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Liver fibrosis is a disease largely driven by resident and recruited macrophages. The phenotypic switch of hepatic macrophages can be achieved by chemo-attractants and cytokines. During a screening of plants traditionally used to treat liver diseases in China, paeoniflorin was identified as a potential drug that affects the polarization of macrophages. The aim of this study was to evaluate the therapeutic effects of paeoniflorin in an animal model of liver fibrosis and explore its underlying mechanisms. Liver fibrosis was induced in Wistar rats via an intraperitoneal injection of CCl4. In addition, the RAW264.7 macrophages were cultured in the presence of CoCl2 to simulate a hypoxic microenvironment of fibrotic livers in vitro. The modeled rats were treated daily with either paeoniflorin (100, 150, and 200 mg/kg) or YC-1 (2 mg/kg) for 8 weeks. Hepatic function, inflammation and fibrosis, activation of hepatic stellate cells (HSC), and extracellular matrix (ECM) deposition were assessed in the in vivo and in vitro models. The expression levels of M1 and M2 macrophage markers and the NF- κ B/HIF-1 α pathway factors were measured using standard assays. Paeoniflorin significantly alleviated hepatic inflammation and fibrosis, as well as hepatocyte necrosis in the CCl4-induced fibrosis model. Furthermore, paeoniflorin also inhibited HSC activation and reduced ECM deposition both in vivo and in vitro. Mechanistically, paeoniflorin restrained M1 macrophage polarization and induced M2 polarization in the fibrotic liver tissues as well as in the RAW264.7 cells grown under hypoxic conditions by inactivating the NF- κ B/HIF-1 α signaling pathway. In conclusion, paeoniflorin exerts its anti-inflammatory and anti-fibrotic effects in the liver by coordinating macrophage polarization through the NF- κ B/HIF-1 α pathway. [ABSTRACT FROM AUTHOR]

Background. Sepsis is a common complication of severe trauma, burns, infection, or major surgery. This disease-related end-organ dysfunction results from systemic inflammatory response syndrome (SIRS). Acute kidney damage (AKI), also known as acute renal failure, is one of the most frequent and serious sequelae of sepsis. Nuclear transcription factor-κB (NF-κB) regulates the transcription of inflammation-related genes and operates as a mediator in the immune system. While parthenolide (PTL) has been reported to prevent harmful inflammatory reactions, its effects on sepsis-associated AKI are unknown. The current study investigates the effects of PTL in sepsis-associated AKI using cell and cecal ligation and puncture (CLP) models. Methods. Lipopolysaccharide (LPS)-stimulated rat glomerular mesangial cells were treated with 10 μM PTL. Inflammatory mediators, including TNF-α, IL-6, and IL-1β, in the culture supernatants were measured by ELISA, and NF-κB levels were assessed by qPCR. After the generation of the septic CLP model, rats were intraperitoneally injected with 500 g/kg PTL and were euthanized after 72 h. Serum and kidney samples were analyzed. Results. TNF-α, IL-1β, and IL-6 levels were elevated after LPS treatment of rat glomerular mesangial cells (p = 0.004 , p = 0.002 , and p = 0.004 , respectively) but were significantly reduced in the PTL treatment group (p ≤ 0.001 , p = 0.01 , and p ≤ 0.001). NF-κB p65 levels were also increased after LPS treatment in this group and were reduced in the PTL treatment group. PTL treatment also reduced kidney damage after CLP induction, as shown by histological analysis and reductions in the levels of BUN, Cre, KIM-1, and NAGL. CLP-induced kidney inflammation together with increased levels of proinflammatory cytokines and inflammatory-related proteins. The elevated levels of renal TNF-α, IL-6, and IL-1β were downregulated after PTL treatment. The PTL treatment also reduced the CLP-induced activation of NF-κB p65 in the damaged kidneys. Conclusion. PTL reduced inflammation induced by CLP-induced AKI in rat models and LPS-induced damage to glomerular mesangial cells by suppressing NF-κB signaling. [ABSTRACT FROM AUTHOR]

This study aimed to use network pharmacology to detail the natural components isolated from Triptergium wilfordii Hook F (TwHF) and examine the effect of the main component (demethylzeylasteral, DEM) on rat models of diabetic nephropathy (DN). In this study, we used network pharmacology to detail the natural components isolated from TwHF, referenced a gene library when screening for components effective in the management of DN, and DEM was confirmed in DN rats. All data were analyzed using the Discovery Studio 4.5 System and the systems Dock online docking method platform. All 24 rats were divided into 4 groups: control, DN, TwHF, and DEM. Blood and urine samples were tested at 0, 8, and 12 weeks. Renal histopathological changes were scored. Network pharmacology indicated that 370 compounds and 46 small molecules (including DEM) were biologically active constituents of TwHF, mainly affecting the inflammatory response through PI3K‐Akt and Jak–STAT pathways. Proteinuria in the TwHF and DEM groups was significantly lower than in the DN group (p ≤.001), and the decrease in proteinuria in the DEM group was more obvious than in the TwHF group (p =.004). The tubular interstitial scores were better in the DEM group than in the TwHF and DN groups. These results indicate that DEM effectively reduced proteinuria and alleviated the tubular interstitial changes in rat models of DN, which may be provide a scientific foundation for the development of novel drugs for treatment of DN. [ABSTRACT FROM AUTHOR]

Intestinal injury has been regarded as an important causative factor for systemic inflammation during heatstroke, and maintaining intestinal integrity has been a potential target for the prevention of HS. Huoxiang Zhengqi Dropping Pills (HZPD) is a modern preparation of Huoxiang Zhengqi and widely used to prevent HS. The present study aims to explore the protective effect of HZDP on intestinal injury during heatstroke and analyze its potential pharmacodynamic basis. Male rats in the control and HS groups were given normal saline, and those in the HZDP groups were given HZDP (0.23, 0.46, and 0.92 g/kg) before induction of HS. Serum contents of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), intestinal fatty acid-binding protein (iFABP), and diamine oxidase (DAO) were determined using ELISA. Histopathology of intestinal injury was observed following H&E staining. The expression of claudin-3 was determined using western blot, immunohistochemistry, and immunofluorescence techniques. Moreover, network pharmacological tools were used to analyze the potential pharmacodynamic basis and the mechanism of HZDP. Treatment with HZDP significantly prolonged the time to reach Tc. Compared with the control group, the contents of TNF-α, IL-6, iFABP, and DAO in HS rats increased markedly. HZDP treatments reduced these levels significantly, and the effects in the middle dose group (0.46 g/kg) were most obvious. HZDP also attenuated intestinal injury and significantly reversed the decrease in claudin-3 expression. Bioinformatics analysis suggested that 35 active ingredients and 128 target genes of HZDP were screened from TCMSP and 93 target genes intersected with heatstroke target genes, which were considered potential therapeutic targets. TNF-α and IL-6 were the main inflammatory target genes of HZDP correlated with HS. These results indicated that HZDP effectively protected intestinal barrier function and prevented acute intestinal injury by increasing the expression of claudin-3 in rats, eventually improving heat resistance. [ABSTRACT FROM AUTHOR]

There is a relationship between lung injury and ulcerative colitis. Currently, traditional Chinese medicine (Huangqi Jiegeng (HQJGD) and Huangqi Huanglian decoctions (HQHLD)) is commonly used for UC-related lung injury; however, the mechanisms of these drugs remain unclear. In this study, UC models were established with the mucous membrane of colon allergize combined with TNBS-alcohol enteroclysis for 4 weeks. The pathological changes in the lung, intestine, liver, and kidney were observed; cytokines, chemokines, and adhesion molecules in lung tissue were detected in order to explore the immunological mechanism of UC-related lung injury and the intervention mechanism of traditional Chinese medicine in treating the lung and intestine in the immune-TNBS-ethanol rat model. Histology examinations demonstrated evident pathological changes in the lungs and intestines of the model groups. Furthermore, all groups treated with TCMs demonstrated reduced expressions of toll-like receptor 4, nuclear factor kappa-B, and macrophage migration inhibitory factor. Additionally, radioimmunoassay and immunohistochemistry showed tumor necrosis factor-α, interleukin-6, and 8 expression downregulation. The results showed that HQJGD and HQHLD could alleviate pulmonary inflammation in UC-related lung injury by obviously improving the pathology and fibrosis of the lung, inhibiting the positive feedback loop of MIF/NF-κB, and reducing lymphocyte homing to bronchial mucosa. This model revealed the immune mechanism of UC-related lung injury and the intervention mechanism of the Chinese medicine, which provided the rationale for treating ulcerative colitis clinically, so as to demonstrate the theory of "the lung and the large intestine being interior-exteriorly related" and "treating the same disease with different approaches." [ABSTRACT FROM AUTHOR]

Background. Sepsis is defined as a host inflammatory response to infection that can result in end-organ dysfunction. One of the most common consequences of sepsis is acute kidney injury (AKI). Panax notoginseng powder (PNP) has been previously reported to protect against overactive inflammation process. However, the potential effect of PNP on septic AKI is poorly described. The current study was conducted to investigate the protective effects of PNP in septic AKI rats. Methods. A model of septic AKI was established on male SD rats by using the cecal ligation and puncture procedure. PNP was administrated by gavage after the cecal ligation and puncture (CLP) procedure, and the mice were sacrificed at 6, 12, and 72 h after induction of sepsis. The serum and kidney samples were collected and assayed for biochemical tests, histopathological staining, inflammation, and apoptosis-related gene/protein expression. In addition, 15 rats in each group were used to calculate the 7-day survival rate. Results. CLP-induced kidney injury was observed by the histopathological score, which markedly was attenuated by PNP treatment. Consistently, PNP intervention significantly alleviated the elevated levels of serum creatinine and blood urea nitrogen in CLP-induced sepsis rats. The CLP procedure also triggered proinflammatory cytokine production and increased the expression of various inflammation-related proteins in the kidneys. However, PNP inhibited the renal expression of IL-18, IL-1β, TNF-α, and IL-6 to substantially improve inflammatory response. Mechanistically, CLP induced the increase of the NF-κB p65 level in the injured kidneys, while PNP notably inhibited the corresponding protein expression. Conclusion. PNP attenuated kidney inflammation to protect against CLP-induced septic AKI in rats via inhibiting the NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) usually occurs at the late stage of chronic liver injury. Oncostatin M (OSM) is a tumor-associated cytokine highly expressed in cirrhosis and HCC patients; however, its role in hepatocarcinogenesis has not been clearly elucidated. In this study, we investigated the effect of OSM on HCC occurrence in a rat model of N-diethylnitrosamine-induced HCC. OSM overexpression significantly increased the number of tumor nodules and shortened the overall survival of the rats. Notably, OSM promoted HPC activation in vivo but did not directly regulate the proliferation of the HPC cell line in vitro. Further, OSM induced tumor necrosis factor-α (TNF-α) secretion and CD68+ macrophage accumulation, which were positively correlated with HPC activation. Additionally, TNF-α or macrophage depletion inhibited the promoting effect of OSM on hepatocarcinogenesis and HPC activation. Furthermore, OSM expression in the peritumoral tissues of HCC was positively correlated with poor overall survival of patients. In conclusion, OSM plays an important role in hepatocarcinogenesis by regulating the liver inflammation environment. Hence, OSM could be used as a potential target for HCC prevention and therapy or as an indicator of HCC prognosis. [ABSTRACT FROM AUTHOR]

The combination of Eucommia ulmoides and Tribulus terrestris (ET) has been widely utilized in clinical practice for thousands of years, but the mechanism underlying its efficacy has not been elucidated to date. This study attempted to investigate the role played by the intestinal microbiota and fecal metabolism in the response of elderly spontaneous hypertensive rats (SHRs) to ET administration as a treatment for hypertension. Fourteen male spontaneously hypertensive rats (SHRs, 18 months old) were randomly divided into an ET group and an SHR group, and 7 Wistar-Kyoto (WKY) rats of the same age were employed as the control group. The ET group was intragastrically administered 1.0 g/kg/d ET for 42 days, and SHRs and WKY rats were administered an equal amount of normal saline intragastrically. The intestinal microbiota and fecal metabolism were analyzed by 16S rRNA sequencing and the GC-MS (gas chromatography-mass spectrometry)/MS assay. ET treatment decreased blood pressure steadily, improved the colonic tissue morphology, and changed the structure and composition of the imbalanced microbiota in SHRs. Specifically, ET treatment increased the abundance of Eubacterium, which might be one of the target microbes for ET, and had a negative correlation with the levels of α-tocopherol, chenodeoxycholic acid, and deoxycholic acid according to the Spearman correlation analysis. The change in the intestinal microbiota affected the fecal metabolic pattern of SHRs. Eight potential biomarkers were determined to be primarily enriched in ABC transporters, phenylalanine metabolism, central carbon metabolism in cancer, purine metabolism, and protein digestion and absorption. The correlation analysis demonstrated that the abundance of Eubacterium and the decreased levels of α-tocopherol, chenodeoxycholic acid, and deoxycholic acid in the ET group were highly correlated. Our results suggest that ET has a good antihypertensive effect, which may be driven by the intestinal microbiota and their beneficial metabolites. The results of this study may help to elucidate the antihypertensive mechanism of ET. [ABSTRACT FROM AUTHOR]

Objective. The masticatory muscles are the most important contributor to bite force, and the temporomandibular joint (TMJ) receives direct occlusal loading. The present study aimed to investigate condylar remodeling after masseter muscle atrophy in rats. Methods. Sixty 5-week-old female Sprague-Dawley rats were divided into the following 3 groups: the control group, soft diet (SD) group, and botulinum toxin (BTX) group. The cross-sectional area (CSA) of the masseter muscles was investigated as well as atrogin-1/MuRF-1 expression. Changes in the condylar head were evaluated by H-E, toluidine blue staining, and contour measurements. The biomechanical sensitive factors PTHrP Ihh, Col2a1, and ColX of condylar cartilage were detected by immunohistochemical staining and western blotting. Furthermore, micro-CT and tartrate-resistant acid phosphatase (TRAP) staining were performed to determine the osteopenia in subchondral bone. Results. The histological and protein analysis demonstrated muscle hypofunction in the SD and BTX groups. Condylar cartilage contour was diminished due to different treatments; the immunohistochemistry and protein examination showed that the expressions of PTHrP, Ihh, Col2a1, and ColX were suppressed in condylar cartilage. A steady osteoporosis in subchondral bone was found only in the BTX group. Conclusion. The current results suggested that a steady relationship between muscular dysfunction and condylar remodeling exists. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate the protective effect of Danhong injection (DHI) on diabetic kidney disease and explore the potential mechanisms. Diabetic kidney disease was induced by unilateral nephrectomy, high-fat diet, and streptozotocin. After DHI administration, the renal function deterioration, 24-hour total urine protein excretion, and elevated serum lipid levels were reversed to some extent, and the renal pathological damage was also ameliorated. The KEGG pathway enrichment analysis demonstrated that the PPARγ signal pathway was significantly upregulated in DH group. And the increased expressions of PPARγ and UCP-1 were confirmed by immunohistochemistry, whereas the p38MAPK was significantly decreased. These data show that DHI could delay the progress of DKD, and the effect might be achieved in part by activating the PPARγ signaling pathway. [ABSTRACT FROM AUTHOR]

Little is known about the effects of Buyang Huanwu decoction on pulmonary fibrosis. Herein, 144 healthy SD rats were randomly divided into six groups: blank control group (B), model control group (M), positive medicine control group (Mp), and high-, moderate-, and low-dose Buyang Huanwu decoction groups (Hd, Md, and Ld). A pulmonary fibrosis model was established by endotracheal injection of bleomycin. On the second day of modeling, the corresponding saline, methylprednisolone suspension, and the three doses of Buyang Huanwu decoction were used to treat the 6 groups of rats by intragastric administration for 7, 14, and 28 consecutive days. After 7, 14, and 28 days of treatment, the mRNA expression of CTGF and AKT, the protein level of CTGF, p-AKT, and collagen types I and III were tested. Finally, we found that the serum collagen type I and III level in Hd, Md, and Ld rats on the 14th and 28th day and the collagen type I and III level in Hd rats on 7th day were significantly lower than in M rats (P<0.01). The protein level of p-AKT and CTGF in Hd and Md rats on the 7th and 14th days and the protein level of p-AKT in Hd rats on the 28th day were lower than in M rats (P<0.01, P<0.05). The level of CTGF mRNA in Hd, Md, and Ld rats and the level of AKT mRNA in Hd and Md rats on the 7th, 14th, and 28th days and the expression level of AKT mRNA in Ld rats on the 14th and 28th days were significantly lower than in M rats (P<0.01). The study suggests that Buyang Huanwu decoction alleviated pulmonary fibrosis of rats by improvement of lung tissue morphology, low level of serum collagen types I and III, and the reduced expression of CTGF and p-AKT protein, which might be a result of its downregulated expression of CTGF and AKT mRNA levels. [ABSTRACT FROM AUTHOR]

Objective: To investigate the influence of acupuncture parameters on the acupuncture effect through the cluster analysis in Wistar rat model with middle cerebral artery occlusion (MCAO). Methods: Duplicated MCAO models by Zea-longa's thread ligation and chose rats with 1-3 scores assessed by Zausinger's six-score method to be grouped. The rats were divided into 6 basic control groups [(including a normal group, a sham group, a model control group, a model group without intervention, a Nimodipine group, a lateral-to-Renzhong (DU6) group] and 6 acupuncture groups [a Neiguan (PC6) group, a Weizhong (BL40) group, a Sanyinjiao (SP6) group, a Chize (LU5) group, a Renzhong (DU6) group and a Feixue (non-acupoint) group]. In the acupuncture groups, for every acupoint or needling site, 9 different parameters [2 factors (frequency and time) and 3 levels (180, 120, and 60 cpm of the frequency and 5, 60, and 180 s of the time)] were set respectively by the orthogonal intersection method, in total 54 groups. The rats were treated by acupuncture with a lifting-thrusting manipulation once every 12 h, in total 6 times. Neurobehavioral scores, cerebral blood flow, infarction rate, microcirculation, light microscopy, etc. were measured. The factor analysis was first applied to get the comprehensive effect scores of the samples in the acupuncture groups and then by which the cluster analysis was made with the statistical software of SPSS17.0. Results: For the Neiguan (PC6) group, the exceptional results of acupuncture comprehensive effect were parameters 7, 8, 9, 10; the valid results were parameters 2, 3, 4, and the invalid were parameters 5, 6. For the Weizhong (BL40) group, the exceptional results were parameters 2, 4; the valid results were parameters 3, 5, 6, 7, and the invalid were parameters 8, 9, 10. For the Chize (LU5) group, the exceptional results were parameters 7, 8; the valid results were parameters 3, 4, 5, 6, 9, 10; and the invalid was parameter 2. For the Sanyinjiao (SP6) group, the exceptional results were parameters 4, 6; the valid results were parameters 2, 3, 5; and the invalid were parameters 7, 8, 9,10. For the Renzhong (DU6) group, the exceptional results were parameters 3, 4, 6, 7, 9, 10; the valid results were parameters 2, 5; and the invalid was parameter 8. For the Non-acupoint group, the exceptional result was parameter 10; the valid results were parameters 2, 3, 4, 7, 9; and the invalid were parameters 5, 6, 8. Conclusions: For each meridian acupoint, different acupuncture parameters could consequently get a different acupuncture effect; each meridian acupoint had the most suitable or optimal acupuncture parameters; acupuncture parameters might be the main factors impacting on acupuncture effect. [ABSTRACT FROM AUTHOR]

Objectives: To study the acupoint specificity through the comprehensive evaluation of the acupuncture effect on rat model with the middle cerebral artery occlusion (MCAO). Methods: Duplicated MCAO model by Zea-longa's thread ligation was assessed by Zausinger's six-point method, and rats with 1-3 scores were chosen to be grouped. According to the randomized and controlled principle, rats were divided into 6 basic control groups (including normal group, sham group, model control group, model group without intervention, Nimodipine group, lateral-to-Renzhong group) and 6 acupuncture groups [including Neiguan (PC6) group, Weizhong (BL40) group, Chize (LU5) group, Sanyinjiao (SP6) group, Renzhong (DU6) group and non-acupoint group]; in each acupoint or non-acupoint 9 different parameter combinations were respectively set by orthogonal intersection method. There were in total 60 groups, and each group had 12 rats. The rats were treated by acupuncture with the lifting-thrusting manipulation every 12 h, in total 6 times. Indices of neurobehavioral scores, cerebral blood flow, infarction rate, microcirculation, and light microscope, etc. were measured. In order to comprehensively evaluate the acupuncture effect to research the specificity of acupoint, a cluster analysis was made with SPSS17.0 for the comprehensive effect scores of the samples computed according to the comprehensive evaluation models, and then sorting and classification were made for the comprehensive effect scores. Results: In the acupuncture groups every acupoint had different therapeutic effect due to different acupuncture parameter combinations; among the acupuncture groups the orders of curative effect were as followings: Neiguan group was of exceptional result, Weizhong group and Sanyinjiao group were of valid results in upper level, Chize group and Renzhong group were of valid results in lower level, and non-acupoint group was of invalid result; the therapeutic result of acupoint group was superior to non-acupoint group; and the curative effect of acupuncture group was also superior to basic control group. Conclusion: The acupoint has the specificity of acupuncture effect, and the acupoint specificity is relative. [ABSTRACT FROM AUTHOR]

Background: Cerebral hypoperfusion is a pivotal risk factor for vascular dementia (VD), for which effective therapy remains inadequate. Persistent inflammatory responses and excessive chemotaxis of microglia/macrophages in the brain may accelerate the progression of VD. Endocannabinoids are involved in neuronal protection against inflammation-induced neuronal injury. Cannabinoids acting at cannabinoid receptor 2 (CB2R) can decrease inflammation. Based on the identification of paeoniflorin (PF) as a CB2R agonist, we investigated the neuroprotective and microglia/macrophages M1 to M2 polarization promoting effects of PF in a permanent four-vessel occlusion rat model. Methods: One week after surgery, PF was intraperitoneally administered at a dose of 40 mg/kg once a day for 28 successive days. The effects of PF on memory deficit were investigated by a Morris water maze test, and the effects of PF on hippocampal neuronal damage were evaluated by light microscope and electron microscope. The mRNA and protein expression levels of key molecules related to the M1/M2 polarization of microglia/macrophages were assessed by RT-qPCR and Western blotting, respectively. Results: Administration of PF could significantly attenuate cerebral hypoperfusion-induced impairment of learning and memory and reduce the morphological and ultrastructural changes in the hippocampal CA1 region of rats. Moreover, PF promoted an M1 to M2 phenotype transition in microglia/macrophages in the hippocampus of rats. In addition to its inhibitory property against proinflammatory M1 mediator expression, such as IL-1β, IL-6, TNF-α and NO, PF dramatically up-regulated expression of anti-inflammatory cytokines IL-10 and TGF-β1. Importantly, CB2R antagonist AM630 abolished these beneficial effects produced by PF on learning, memory and hippocampus structure in rats, as well as the polarization of microglia/macrophages to the M2 phenotype. Additionally, PF treatment significantly inhibited cerebral hypoperfusion-induced mTOR/NF-κB proinflammatory pathway and enhanced PI3K/Akt anti-inflammatory pathway. Effects of PF on these signaling pathways were effectively attenuated when rats were co-treated with PF and AM630, indicating that the mTOR/NF-κB and PI3K/Akt signaling pathways were involved in the PF effects through CB2R activation. Conclusion: These findings demonstrated PF exerts its neuroprotective effect and shifts the inflammatory milieu toward resolution by modulation of microglia/macrophage polarization via CB2R activation. [ABSTRACT FROM AUTHOR]