The effectiveness of Hedyotis diffusa Willd extract in a mouse model of experimental autoimmune prostatitis.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a frustrating and often debilitating disease. Current studies have shown that Traditional Chinese Medicine (TCM) can improve patients' quality of life and alleviate CP/CPPS symptoms. In this study, the efficacy of Hedyotis diffusa Willd aqueous extraction in experimental autoimmune prostatitis (EAP) mice models was revealed. The C57BL/6 mice were randomly assigned to three groups. Except for the control group, all other groups were subcutaneously injected with 0.2 ml emulsion of T2 peptide, on day 0 and day 14, for inducing EAP models. After the EAP modelling, oral saline was given to the model group, while the H. diffusa group was treated with aqueous extract of H. diffusa Willd. Micturition habits and withdrawal response frequencies were measured. Haematoxylin and eosin staining and immunohistochemistry were used to investigate inflammatory cell infiltration and TNF-α in the prostate tissue respectively. TNF-α levels in the serum were evaluated by ELISA. The H. diffusa Willd aqueous extraction considerably reduced the urine spots number and increased the pain threshold in H. diffusa group. H. diffusa group showed significantly reduced inflammatory lesion and inflammatory cell infiltration than the model group. The levels of TNF-α in H. diffusa group were considerably reduced.

Therapeutic effects of Qianlie Tongli decoction on chronic prostatitis/chronic pelvic pain syndrome induced by peptide T2 in mice.

OBJECTIVES: This study was undertaken to reveal therapeutic effects and the preliminary mechanism of Chinese medicine formula Qianlie Tongli decoction (QTD) in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: A total of 50 male C57BL/6 mice were randomly divided into five groups. All groups except the control group were injected subcutaneously T2 peptide emulsion, which induced the CP/CPPS model. After the induction of CP/CPPS, the model group was given normal saline by oral gavage while low-dose, medium-dose and high-dose groups were treated with Chinese medicine formula. Micturition habits and pain behaviour of mice were analysed for each group. Haematoxylin and eosin (H&E) staining was used to investigate prostate inflammation. The serum level of tumour necrosis factor-α (TNF-α) was measured by enzyme-linked immunosorbent assay (ELISA) kit. KEY FINDINGS: Chinese medicine formula significantly reduced the number of urine spots and improved pain response frequency in the medium-dose and high-dose group. The high-dose group showed reduced considerably inflammatory lesion and inflammatory cell infiltration than the low-dose and medium-dose groups. Serum levels of TNF-α in the high-dose group were significantly reduced compared with the model group. CONCLUSIONS: The results demonstrated the therapeutic effects of Qianlie Tongli decoction in CP/CPPS mice by analysing clinically relevant symptoms (urinary tract system, pelvic pain and prostate inflammation) and preliminarily explored the inflammatory-related treatment mechanisms by measuring TNF-α.

Systemic and local delivery of mesenchymal stem cells for heart renovation: Challenges and innovations.

In the beginning stage of heart disease, the blockage of blood flow frequently occurs due to the persistent damage and even death of myocardium. Cicatricial tissue developed after the death of myocardium can affect heart function, which ultimately leads to heart failure. In recent years, several studies carried out about the use of stem cells such as embryonic, pluripotent, cardiac and bone marrow-derived stem cells as well as myoblasts to repair injured myocardium. Current studies focus more on finding appropriate measures to enhance cell homing and survival in order to increase paracrine function. Until now, there is no universal delivery route for mesenchymal stem cells (MSCs) for different diseases. In this review, we summarize the advantages and challenges of the systemic and local pathways of MSC delivery. In addition, we also describe some advanced measures of cell delivery to improve the efficiency of transplantation. The combination of cells and therapeutic substances could be the most reliable method, which allows donor cells to deliver sufficient amounts of paracrine factors and provide long-lasting effects. The cardiac support devices or tissue engineering techniques have the potential to facilitate the controlled release of stem cells on local tissue for a sustained period. A novel promising epicardial drug delivery system is highlighted here, which not only provides MSCs with a favorable environment to promote retention but also increases the contact area and a number of cells recruited in the heart muscle.

Morphological reseach on expression of inflammatory mediators in murine models of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) induced by T2 antigen.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common clinical syndrome with unknown aetiology. In this study, we used the T2 peptide in C57BL/6 (B6) mice and Sprague Dawley (SD) rats model during different stages. We sought to understand the role of CD4+ T cells and macrophages in CP/CPPS. A total of 16 B6 mice and 18 SD rats were divided into five groups: B6-naïve (n = 6), B6 model (n = 10), SD-naïve (n = 6), SD-45-day model (n = 6) and SD-56-day model (n = 6). The B6 model group was subcutaneously injected with 0.2 ml of (225µg/ml) T2 peptide on 0 and 14th day and was finally sacrificed on 28th day. The SD-45- and SD-56-day model groups were subcutaneously injected with 1ml of (50 µg/ml) T2 peptide on 0 and 14th day and were finally sacrificed on 45th and 56th day respectively. An equivalent volume of normal saline (NS) solution was injected to the naïve groups and analysed the pain and voiding behaviour. We have calculated the prostate index, H&E staining and immunofluorescence of CD4+ T cells and macrophages (CD68) in each group. T2 peptide immunization in B6 mice and SD rats caused severe prostatitis and cell infiltration, mainly composed of CD4+ T cells and macrophages. The SD-56-day model group showed more severe inflammatory cells infiltration than SD-45-day model group. Moreover, inflammatory cells infiltration and red secretions in B6 model were less than SD model. Expression of CD4+ T cells and macrophages was also consistent with H&E results. These results indicated that different stages of CP/CPPS, inflammatory response, and the inflammation of the rat were stronger than the mouse. Our study suggests that CD4+ T cells and macrophages are key factors in the development of CP/CPPS.

Effect of Oral T2 Antigen on Chronic Prostatitis/Chronic Pelvic Pain Syndrome in Mice Model.

The exact etiology and pathogenesis of chronic prostatitis (CP/CPPS) remain unclear. However, autoimmunity is a widely known theory. Precise treatment of CP/CPPS is not available. Here, we developed a new effective treatment method to prevent the occurrence of CP/CPPS. A total of 40 male C57BL/6 mice were randomly divided into four groups (n = 10): i.e., naive, model, high-dose (500 µg/ml), and low-dose (50 µg/ml) groups. High-dose and low-dose groups were orally given 0.4 ml of T2-containing soybean trypsin inhibitor (STI) at once after every 2 days for a total of 10 days. On day 10 and day 24 all the groups except naïve group were subcutaneously injected with 0.2 ml of T2 peptide along with CFA to make valid CP/CPPS models. Hematoxylin and eosin staining were used to evaluate the variation in CP/CPPS manifestation. Voiding behavior was recorded for the evaluation of urine frequencies. ELISA was used to measure the serum level of TNF-α in each group. The high- and low-dose groups of T2-containing STI displayed a reduction in urine frequencies, and inflammation, and there was a slight inflammatory infiltration as compared to the model group. In contrast, there was no difference observed in the TNF-α concentration of model as well as high- and low-dose groups compared to the naïve group. Our study demonstrates that oral T2-containing STI prevents CP/CPPS and provides an effective approach for the treatment of CP/CPPS.

Phytotherapy and physical therapy in the management of chronic prostatitis-chronic pelvic pain syndrome.

Chronic prostatitis (CP)/chronic pelvic pain syndrome (CPPS) is one of the four category prostatitis, and the prevalence is over 90-95% in prostatitis. Because of its pain and obstructive voiding difficulties, it severely affects the quality of life of the patient. However, the standard treatment is still unclear. Given the lack of proven efficacy of conventional therapies (such as antibiotics, anti-inflammatory medications, and alpha-blockers), many patients have turned to phytotherapy and other alternative treatments. In recent years, phytotherapy and physical therapy have advanced a lot because of the safety, efficacy and high compliance. This review covers phytotherapy (quercetin, bee pollen, pumpkin seed oil, eviprostat, terpene mixture) and physical therapy (acupuncture, shock wave, thermobalancing, transurethral needle ablation, transcutaneous electrical nerve stimulation sono-electro-magnetic therapy) commonly used in chronic prostatitis to help the clinician and researchers.

Novel Treatment of Experimental Autoimmune Prostatitis by Nanoparticle-Conjugated Autoantigen Peptide T2.

The exact etiology and pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) are still unknown, as a result, available therapeutic options for patients are far from satisfactory. Therefore, there is a need to develop a valid therapeutic approach that can ameliorate the manifestations of CP/CPPS. Fifty male C57BL/6 mice were randomly divided into five groups of ten mice each. All groups except naïve were subcutaneously injected with 0.2 ml of T2 plus complete Freund adjuvant (CFA) on day 0 and 14 to generate valid CP/CPPS model. After successful CP/CPPS induction, model group was injected with 0.2 ml of normal saline while PLGA, PLGA-OVA, and PLGA-T2 groups were administered intravenously with 0.2 ml mixture of PLGA, PLGA-OVA, and PLGA-T2, respectively. Voiding behavior, pain threshold, and hematoxylin and eosin staining were used to assess micturition habits, pain intensity as well as prostate inflammation. Additionally, TNF-α, CRP, and IL-10 levels in plasma were measured by using ELISA kits. Mice administered with PLGA-T2 showed higher pain threshold, lower urine frequencies, mild edema, and inflammation in prostate tissue in comparison to other groups. Moreover, the expression of TNF-α and CRP levels was markedly decreased while IL-10 expression was increased in the PLGA-T2 treatment group as compared to the other groups. Our results showed that nanoparticles conjugated with autoantigen novel peptide T2 could successfully alleviate or even heal CP/CPPS to some extent in mice. This study provides an easy, useful, and economic tool for ameliorating the manifestations of CP/CPPS that will improve the therapeutic approaches.

A nanoparticle-coupled T2 peptide induces immune tolerance and ameliorates chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in mice model.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a complex disease of unclear etiology. Precise treatment of CP/CPPS is not available due to lack of specific cause; however, autoimmunity is the most valid theory. We develop a new treatment strategy that involves synthesis and coupling of biodegradable nanoparticles to antigenic T2 peptide to induce immune tolerance in CP/CPPS mice models. A total of 50 male C57BL/6 mice were randomized into five groups, that is, naïve, Model, PLGA-PEMA, PLGA-PEMA-OVA323-339 , and PLGA-PEMA-T2 group. All groups except naïve were injected subcutaneously on day 0 with 0.2 mL of T2 peptide with CFA to generate valid CP/CPPS models. After successful induction of CP/CPPS, Model group, PLGA-PEMA, PLGA-PEMA-OVA, and PLGA-PEMA-T2 groups were treated with 0.15 mL of normal saline, 0.2 mg of PLGA-PEMA and PLG-PEMA-T2 and 0.3 mg PLGA-PEMA-OVA nanoparticles, respectively, on day 28. Hematoxylin and eosin staining, and ELISA were used to evaluate the variation in CP/CPPS manifestations and seral level of IL-10 in each group. Pain threshold and voiding behavior were also recorded for every group. Mice treated with PLGA-PEMA-T2 exhibited enhanced pain threshold, reduced urine frequency, and prostate pathology. Furthermore, serum level of inflammatory mediators (TNF-α and CRP) were reduced and anti-inflammatory IL-10 was enhanced in PLGA-PEMA-T2 group as compared to other groups. Our results demonstrate that PLGA-PEMA-T2 nanoparticle ameliorates disease manifestations in CP/CPPS mice models and upregulates IL-10 which is essential for tolerance induction. This strategy highlights the new therapeutic approach utilizing biodegradable nanoparticles for the treatment of CP/CPPS.

Fc Gamma Receptor IIb Expressed in Hepatocytes Promotes Lipid Accumulation and Gluconeogenesis.

Non-alcoholic fatty liver disease (NAFLD) is characterized by ectopic lipid accumulation in the liver, usually combined with hepatic insulin resistance. Fc-gamma receptor-IIb (FcγRIIb) and its ligand are reported to be associated with obesity and type 2 diabetes mellitus (T2DM). As knowledge about FcγRIIb in the literature is mostly generated from studies on skeletal muscle tissue, the expression and function of FcγRIIb in the liver and hepatocytes are largely unknown. In this study, we identified the expression of FcγRIIb in primary cultured mouse hepatocytes: FcγRIIb was upregulated in response to oleic acid (OA) in a dose dependent manner. FcγRIIb knockdown using shRNA suppressed the lipid and triglyceride accumulation, and mRNA expression of ACC1, FASn, CD36, MTTP, and ApoB in OA-treated HepG2 cells. FcγRIIb deficiency mice fed with high fat diet (HFD) had significantly lower liver weight and liver to body weight ratio, as well as less triglyceride accumulation in the livers. In glycometabolism, FcγRIIb hindered insulin-induced phosphorylation of AKT and FOXO1, and in turn upregulated G6Pase and PEPCK mRNA expression, suggesting that FcγRIIb promotes gluconeogenesis by suppressing the AKT/FOXO1/G6Pase/PEPCK pathway in hepatocytes. This study reveals a novel role for FcγRIIb in regulating lipid metabolism and glycometabolism, and provides a new therapeutic target to improve NAFLD.

The promising future of ventricular restraint therapy for the management of end-stage heart failure.

Complicated pathophysiological syndrome associated with irregular functioning of the heart leading to insufficient blood supply to the organs is linked to congestive heart failure (CHF) which is the leading cause of death in developed countries. Numerous factors can add to heart failure (HF) pathogenesis, including myocardial infarction (MI), genetic factors, coronary artery disease (CAD), ischemia or hypertension. Presently, most of the therapies against CHF cause modest symptom relief but incapable of giving significant recovery for long-term survival outcomes. Unfortunately, there is no effective treatment of HF except cardiac transplantation but genetic variations, tissue mismatch, differences in certain immune response and socioeconomic crisis are some major concern with cardiac transplantation, suggested an alternate bridge to transplant (BTT) or destination therapies (DT). Ventricular restraint therapy (VRT) is a promising, non-transplant surgical treatment wherein the overall goal is to wrap the dilated heart with prosthetic material to mechanically restrain the heart at end-diastole, stop extra remodeling, and thereby ultimately improve patient symptoms, ventricular function and survival. Ventricular restraint devices (VRDs) are developed to treat end-stage HF and BTT, including the CorCap cardiac support device (CSD) (CSD; Acorn Cardiovascular Inc, St Paul, Minn), Paracor HeartNet (Paracor Medical, Sunnyvale, Calif), QVR (Polyzen Inc, Apex, NC) and ASD (ASD, X. Zhou). An overview of 4 restraint devices, with their precise advantages and disadvantages, will be presented. The accessible peer-reviewed literature summarized with an important considerations on the mechanism of restraint therapy and how this acquaintance can be accustomed to optimize and improve its effectiveness.

IgE induces hypotension in asthma mice by down-regulating vascular NCX1 expression through activating MiR-212-5p.

Immunoglobulin E (IgE) has been suggested as a risk factor for allergy-induced low blood pressure, which has not been well explained in molecular details. Our current study shows a novel mechanism involving IgE, FcɛR1, miRNA-212-5p (miR-212-5p), and sodium/calcium exchanger protein 1(NCX1) for asthma to induce hypotension. In arterial smooth muscle cells, IgE up-regulated miR212-5p via its receptor FcɛR1, which resulted in down-regulation of NCX1 that is a regulating factor for blood pressure. In mice, asthma induced hypotension by interfering vasoconstrictive function; knockout of FcɛR1 kept the asthmatic mice from developing hypotension; knock-down of miR-212-5p in asthmatic mice resulted in a significant restoration of blood pressure. In human, asthma and IgE were positively correlated with hypotension in cohort study on NIH epidemiological data. This study suggests a novel therapeutic target (miR-212-5p) for treatment of asthma-induced hypotension.

Glutaredoxin 1 mediates the protective effect of steady laminar flow on endothelial cells against oxidative stress-induced apoptosis via inhibiting Bim.

Endothelial cell apoptosis induced by oxidative stress is an early event in the development of atherosclerosis. Several antioxidant enzymes which can cope with oxidative stress are up-regulated by the anti-atherogenic laminar blood flow often seen in straight or unbranched regions of blood vessels. However, the molecular mechanism responsible for flow-induced beneficial effects is incompletely understood. Here we report the role of glutaredoxin 1 (Grx1), an antioxidant enzyme, in flow-mediated protective effect in endothelial cells. Specifically, we found that Grx1 is markedly up-regulated by the steady laminar flow. Increasing Grx1 reduces the pro-apoptotic protein Bim expression through regulating Akt-FoxO1 signaling and also attenuates H2O2-induced Bim activation via inhibiting JNK phosphorylation, subsequently preventing the apoptosis of endothelial cells. Grx1 knockdown abolishes the inhibitory effect of steady laminar flow on Bim. The inhibitory effect of Grx1 on Bim is dependent on Grx1's thioltransferase activity. These findings indicate that Grx1 induction plays a key role in mediating the protective effect of laminar blood flow and suggest that Grx1 may be a potential therapeutic target for atherosclerosis.

[Advances in the Pathogenesis of Abdominal Aortic Aneurysms and Inflammation].

Abdominal aortic aneurysm (AAA)is one of the most catastrophic arterial disease,with the severe outcome of sudden death due to the aortic rupture of weak arterial wall.Currently there is a lack of effective drug therapy for AAAs.Since the aging population situation is worsening,the prevalence of AAAs is rising constantly in China.There has already been plenty of factors known,which could led to AAA,however,the mechanism of AAA has not been very clearly.It has been recognized that many risk factors contribute to the development of AAA such as smoking,reactive oxygen species,matrix metallo-proteinase,and atherosclerosis,however,the mechanism of AAA formation has not been well under-stood.With the recent progressions in researches on inflammation and AAA,the role of inflammation in the pathogenesis of AAA has drawn increasing attention..This review will summarize recent advances in the investigations of leukocyte related mechanisms of aneurismal initiation and progression.