Reduced Inflammation Response Research Articles

Mesenchymal Stem Cells-Derived Exosomes Alleviate Acute Lung Injury by Inhibiting Alveolar Macrophage Pyroptosis.

Acute lung injury (ALI) is an important pathological process of acute respiratory distress syndrome, yet there are limited therapies for its treatment. Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been shown to be effective in suppressing inflammation. However, the effects of MSCs-Exo on ALI and the underlying mechanisms have not been well elucidated. Our data showed that MSCs-Exo, but not exosomes derived from MRC-5 cells (MRC-5-Exo), which are human fetal lung fibroblast cells, significantly improved chest imaging, histological observations, alveolocapillary membrane permeability, and reduced inflammatory response in ALI mice model. According to miRNA sequencing and proteomic analysis of MSCs-Exo and MRC-5-Exo, MSCs-Exo may inhibit pyroptosis by miRNAs targeting caspase-1-mediated pathway, and by proteins with immunoregulation functions. Taken together, our study demonstrated that MSCs-Exo were effective in treating ALI by inhibiting the pyroptosis of alveolar macrophages and reducing inflammation response. Its mechanism may be through pyroptosis-targeting miRNAs and immunoregulating proteins delivered by MSCs-Exo. Therefore, MSCs-Exo may be a new treatment option in the early stage of ALI.

Repairing Volumetric Muscle Loss with Commercially Available Hydrogels in an Ovine Model.

Volumetric muscle loss (VML) is the loss of skeletal muscle that exceeds the muscle's self-repair mechanism and leads to permanent functional deficits. In a previous study, we demonstrated the ability of our scaffold-free, multiphasic, tissue-engineered skeletal muscle units (SMUs) to restore muscle mass and force production. However, it was observed that the full recovery of muscle structure was inhibited due to increased fibrosis in the repair site. As such, novel biomaterials such as hydrogels (HGs) may have significant potential for decreasing the acute inflammation and subsequent fibrosis, as well as enhancing skeletal muscle regeneration following VML injury and repair. The goal of the current study was to assess the biocompatibility of commercially available poly(ethylene glycol), methacrylated gelatin, and hyaluronic acid (HA) HGs in combination with our SMUs to treat VML in a clinically relevant large animal model. An acute 30% VML injury created in the sheep peroneus tertius (PT) muscle was repaired with or without HGs and assessed for acute inflammation (incision swelling) and white blood cell counts in blood for 7 days. At the 7-day time point, HA was selected as the HG to use for the combined HG/SMU repair, as it exhibited a reduced inflammation response compared to the other HGs. Six weeks after implantation, all groups were assessed for gross and histological structural recovery. The results showed that the groups repaired with an SMU (SMU-Only and SMU+HA) restored muscle mass to greater degree than the groups with only HG and that the SMU groups had PT muscle masses that were statistically indistinguishable from its uninjured contralateral PT muscle. Furthermore, the HA HG, SMU-Only, and SMU+HA groups displayed notable efficacy in diminishing pro-inflammatory markers and showed an increased number of regenerating muscle fibers in the repair site. Taken together, the data demonstrates the efficacy of HA HG in decreasing acute inflammation and fibrotic response. The combination of HA and our SMUs also holds promise to decrease acute inflammation and fibrosis and increase muscle regeneration, advancing this combination therapy toward clinically relevant interventions for VML injuries in humans.

Superhydrophobic polyether sulfone (PES) dialysis membrane with enhanced hemocompatibility and reduced human serum protein interactions: Ex vivo, in situ synchrotron imaging, experimental, and computational studies

This study aimed to enhance the hemocompatibility of polyethersulfone (PES) membranes by increasing their hydrophobicity. Two methods were used: chemical modification with a hydrophobic substance and creating a micropatterned structure using modified silica nanoparticles (SiO2 NP) in a mixed matrix membrane (MMM). Fibrinogen adsorption was assessed using synchrotron radiation micro-computed tomography (SR-µCT), and surface roughness was analyzed with atomic force microscopy (AFM). Hemocompatibility was evaluated by studying interactions with patients' serum and measuring the release of inflammatory biomarkers (C5a, IL-1α, IL-1β, IL-6, vWF, C5b-9 and PF-4). Differential Scanning Calorimeter (DSC) analysis determined the stability of the membrane hydration layer, and water contact angle (WCA) measurements assessed hydrophobic properties. Fourier-transform infrared spectroscopy (FTIR) and surface charge analysis examined surface stability. Molecular docking analysis showed reduced interaction between hydrophobized PES membranes and fibrinogen and albumin in human serum. SR-µCT analysis revealed 20% less fibrinogen adsorption on hydrophobized PES membrane surfaces. MMM PES membranes exhibited minimal fibrinogen adsorption due to the micropatterned structure. Both hydrophobized PES membranes demonstrated reduced vWF biomarker release (25–28%) compared to unmodified PES, with MMM PES membranes performing best. However, both hydrophobized PES membranes led to a significant increase (150%) in IL-6 upon blood contact, attributed to the reduced hydration layer. MMM PES membranes contained the least strongly bound water (0.2%) and exhibited the highest hydrophobicity (98°). This study highlights the potential of hydrophobized PES membranes and MMM structures for enhancing hemocompatibility, with opportunities for optimizing surface modifications to reduce inflammation responses while maintaining desirable properties.

Pulmonary administration of tetrandrine loaded Zinc-Alginate nanogels attenuates pulmonary fibrosis in rats

Pulmonary fibrosis is a chronic and progressive disease, current systemic administration is not fully effective with many side effects, such as gastrointestinal and liver injury. The pulmonary delivery system for pulmonary fibrosis may contribute to maximize therapeutic benefit. Natural compounds might have prominence as potential drug candidates, but the low bioavailabilities affect their clinical use. Tetrandrine is a natural alkaloid with good anti-inflammatory, antifibrogenetic and antioxidant effects, and it is used as a clinical therapeutic drug for the treatment of silicosis in China. In the present study, we explore a new strategy of pulmonary delivery system to improve low solubility and pesticide effect of tetrandrine. Tetrandrine was loaded into alginate nanogels by reverse microemulsion method. The release behavior of tetrandrine reached zero-order kinetics release and the maximum free radical clearance rates reached up to 90%. The pulmonary fibrosis rats were treated with tetrandrine nanogels by using ultrasonic atomizing inhalation. Tetrandrine nanogels decreased the development and progression of fibrosis by reducing inflammation response and bating the deposition of extra cellular matrix. In conclusion, ultrasonic atomizing inhalation of tetrandrine nanogels provided a new therapeutic strategy for pulmonary fibrosis.

Low‐Dose Cu Ions Assisted by Mild Thermal Stimulus Inducing Bacterial Cuproptosis‐Like Death for Antibiosis and Biointegration

AbstractMethicillin‐resistant Staphylococcus aureus (MRSA) is threatening human health due to its resistance to multiple antibiotics. Excessive copper (Cu) ions target the lipoylated proteins of tricarboxylic acid cycle of cancer cells, inducing proteotoxic stress and their cuproptosis death. Whether cuproptosis plays a part in killing MRSA by low‐dose supplement of Cu ions remains to be explored. Herein, Cu‐doped hydroxyapatite nanorods (PC) are prepared on polyetheretherketone (PEEK) to resist infection and improve PEEK performance in tissue integration with the assistance of near‐infrared (NIR) irradiation, and the mechanism against MRSA is elucidated. Mild photothermal stimulation increases bacterial membrane permeability, accelerating Cu ions’ intake and consequently inducing cuproptosis‐like death of MRSA. It is confirmed by aggregation of dihydrolipoamide S‐acetyltrans‐ferase (DLAT), deactivation of glutathione peroxides 4 (GPX4), and destabilization of Fe─S cluster proteins ferredoxin (FDX1) and lipoyl synthase (LIAS). Fortunately, fibroblast behaviors are upregulated on NIR‐irradiated PC. In vivo, PC with NIR irradiation exhibits outstanding MRSA elimination, reduced inflammation response, and improved biointegration. Overall, it is demonstrated that bacterial cuproptosis‐like death can be induced by Cu ions at a non‐cytotoxic dose when cooperated with mild heat stimulus, and this photothermal strategy of PC has greatly promising application in improving PEEK performance in clinic.

Research progress of postoperative cognitive dysfunction in cardiac surgery under cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) is often used in cardiothoracic surgery because its nonphysiological state causes pathophysiological changes in the body, causing multiorgan and multitissue damage to varying degrees. Postoperative cognitive dysfunction (POCD) is a common central nervous system complication after cardiac surgery. The etiology and mechanism of POCD are not clear. Neuroinflammation, brain mitochondrial dysfunction, cerebral embolism, ischemia, hypoxia, and other factors are related to the pathogenesis of POCD. There is a close relationship between CPB and POCD, as CPB can cause inflammation, hypoxia and reperfusion injury, and microemboli formation, all of which can trigger POCD. POCD increases medical costs, seriously affects patients' quality of life, and increases mortality. Currently, there is a lack of effective treatment methods for POCD. Commonly used methods include preoperative health management, reducing inflammation response during surgery, preventing microemboli formation, and implementing individualized rehabilitation programs after surgery. Strengthening preventive measures can minimize the occurrence of POCD and its adverse effects.

Tannic acid-Fe3+ dual catalysis induced rapid polymerization of injectable poly(lysine) hydrogel for infected wound healing

Infected wounds are difficult to heal because they are vulnerable to bacterial attacks, inflammatory responses, and oxidative stress. To promote the healing of infected wounds, we developed an injectable dual-network hydrogel TFAEP (TA-Fe, APS, EPL-GMA, PVA) based on ε-poly-l-lysine-graft-glycidyl methacrylate (EPL-GMA), polyvinyl alcohol (PVA), and tannic acid-iron (TA-Fe). TA-Fe formed a stable redox pair, which acted as a dual-autocatalytic system to activate ammonium persulfate, generate free radicals, and subsequently induce EPL-GMA polymerization. Then PVA formed hydrogen bonds with TA molecules. Here, TA-Fe not only simulated peroxidase to convert H2O2 into hydroxyl radicals (OH), but also exhibited good near-infrared photothermal conversion efficiency, which all endowed the hydrogel with excellent antibacterial ability. In addition, the hydrogel could remove excessive reactive oxygen species and reactive nitrogen species, alleviating oxidative stress and reducing inflammation response due to the presence of TA molecules. Moreover, the hydrogel showed good injectability and tissue adhesion, ensuring the close adhesion of the hydrogel to the wound and achieving the maximum function. In vivo experiments demonstrated that the hydrogel promoted infected wound healing by accelerating epidermal regeneration, promoting angiogenesis and collagen deposition, and facilitating the expression of anti-inflammatory factors.

Oolong tea polyphenols affect the inflammatory response to improve cognitive function by regulating gut microbiota

Oolong tea polyphenols (OTP) has received increasing attention for their ability to reduce cognitive dysfunction by modulating the gut microbiota and related metabolites. In our study, the circadian rhythm disorder (CRD) mice showed gut microbial disruption and cognitive impairments. OTP treatment restored the gut microbiota disruption including up-regulated the relative abundance of Akkermansia and Muribaculum, and down-regulated Desulfovibrio. Moreover, OTP reduced inflammation response, decreased lipopolysaccharide (LPS) levels, and strengthened tight junction proteins (TJPs) to ameliorate intestinal barrier dysfunction. These changes inhibited the elevated levels of pro-inflammatory factors, therefore, attenuated neuronal damage and Aβ protein aggregation in the hippocampus. Additionally, OTP supplementation also regulated the levels of metabolites related to cognitive function, some of them closely associated with microbiota. Our findings speculate that OTP potentially modulates cognitive impairment and inflammation caused by circadian disruption by modulating the gut microbiota.

Hepatoenteric Protective Effect of Melanin from Inonotus hispidus on Acute Alcoholic Liver Injury in Mice.

Alcoholic liver disease (ALD) is a common disease with a high incidence. Because traditional drugs have obvious side effects, it is desired to find more effective drugs. This study investigates the effects of melanin from Inonotus hispidus fruiting bodies (IHFM) on acute alcoholic injury mice and detects the protective mechanisms via the gut-microbiota-liver axis. The results show that IHFM alleviates mouse liver injury by enhancing alcohol metabolism capacity, reducing inflammation response level and strengthening antioxidant activities. IHFM also improves mouse liver injury by activating Nrf2 signaling pathway and inhibiting toll-like receptor4 (TLR4)/nuclear factor-κβ (NF-κβ) signaling pathway. Furthermore, 16S amplification sequencing shows that IHFM can significantly increase the relative abundance of Lactobacillus reuteri and Lactobacillus johnsonii. The relative abundance of L. reuteri positively correlates with an antioxidant index, while negatively correlates with inflammatory factors. IHFM can protect mice from acute alcoholic liver injury by upregulating the Nrf2 signaling pathway, downregulating the TLR4/NF-κβ signaling pathway, and upregulating the relative abundance of L. reuteri and L. johnsonii, representing a step forward in the development of IHFM.

Effects of microplastics and lead exposure on gut oxidative stress and intestinal inflammation in common carp (Cyprinus carpio L.)

Microplastics (MPs) are increasingly being detected in freshwater environments, which have the potential to cause combined toxicity with other contaminants on aquatic organisms. To reveal the ecological risks, the combined effects of lead (Pb) and polyvinyl chloride microplastics (MPs) were explored in the gut of common carp (Cyprinus carpio L.). The results confirmed that exposure of Pb alone accelerated Pb accumulation, increased oxidative stress, and activated the inflammation response of the gut. However, the aforementioned effects all decreased under the co-exposure of Pb and MPs. In addition, MPs altered intestinal microbial community of common carp, especially the abundance of immune system-related species. All measured variables were organized for partial least square path modeling, which revealed the combined effects of Pb and MPs on inflammation response. The results implied that MPs reduced inflammation response in two ways, including the reduction of intestinal Pb accumulation and the alteration of the intestinal microbial community. Overall, this study provides a novel aspect of ecological effects on aquatic animals from Pb and MPs exposure. The interesting results remind us that when exploring the ecological risks of MPs, combined effects from other toxic substances must be considered simultaneously.

Sustained release of EGF/bFGF growth factors achieved by mussel-inspired core–shell nanofibers with hemostatic and anti-inflammatory effects for promoting wound healing

Developing wound dressings with high-effective antibacterial activity, rapid hemostasis and accelerated wound healing are urgently needed in clinical wound treatment. Herein, in terms of coaxial electrospinning and mussel-inspired chemistry, a multifunctional polydopamine modified core–shell nanofiber membrane loaded with antibacterial quaternary ammonium salt grafted sulfonated chitosan (QAS-SCS) and bioactive EGF/bFGF in the core layer was constructed for hemostasis and promoting wound healing. The coaxial nanofibers exhibited excellent hydrophilicity,thermalstability, and suitable mechanical strengthand stretchability match human skin. The incorporation of QAS-SCS in the coaxial nanofibers led to efficient inherent antibacterialactivity, with bacteria inhibition rate of 95.15 ± 0.77% and 93.63 ± 1.44% against S. aureus and E. coli, respectively. The biocompatibility of nanofibers was studied through hemocompatibility and cell compatibility tests. In mouse full-thickness skin defect model, together with sustained release of dual growth factors (EGF/bFGF) achieved by core–shell structure, the multifunctional nanofibers were revealed to suppress the release of inflammatory cytokines, and reduce inflammation response, and enhance collagen deposition, and promote angiogenesis as well as hair follicles regeneration at the injury site, and finally accelerate wound healing. Overall, the as-prepared coaxial nanofibers simultaneously incorporated with QAS-SCS and EGF/bFGF provide an alternative strategy for skinwoundrepair.

Leukocyte and Platelet-Rich Plasma (L-PRP) in Tendon Models: A Systematic Review and Meta-Analysis of in vivo/in vitro Studies.

To perform a systematic review on the application of leukocyte- and platelet-rich plasma (L-PRP) in tendon models by reviewing in vivo/in vitro studies. The searches were performed via electronic databases including PubMed, Embase, and Cochrane Library up to September 2022 using the following keywords: ((tenocytes OR tendon OR tendinitis OR tendinosis OR tendinopathy OR tendon injury) AND (platelet-rich plasma OR PRP OR autologous conditioned plasma OR leukocyte- and platelet-rich plasma OR L-PRP OR leukocyte-richplatelet-rich plasma Lr-PRP)). Only in vitro and in vivo studies that assessed the potential effects of L-PRP on tendons and/or tenocytes are included in this study. Description of PRP, study design and methods, outcomes measured, and results are extracted from the data. A total of 17 studies (8 in vitro studies and 9 in vivo studies) are included. Thirteen studies (76%) reported leukocyte concentrations of L-PRP. Four studies (24%) reported the commercial kits. In in vitro studies, L-PRP demonstrated increased cell proliferation, cell migration, collagen synthesis, accelerated inflammation, and catabolic response in the short term. In addition, most in vivo studies indicated increased collagen type I content. According to in vivo studies reporting data, L-PRP reduced inflammation response in 71.0% of studies, while it enhanced the histological quality of tendons in 67.0% of studies. All 3 studies reporting data found increased biomechanical properties with L-PRP treatment. Most evidence indicates that L-PRP has some potential effects on tendon healing compared to control. However, it appears that L-PRP works depending on the biological status of the damaged tendon. At an early stage, L-PRP may accelerate tendon healing, but at a later stage, it could be detrimental.

Mesoporous silica-coated silver nanoparticles as ciprofloxacin/siRNA carriers for accelerated infected wound healing

The colonization of bacterial pathogens is a major concern in wound infection and becoming a public health issue. Herein, a core–shell structured Ag@MSN (silver core embedded with mesoporous silica, AM)-based nanoplatform was elaborately fabricated to co-load ciprofloxacin (CFL) and tumor necrosis factor-α (TNF-α) small interfering RNA (siTNF-α) (AMPC@siTNF-α) for treating the bacterial-infected wound. The growth of bacterial pathogens was mostly inhibited by released silver ions (Ag+) and CFL from AMPC@siTNF-α. Meanwhile, the loaded siTNF-α was internalized by macrophage cells, which silenced the expression of TNF-α (a pro-inflammatory cytokine) in macrophage cells and accelerated the wound healing process by reducing inflammation response. In the in vivo wound model, the Escherichia coli (E. coli)-infected wound in mice almost completely disappeared after treatment with AMPC@siTNF-α, and no suppuration symptom was observed during the course of the treatment. Importantly, this nanoplatform had negligible side effects both in vitro and in vivo. Taken together, this study strongly demonstrates the promising potential of AMPC@siTNF-α as a synergistic therapeutic agent for clinical wound infections.Graphical

Pomegranate juice ameliorates pulmonary fibrosis by regulating inflammatory response and epithelial mesenchymal transformation

POMJ could ameliorate pulmonary fibrosis in vivo and in vitro . Based on the analysis of the bioactive ingredients and the anti-oxidation ability of POMJ, we explored the potential role and underlying mechanisms of POMJ against PF both in in vivo and in vitro experimental model. POMJ could improve BLM-induced PF by alleviating the inflammatory response and the progression of EMT, and also could ameliorate EMT process in TGF-β1 stimulated cell model by inhibiting the activation of NF-κB pathway. • The potential bioactive ingredients in POMJ were analyzed using LC-HR/MS. • POMJ prevents bleomycin-induced lung injury by reducing inflammation response. • POMJ alleviated EMT in vivo and in vitro . • POMJ suppressed TGF‐β1‐induced NF‐κB pathway activation in EMT. Pulmonary fibrosis (PF) is a chronic, progressive interstitial pneumonia characterized by abnormal epithelial -mesenchymal transition (EMT) and persistent inflammatory injury. Pomegranate has multiple biological activities, including antioxidant, anti-inflammatory and anticancer activities. In this study, we evaluated the effect of pomegranate juice (POMJ) in ameliorating PF and explored the underlying mechanisms in vivo and in vitro . Compared to the Vehicle group, POMJ attenuated bleomycin (BLM)-induced histopathological changes and collagen deposition in the lungs and alleviated the inflammatory response. Western blot and immunohistochemistry results revealed that POMJ treatment reduced the expression of Collagen I and Vimentin and increased the expression of E-cadherin. In addition, in TGF-β1-treated A549 cells, it was further confirmed, which may be associated with inhibition of NF-κB pathway activation. Taken together, these findings suggest that POMJ ameliorates lung injury by regulating the inflammatory response and the process of EMT, exhibiting great potential to ameliorate pulmonary fibrosis.

Pyroptosis executor gasdermin D plays a key role in scleroderma and bleomycin-induced skin fibrosis

The NLRP3 inflammasome and IL-1β are essential for scleroderma pathogenesis. Nevertheless, the role of pyroptosis executor gasdermin D(GSDMD), which is a downstream molecule of NLRP3 and is required for IL-1β release in some situations, has not yet been well elucidated in scleroderma. Here, we found that GSDMD was significantly up-regulated and activated in the skin of scleroderma patients and bleomycin-induced mouse model. What’s more, the ablation of GSDMD ameliorates bleomycin-induced skin fibrosis according to HE staining, Masson staining and the detection of hydroxyproline contents. GSDMD deficiency also impaired macrophages infiltration and reduced inflammation response. Furthermore, the loss of GSDMD reduced Th17 differentiation in vivo and in vitro. Collectively, these findings provide the first demonstration that GSDMD related pyroptosis plays an important role in scleroderma pathogenesis.

Antimicrobial hydrogel microspheres for protein capture and wound healing

Growth factors are vital to regulate cellular responses for wound healing process. Engineered microspheres provide a promising tool for developing effective growth factor-loaded matrix for regenerative medicine therapy. Here, we report a novel multifunctional chitosan microsphere that enables facile one-step capture and efficient growth factor delivery for enhanced wound repair. The microfluidic technique was used to fabricate magnetic chitosan (MCS) microspheres. By immobilization with Zn2+ ions, the biohybrid MCS allowed for the flexible operation to capture histidine-tagged vascular endothelial growth factor (VEGF) produced in Escherichia coli (E. coli). The VEGF-conjugated MCS were then applied onto the wounds to examine their capabilities in promoting wound healing. Zn2+ and chitosan in MCS exhibited a synergetic antibacterial effect towards both Gram-positive and Gram-negative bacteria. Using a rat model, we further demonstrated that the microspheres significantly promoted wound healing process, as evidenced by rapid wound closure, induced epithelialization and angiogenesis, and reduced inflammation response. Together, our data indicated the presented MCS as a versatile tool for capturing and locally delivering growth factors, which can be applied to wound repair. Moreover, with the functional flexibility, this biohybrid MCS could be empolyed in a wide range of biomedical applications by conjugating proteins of interest.

Novel dopamine-modified oxidized sodium alginate hydrogels promote angiogenesis and accelerate healing of chronic diabetic wounds

Herein, the dopamine (DA) was grafted with oxidized sodium alginate (OSA) via Schiff base reduction reaction, aiming to fabricate novel DA-grafted OSA (OSA-DA) hydrogels with enhanced biocompatibility and suitable adhesion for clinical applications. The chemical structures of OSA-DA were characterized via UV–Vis, FTIR and 1H NMR spectroscopy analysis. The hydrogel characteristics, biocompatibility, as well as the chronic diabetic wound healing efficacy were investigated. Our results demonstrated that DA was grafted with OSA successfully with highest grafting rate of 7.50%. Besides, OSA-DA hydrogels possessed suitable swelling ratio and appropriate adhesion characteristics. Additionally, OSA-DA exhibited satisfactory cytocompatibility and cell affinity in L-929 cells, and superior biocompatibility in SD rats. Moreover, OSA-DA exerted remarkable promoting effects on migration and tube formation of human umbilical vein endothelial cells (HUVECs). Studies on full-thickness excision chronic diabetic wounds further revealed that OSA-DA hydrogels could accelerate healing via promoting angiogenesis, reducing inflammation response, and stimulating collagen deposition. Overall, our studies would provide basis for SA-based hydrogels as clinical wound dressings.

Use of Batroxobin in Central and Peripheral Ischemic Vascular Diseases: A Systematic Review.

Background and Purpose: The mechanism of action of Batroxobin included the decomposition of the fibrinogen to fibrin degradation products (FDPs) and D-dimer and mobilization of endothelial cells to release endogenous nt-PA and to promote thrombolysis. This review aims to summarize current study findings about batroxobin on correcting cerebral arterial, venous, and peripheral vascular diseases, to explore the mechanism of batroxobin on anti-thrombosis process.Methods: A thorough literature search was conducted utilizing the PubMed Central (PMC) and EMBASE databases to identify studies up to June 2021. Data from clinical studies and animal experiments about batroxobin were extracted, integrated and analyzed based on Cochrane handbook for systematic reviews of interventions approach and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P), including the condition of subjects, the usage and dosage, research observation index and main findings.Results: A total of 62 studies were enrolled in this systematic review, including 26 clinical studies and 36 animal experiments. The 26 clinical studies involved 873 patients with arterial ischemic events, 92 cases with cerebral venous thrombosis, 13 cases with cerebral cortical vein thrombosis, and 1,049 cases with peripheral vascular diseases. These patients included 452 males and 392 females aged 65.6 ± 5.53 years. The results revealed that batroxobin had broad effects, including improving clinical prognosis (n = 12), preventing thrombosis (n = 7), promoting thrombolysis (n = 6), and improving vascular cognitive dysfunction (n = 1). The effects of batroxobin on reducing neuronal apoptosis (n = 8),relieving cellular edema (n = 4), improving spatial memory (n = 3), and promoting thrombolysis (n = 13) were concluded in animal experiments. The predominant mechanisms explored in animal experiments involved promoting depolymerization of fibrinogen polymers (n = 6), regulating the expression of related molecules (n = 9); such as intercellular adhesion molecule, heat shock proteins, tumor necrosis factor), reducing oxidative stress (n = 5), and reducing inflammation response (n = 4).Conclusion: Batroxobin can correct both arterial and venous ischemic diseases by promoting depolymerization of fibrinogen polymers, regulating the expression of related molecules, reducing oxidative stress, and reducing the inflammation response.

Effects of curcumol on liver function and fibrosis in rats of nonalcoholic fatty liver disease and its mechanism

Objective: To investigate the effects and mechanism of curcumol (CC) on liver function and fibrosis in rats of nonalcoholic fatty liver disease (NAFLD). Methods: The rat models of nonalcoholic steatohepatitis (NASH) combined with liver fibrosis were constructed by high-fat diet. Sixty SD rats were randomly divided into blank control group, model group (NASH), NASH + Compound Biejiarangan Troche (CBT) group (positive control group), and NASH + CC groups (25, 50, 100 mg/kg) , 10 rats in each group. The percentage of liver to body weight, and the levels of high density lipoprotein (HDL), triglyceride (TG), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured. The liver fibrosis was observed by HE staining. The expressions of α-smooth muscle actin (α-SMA) and positive staining of nuclear factor κB p65 (NF-κB p65) were detected by immunohistochemistry. The expression levels of α-SMA, matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and toll-like receptor-4 (TLR4), transforming growth factor-activated kinase-1 (TAK1), NF-κB p65 and vascular cell adhesion molecule-1 (VCAM-1) were detected by Western blot. The expression levels of interleukin (IL-6, IL-10, IL-1β) and tumor necrosis factor-α (TNF-α) were detected by enzyme linked immunosorbent assay (ELISA). Results: Compared with blank control group, the contents of HDL and IL-10 and the expression level of MMP-1 protein were decreased in model group significantly (P＜0.05), while the levels of TG, ALT and AST, the positive rate of P65, α-SMA, TIMP-1, TLR4, TAK1, NF-κB p65, VCAM-1, IL-6, TNF-α and IL-1β were increased significantly (P＜0.05). Compared with model group, the levels of HDL, IL-10 and MMP-1 protein were significantly increased after treatment with CBT and CC (P＜0.05), while the levels of TG, ALT, and AST, the positive rate of P65, α-SMA, TIMP-1, TLR4, TAK1, NF-κB p65, VCAM-1, IL-6, TNF-α and IL-1β were decreased significantly (P＜0.05). The improvement in model+high- concentration CC group was the most significant, and which in all concentration groups was lower than that in model+CBT group (P＜0.05). Conclusion: CC can reduce inflammation response and improve liver function by regulating TLR4, TAK1 and NF-κB/p65 signaling pathway, and thus alleviating liver fibrosis, showing concentration-dependence within certain range.

Epoxyeicosatrienoic acids prevent cardiomyocytes against sepsis by A2AR-induced activation of PI3K and PPARγ

Although epoxyeicosatrienoic acids (EETs) have multiple protective effects against different diseases, whether they can improve the pathogenesis of lipopolysaccharide (LPS)-induced septic cardiac dysfunction remains unknown. We investigated the effects of EETs on the LPS-induced inflammatory response in myocardial dysfunction mice and H9c2 cardiac myocytes. Cardiac-specific CYP2J2 transgenic mice (Tr) showed improved cardiac function and reduced inflammation response after administration with LPS, while the protective effects were not observed in A2A adenosine receptor (A2AR/ADORA2A)–deficient mice (knockout/KO). In vitro, EETs prevented LPS-induced inflammation and apoptosis in the cardiomyocytes via A2AR activation. Moreover, ZM241385 (A2AR inhibitor) attenuated the cardioprotective properties of EETs. Further investigation demonstrated that A2AR signal pathway activation partly regulated phosphatidylinositol 3-kinase (PI3K) and peroxisome proliferator-activated receptor-γ (PPARγ) expression. This is the first report on EETs exerting cardioprotective effects against LPS-induced cardiomyocyte injury via A2AR activation.