stasis.

Development and assessment of the efficacy and safety of human lung-targeting liposomal methylprednisolone crosslinked with nanobody.

Glucocorticoid (GC) hormone has been commonly used to treat systemic inflammation and immune disorders. However, the side effects associated with long-term use of high-dose GC hormone limit its clinical application seriously. GC hormone that can specifically target the lung might decrease the effective dosage and thus reduce GC-associated side effects. In this study, we successfully prepared human lung-targeting liposomal methylprednisolone crosslinked with nanobody (MPS-NSSLs-SPANb). Our findings indicate that MPS-NSSLs-SPANb may reduce the effective therapeutic dosage of MPS, achieve better efficacy, and reduce GC-associated side effects. In addition, MPS-NSSLs-SPANb showed higher efficacy and lower toxicity than conventional MPS.

Mechanisms of traditional Chinese medicine in modulating gut microbiota metabolites-mediated lipid metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: The gut microbiome plays an important role in advancing the process of host lipid metabolism directly or indirectly. Traditional Chinese medicine (TCM) can improve the intestinal environment by intervening with gut microbiota metabolites to potentially regulate lipid levels. However, the underlying mechanisms remain unclear. Therefore, we examined the current databases to search for studies related to influence of TCM on the gut microbiota metabolites-mediated lipid metabolism. AIM OF THE STUDY: This paper aims to review the TCM that could regulate lipid metabolism mediated by microbial metabolites and their pharmacological targets and provides perspectives for future investigation. METHODS: Electronic databases including PubMed, Web of Science, EMBASE, the Cochrane Library, Chinese Biological Medicine Database, and China National Knowledge Infrastructure were searched up to April 2021 to identify eligible studies. RESULTS: A total of 30 active compounds, five Chinese herbal formulae, and three proprietary Chinese medicines were included in this review. We found that TCM can effectively improve lipid metabolism by increasing short chain fatty acids (SCFA) levels, regulating bile acid (BA) metabolism, reducing the production of trimethylamine N-oxide (TMAO), alleviating the release of inflammatory factors, and altering branched-chain amino acids (BCAA) biosynthesis. This process is accompanied by changes in the structure of the gut microbiota, blood lipids, and expression of lipid metabolism genes. CONCLUSION: In summary, studies on the regulation of lipid metabolism by microbial metabolites in TCM will provide a new approach for better management of dyslipidemia, which may facilitate future clinical treatments.

Development of a self-management support program for caregivers of relatives with dementia in Shanghai.

The purposes of this study were to develop a caregiver-education booklet and to elicit intervention strategies for a self-management support program for caregivers of relatives with dementia in Shanghai. Two focus groups with 32 eligible caregivers were conducted to clarify the knowledge and information about the scope and main points of, as well as the barriers to and support for caregiver self-management. Content analysis revealed that the main challenges caregivers faced were a lack of reliable and accessible information about dementia care, frustrations related to communication with the care recipient, disturbances in daily routines, and unfamiliarity with and/or difficulty in balancing the caregiver's own health needs. Access to individualized and reliable instruction and/or group support were the major types of support the participants expected for their self-management. Based on the findings and relevant literature, an illustrated caregiver-education booklet was developed and the intervention strategies were also discussed for the program.

IL-17A Can Promote Propionibacterium acnes-Induced Sarcoidosis-Like Granulomatosis in Mice.

The etiology of sarcoidosis is unknown. In this study, Propionibacterium acnes (PA) was used to induce sarcoidosis-like granulomatous inflammation in a mouse model. Wild-Type (WT) C57BL/6 mice were divided into three groups: (1) WT-PA group; (2) WT-PA + Incomplete Freund's Adjuvant (IFA) group; and (3) WT-PBS group. Loose granuloma formation was observed in the lungs on day 56 in the WT-PA and WT-PA + IFA groups. The proportions of peripheral Th17 cells in the WT-PA (p = 0.0004) and WT-PA + IFA groups (p = 0.0005) were significantly higher than that in the WT-PBS group. The proportions of peripheral Treg cells in the WT-PA (p < 0.0001) and WT-PA + IFA groups (p < 0.0001) were lower than that in the WT-PBS group. Then, to explore the mechanism of IL-17, Wild-Type (WT) C57BL/6 mice were divided into three groups: (1) WT-PBS group (2) WT-PA group; (3) WT-PA + mouse IL-17A neutralizing antibody (IL-17Ab) group. IL-17A gene knockout mice (KO) were divided into two groups: (1) KO -PA group; (2) KO-PBS group. The KO-PA and WT-PA + IL-17Ab groups showed reduced inflammation and no loose granuloma formation on day 56. As compared to the WT-PA group, the ratio of peripheral Th17 in the KO-PA (p < 0.0001) and WT-PA + IL-17Ab groups (p < 0.0001) decreased, while the ratio of peripheral Treg in the KO-PA (p < 0.0001) and WT-PA + IL-17Ab (p = 0.0069) groups increased on day 56. Hence, PA can be used to establish a mouse model of sarcoidosis-like granuloma. IL-17A plays an important role in experimental sarcoidosis-like granuloma formation.

Bioactive compounds from herbal medicines to manage dyslipidemia.

Dyslipidemia is a key risk factor for cardiovascular diseases, which are a major cause of morbidity and mortality worldwide. However, despite the advancement of the treatment and prevention of dyslipidemia, medications used to treat dyslipidemia are limited to chemical drugs. Herbal medicine, as an alternative treatment, has a long history of usage and provides more treatment options, and related studies have revealed intervention targets for dyslipidemia. Four lipid-lowering mechanisms of herbal medicines have been proposed and are discussed in this paper. These mechanisms are the inhibition of cholesterol absorption in enterocytes, reduction of cholesterol synthesis, elevation of reverse cholesterol transport, and promotion of cholesterol excretion in the liver. This review elaborates on the underlying molecular pathways involved in plasma lipid balance via bioactive compounds from herbal medicines.

Azithromycin treats diffuse panbronchiolitis by targeting T cells via inhibition of mTOR pathway.

Azithromycin (AZM), that is a macrolide antibiotic, has been found to treat diffuse panbronchiolitis (DPB) effectively. However, the mechanism of action underlying the therapeutic effects remains unclear. We selected 64 patients with DPB from 305 patients who were diagnosed with DPB at the outpatient clinic in Shanghai Pulmonary Hospital from Jan 2010 to Oct 2014. The primary PBLs, CD4 + T cells, and Jurkat T cells were treated with AZM or erythromycin (EM), and the effects of AZM and EM on IL-17A and CXCL-2 production, proliferation, apoptosis and autophagy were evaluated. AZM and EM significantly inhibited IL-17A and CXCL-2 production in patients' PBLs (all P < 0.05). AZM significantly inhibited proliferation and promoted apoptosis of T cells from DPB patients. AZM can enhance autophagosome formation of T cells by suppressing S6RP phosphorylation, which is a downstream target of mTOR pathway (all P < 0.05). AZM and EM significantly decreased secreted IL-17A levels (P < 0.05) in the primary CD4 + T cells of patients with DPB. AZM may treat DPB patients by targeting cytokine production, proliferation, apoptosis and autophagy of T cell. The mechanism of therapeutic effects of AZM on DPB may be associated with a specific inhibition of mTOR pathway in the T lymphocytes.

IL-17A contributes to HSV1 infection-induced acute lung injury in a mouse model of pulmonary fibrosis.

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) often experience acute exacerbation (AE) after an episode of common cold. AIMS: To establish a mouse model of virus infection-induced AE-IPF and investigate the mechanism underlying the AE-IPF. METHODS: Herpes simplex virus 1 (HSV1) was inoculated intranasally to wild-type (WT) and IL-17A gene knockout (IL-17A-/- ) mice 21 days after intratracheal administration of bleomycin (BLM). RESULTS: HSV1 infection caused acute exacerbation in mice with BLM-induced fibrosis. Compared with the BLM+Saline mice, the mice with BLM+HSV1 showed significantly higher acute lung injury (ALI) score (P < 0.0001), lower survival rate (100% vs 21.4%, P < 0.0001), poorer lung function and higher inflammatory response representing by increased total inflammatory cells in bronchoalveolar lavage fluid (BALF) (P = 0.0323), increased proportion of Th17 cells in peripheral blood (P = 0.0004) and higher inflammatory factors in BALF. In addition, HSV1 infection increased the expression of endoplasmic reticulum stress (ERS)-related proteins in mice with BLM-induced fibrosis. The inhibition of ERS by tauroursodeoxycholic acid (TUDCA, an ERS inhibitor) significantly reduced the IL-17A levels in BALF (P = 0.0140) and TH17 cells in the peripheral blood (P = 0.0084) of mice with BLM+HSV1, suggesting that suppression of ERS may reduce TH17 response in mice with AE-IPF. Compared with WT mice with BLM+HSV1, IL-17A-/- mice with BLM+HSV1 had lower ALI score (P = 0.0119), higher survival rate (78.6% vs 21.4%, P = 0.004), improved lung function, and milder inflammatory response. CONCLUSIONS: HSV1 infection in addition to BLM-induced IPF can successfully establish AE-IPF in mice. IL-17A and ERS promote lung inflammation in AE-IPF development.

Highly sensitive wearable sensor based on a flexible multi-layer graphene film antenna.

The use of advanced carbon nanomaterials for flexible antenna sensors has attracted great attention due to their outstanding electromechanical properties. However, carbon nanomaterial based composites have yet to overcome drawbacks, such as low conductivity and toughness. In this work, a flexible multi-layer graphene film (FGF) with a high conductivity of 106 S/m for antenna based wearable sensors is investigated. A 1.63 GHz FGF antenna sensor exhibits significantly high strain sensitivity of 9.8 for compressive bending and 9.36 for tensile bending, which is super than the copper antenna sensor (5.39 for compressive bending and 4.05 for tensile bending). Moreover, the FGF antenna sensor shows very good mechanical flexibility, reversible deformability and structure stability, and thus is well suited for applications like wearable devices and wireless strain sensing.

XuefuZhuyu decoction protected cardiomyocytes against hypoxia/reoxygenation injury by inhibiting autophagy.

BACKGROUND: XuefuZhuyu decoction (XFZY) is a well-known traditional Chinese herbal medicine for the treatment of various cardiovascular diseases, such as unstable angina pectoris and myocardial ischemia-reperfusion injury. However, the mechanism by which XFZY contributes to the amelioration of cardiac injury remains unclear. METHODS: H9C2 cells were cultured under the hypoxic condition for 10 h and reoxygenated for 2 h. In the presence of various concentrations of XFZY for 12 h, the cell viability was measured by MTT assay. The protective effect of XFZY in hypoxia/reoxygenation (H/R) cell model was confirmed by measuring the amount of LDH released into the extracellular fluid. Cell apoptosis was measured by western blotting. The autophagy level of H9C2 cells and the correlative pathway were determined by transmission electron microscopy, Cyto-ID® Autophagy Detection Kit, and western blotting. RESULTS: In this study, we investigated the effects of XFZY on H/R induced cardiac injury. The results showed that treatment with XFZY significantly inhibited autophagy induced by H/R, with decreased formation of autophagosomes as well as the expression of LC3-II/LC3-I ratio and Beclin 1 after H/R. Importantly, inhibition of autophagy by XFZY resulted in enhanced cell viability and decreased apoptosis. XFZY also inhibited the activation of AMPK and upregulated the phosphorylation of mammalian target of Rapamycin (mTOR). CONCLUSIONS: The cardioprotective effects of XFZY during H/R were mediated by inhibiting autophagy via regulating AMPK-mTOR signaling pathways.

Can hemozoin alone cause host anaemia?

Both schistosomes and malaria parasites produce hemozoin and cause host anaemia. However, the relationship between anaemia and hemozoin is unclear. Although some studies have proposed that hemozoin is related to anaemia in malaria patients, whether hemozoin alone can cause anaemia in patients infected by malaria parasites or schistosomes is uncertain. To investigate the effect of hemozoin on hosts, ß-haematin was injected intravenously to normal mice. Then, liver and spleen tissues were observed. Mouse blood was examined. Red blood cells (RBCs), white blood cells (WBCs) and haemoglobin were analysed. Macrophage changes in the spleens and marrow cells were compared using immunofluorescence and H&E or Giemsa stain, respectively. We found that after 15 injections of ß-haematin, a large amount of ß-haematin was observed to deposit in the livers and spleens. Splenomegaly and bone marrow mild hyperplasia were detected. The average number of RBCs, average number of WBCs and average concentration of haemoglobin decreased significantly from 9.36 × 1012 cells/L to 8.7 × 1012 cells/L, 3.8 × 109 cells/L to 1.7 × 109 cells/L and 142.8 g/L to 131.8 g/L, respectively. In specific, the number of macrophages in the spleens greatly increased after ß-haematin infection. The results showed that injections of ß-haematin alone can cause anaemia possibly through hypersplenism.

Wen-Xin Decoction ameliorates vascular endothelium dysfunction via the PI3K/AKT/eNOS pathway in experimental atherosclerosis in rats.

BACKGROUND: Nitric oxide (NO) is the most powerful vasodilator that inhibits leukocyte adhesion, platelet aggregation, and vascular smooth muscle cell proliferation. However, excessive NO can cause lipid peroxidation and direct endothelial cell damage. Therefore, investigation of the role of NO in artherosclerosis development is important. Wen-Xin Decoction (WXD) has been shown to relieve myocardial ischemia reperfusion injury and prevent leukocyte adhesion and invasion; in addition, it can accelerate angiogenesis and prevent platelet activation and aggregation. In this study, we focused on the NO pathway to further clarify the protective effects of WXD on the vascular endothelium in rat models of artherosclerosis. METHODS: Wistar rats were randomly divided into a normal group (n = 10) and a model group (n = 75). Rat models of atherosclerosis were generated by intraperitoneal vitamin D3 (3 months) injections and administration of a high-fat diet (3 months with vitamin D3 and 2 months alone). The model rats were randomly divided into five groups (n = 15 each): model (saline), atorvastatin (4.8 mg/kg/d atorvastatin), high-dose WXD (9 g/kg/d), medium-dose WXD (4.5 g/kg/d), and low-dose WXD (2.25 g/kg/d) groups. Each group received continuous drug or saline administration (suspended liquid gavage) for 30 days, following which all animals were sacrificed. The ultrastructure and histopathological changes of vascular endothelial cells and the expression of PI3K/AKT/eNOS and iNOS in the thoracic aorta tissue were analyzed. RESULTS: WXD increased NO levels, modulated the NO/ET-1 ratio, and promoted repair of the injured vascular endothelium in a dose-dependent manner. At a high dose, WXD regulated the NO/ET-1 ratio as effectively as atorvastatin; furthermore, it increased NO levels within the physiological range to prevent endothelial damage caused by excessive NO expression. Real-time polymerase chain reaction and Western blot analysis showed that WXD significantly upregulated the mRNA and protein expressions of PI3K, AKT, and eNOS mRNA and significantly increased AKT and eNOS phosphorylation. CONCLUSIONS: Our results suggest that WXD protects and maintains the integrity of the vascular endothelium by activating the PI3K/AKT/eNOS pathway, decreasing iNOS expression, and promoting the release of physiological NO levels.

[Effects of Tanyu Tongzhi recipe on hemorheology, blood lipid and inflammatory factors in rats with mycardial ischemia-reperfusion injury and hyperlipidemia].

OBJECTIVE: To investigate the influence of Tanyu Tongzhi (TYTZ) recipe on chemorheology, blood lipid and inflammatory factors of hyperlipidemia and myocardial ischemia-reperfusion injury in rats. METHOD: Sixty SD male rats were divided into 5 groups randomly, sham-operated group, model group, high dose group of reproduced by ligation of left descending artery for 30 min followed by releasing the TYTZ and low group of TYTZ. The model of MI/RI injury of the myocardium was ligation for 2 hours in rats. Serum contents of CHO, TG, HDL-L, LDL-L and whole blood viscosity, plasma viscosity and ICAM-1, TNF-alpha, IL-10 were measured after myocardial reperfusion injury. RESULT: Compared with sham-operated group, the levels of CHO, TG, LDL-L, whole blood viscosity (1.0,3.0) plasma viscosity and the contents of ICAM-1 were significantly higher, however, HDL-L, IL-10 levels were lower in model group (P < 0.01 and P < 0.05). CHO, TG, whole blood viscosity (1.0, 3.0, 30) and expression of ICAM-1, TNF-alpha were obviously lower in low group than the model group (P < 0.01 and P < 0.05). CONCLUSION: The TYTZ recipe can relieve reperfusion injury through regulating blood lipid, improving hemorheological characteristic and inhibiting inflammatory reaction.

Gualou xiebai banxia decoction inhibits NF-kappa B-dependent inflammation in myocardial ischemia-reperfusion injury in rats.

OBJECTIVE: To evaluate the myocardial protective effect of Gualou Xiebai Banxia decoction GXBD) and explore the mechanisms of inhibition of NF-kappa B activation and blockade of inflammatory responses induced by ischemia-reperfusion in rats. METHODS: Twenty-four Sprague Dawley (SD) rats were randomly divided into three groups. Rats in the treatment group received GXBD (13 g crude drug/kg) for three weeks, while rats in the model control and normal control groups received equal volumes of distilled water. On the 22nd day, rats in the ischemia-reperfusion (I/R) control and GXBD-treated groups underwent 30 min occlusion of the left anterior descending (LAD) coronary artery, followed by 120 min reperfusion. Electrocardiogram was recorded, and the activities of cardiac enzymes, cytokines, and NF-kappaB were assessed after I/R. RESULTS: Compared with the I/R control group, GXBD treatment restored the activity of the specific myocardial-injury marker creatine kinase (CK) and lactate dehydrogenase (LDH), and inhibited the inflammatory response involving the nuclear factor-kappaB (NF-KB) pathway, including down-regulation of interleukin (IL)-1beta and IL-6, and up-regulation of IL-10 gene expression. CONCLUSION: GXBD strongly reduced myocardial impairment in our I/R model, including inhibition of NF-kappaB activation and inflammatory cytokine responses.

[Protective effects of xuefu zhuyu decoction on myocardium ischemia reperfusion injury in rats].

OBJECTIVE: To investigate the protective effects of Xuefu Zhuyu decoction on myocardium ischemia reperfusion injury in rats. METHOD: 36 SD rats were divided into 3 groups randomly, sham-operated group, model group, Xuefu Zhuyu decoction group. The model of MI/RI of the myocardium was reproduced by ligation of left descending artery for 30 min followed by releasing the ligation for 2 hours in rats. Serum contents of LDH-L, CK were measured, the levels of serum IL-1beta, IL-6 and IL-10 were measured and myocardial ultrastructure at the ischemia region was observed under the transmission electron microscope after myocardial reperfusion injury. RESULT: Compared with model group, IL-1beta, IL-6 and IL-10 levels were lower, myocardial ultrastructural changes were improved in Xuefu Zhuyu decoction group (P < 0.01), however, serum contents of LDH-L and CK no significant difference were found among the model group and Xuefu Zhuyu decoction group. CONCLUSION: Xuefu Zhuyu decoction can protect myocardium from MI/RI, the mechanism of action was related to inhibiting inflammatory reaction and reducing arrhythmia and the injury of the myocardial ultrastructure.